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NCCN unveils 'Evidence Blocks' to facilitate treatment discussions
SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.
“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.
The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.
Development of the Evidence Blocks
The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.
“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.
Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.
Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.
The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.
“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.
The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.
“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”
The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”
It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.
Oncologist perspective
There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.
Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”
Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”
Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.
“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.
Patient perspective
Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.
Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.
Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.
“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.
Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.
“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”
Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.
SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.
“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.
The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.
Development of the Evidence Blocks
The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.
“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.
Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.
Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.
The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.
“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.
The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.
“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”
The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”
It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.
Oncologist perspective
There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.
Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”
Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”
Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.
“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.
Patient perspective
Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.
Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.
Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.
“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.
Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.
“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”
Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.
SAN FRANCISCO – The National Comprehensive Cancer Network (NCCN) has introduced an easy-to-use visual tool called Evidence Blocks to help physicians and patients compare various treatment options and individualize the selection among them.
“This information can serve as a starting point for shared decision making between the patient and health care team based on individual patients’ value systems,” chief executive officer Dr. Robert W. Carlson said at the NCCN Annual Congress: Hematologic Malignancies, where the tool was unveiled in a session and related press conference.
The first two NCCN guidelines to incorporate the Evidence Blocks – those for multiple myeloma and chronic myelogenous leukemia – were released at the same time. The organization hopes to incorporate them into all of its guidelines by early 2017, he said.
Development of the Evidence Blocks
The NCCN developed the Evidence Blocks to address requests from various stakeholders, according to Dr. Carlson. Guideline users wanted to know more about the rationale behind recommended therapies, asked for inclusion of information on costs, and sought an aid that would allow patients to make decisions based on their individual values.
“The patient perception of value is what should be most important to us,” he commented. “But even among patients, the concept of value differs greatly from patient to patient,” based on factors such as age, comorbidities, treatment goals, and health insurance coverage.
Each Evidence Block graphically displays five measures of information on a recommended therapy: efficacy, safety, quality of the evidence supporting the recommendation, consistency of the evidence supporting the recommendation, and affordability. Each column in the block represents one measure.
Blue shading indicates panelists’ average numeric score for the therapy on that measure rounded to the nearest integer, ranging from 1 (least favorable) to 5 (most favorable). Therefore, the more shading a therapy has, the more favorable its score.
The Evidence Blocks are added to the guidelines and aligned vertically on pages. “This display of the information graphically allows for very efficient scanning of multiple options for therapy. Comparisons across several regimens can be done very quickly and intuitively,” Dr. Carlson noted.
“We believe that the presentation of this type of information allows the health care provider and patient to make their own judgments of the value of specific interventions,” he added.
The affordability measure has generated the most discussion among panelists and stakeholders, according to Dr. Carlson. For this measure, panelists estimated the total cost of care for a therapy, including the costs of drugs, administration, required supportive care, toxicity monitoring, and care associated with management of toxicity. Scores range from very expensive to very inexpensive.
“We don’t use a dollar amount. Rather, it’s sort of what’s the total cost to society, if you will, of the medical intervention part of this,” he explained. “It’s important to understand that these estimates are not necessarily what a patient would pay because many patients have insurance programs that cover all of this cost.… However, we felt it was important to give patients as well as providers an estimate of what the overall magnitude of expense is because there are patients who have huge deductibles, there’s the doughnut hole within Medicare, and there are patients who have no insurance.”
The Evidence Blocks may help address a “conspiracy of silence” between physicians and patients when it comes to discussing treatment costs, whereby neither party wants to bring up this thorny issue, according to Dr. Carlson. “The Evidence Blocks demystify the discussion of cost because the affordability issue is there in front of you. So it gives people permission to talk about cost and affordability.”
It should be relatively easy to teach patients to use the Evidence Blocks. “I think you’ll find your patients will actually be interested in this and that they will not have as much difficulty interpreting this as you think they will, because the patient advocacy groups and the patient advocates that we have spoken with about this, they get this almost instantly,” he said.
Oncologist perspective
There is a critical need for tools such as the Evidence Blocks in making treatment decisions today, according to Dr. George Somlo, professor in the department of medical oncology and therapeutics research at the City of Hope Comprehensive Cancer Center in Duarte, Calif., and also a member of the NCCN multiple myeloma and breast cancer guideline panels.
Treatment options for multiple myeloma, as for many cancers, have exploded in the past few decades, he noted. “How do you go from making sense of having two drugs with a very poor outcome predicted to having literally dozens of agents approved and used in combination, and in essence being at the verge of curing patients with multiple myeloma?”
Dr. Somlo agreed that inclusion of costs in the Evidence Blocks would likely be beneficial as a conversation starter, recalling, “I’ve had patients who did not fill their prescription for a potentially curative medication because they were worried about the $2,500 or $3,500 copay.”
Patient-physician discussion will be important when it comes to using information from the new tool, he said. For example, in the NCCN guideline for multiple myeloma, some of the first-line regimens have identical Evidence Blocks; thus, consideration of factors such as comorbidities will become important.
“This kind of evidence-based scoring system can guide that kind of discussion with the patient and can tailor the individual therapeutic regimens,” he concluded.
Patient perspective
Breast cancer survivor Marta Nichols, who is vice president of investor relations at GoDaddy and a member of the California Breast Cancer Research Council based in San Francisco, welcomed the Evidence Blocks as a tool that will allow patients to make more informed decisions according to what matters most to them.
Only 33 years old at diagnosis, she and her husband had just begun to think about starting a family. “So my primary concern coming into my physician’s office was my fertility and what impact the treatment would have on my fertility. Certainly most physicians are concerned with efficacy – they want to see you survive. My concern was not just surviving, but also thriving and being able to give birth to children down the line,” she explained.
Patients today are overwhelmed not only by their cancer diagnosis, but also by the many treatment options and the new emphasis on shared decision making, Ms. Nichols noted. And that’s where the Evidence Blocks can make a difference.
“When I was diagnosed, it would have been hugely helpful for me to have information laid out in this very clear and systematic way… It would have given us the ability to make a much more informed decision,” she commented.
Multiple myeloma survivor Donald B. Orosco, who is president and chief financial officer of Orosco & Associates and owner of Monterey (Calif.) Speed and Sport, agreed, noting that his priorities when given the diagnosis more than two decades ago at age 47 differed somewhat.
“I adopted the feeling early on that I probably wasn’t going to see a cure for the disease in my lifetime, but I could accept that,” he elaborated. “I just said ‘Really, I’m interested in quality-of-life issues. I’d like to see my kids go into high school or possibly college.’ So I adopted [an approach of] trying to find something for me that would keep me alive and give me a relatively comfortable quality of life, that would allow me to continue to race cars or do whatever I had to do.”
Dr. Carlson, Dr. Somlo, Ms. Nichols, and Mr. Orosco disclosed no relevant conflicts of interest.
AT NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
Emerging evidence is resolving questions in CML management
SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.
How do you choose front-line therapy?
Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.
Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.
The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.
The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”
In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.
But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.
Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.
When do you switch therapies?
There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.
Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.
However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.
Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”
Which second-line TKI should patients get?
The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).
About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.
Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.
Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).
“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”
In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”
Can you discontinue therapy?
“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.
“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”
“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.
A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.
“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.
“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.
Take-home message
The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.
“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”
Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.
SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.
How do you choose front-line therapy?
Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.
Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.
The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.
The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”
In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.
But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.
Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.
When do you switch therapies?
There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.
Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.
However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.
Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”
Which second-line TKI should patients get?
The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).
About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.
Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.
Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).
“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”
In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”
Can you discontinue therapy?
“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.
“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”
“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.
A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.
“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.
“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.
Take-home message
The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.
“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”
Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.
SAN FRANCISCO – “We really have an embarrassment of riches in chronic myelogenous leukemia, and the question is, which patients get which drugs? That’s really the major question that drives clinical care right now,” Dr. Jerald P. Radich, chair of the NCCN guidelines panel for chronic myelogenous leukemia (CML), told attendees of the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
He discussed a variety of setting-specific quandaries in disease management and recent evidence from trials that is helping to provide some answers. He also reviewed some of the finer points of the NCCN’s CML guidelines, a new version of which was released at the congress.
How do you choose front-line therapy?
Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, according to Dr. Radich, who is a member of the clinical research division, Fred Hutchinson Cancer Research Center, and an associate professor in the medical oncology division, University of Washington, both in Seattle.
Today, three TKIs—imatinib (Gleevec) and the second-generation agents nilotinib (Tasigna) and dasatinib (Sprycel)—are approved by the Food and Drug Administration as front-line therapy.
The 8-year data from the IRIS trial (International Randomized Study of Interferon Vs STI571), which tested imatinib in patients with newly diagnosed chronic-phase CML, showed that event-free survival was 81% and overall survival was 85% (Blood. 2009;114:462. Abstract 1126). “No matter how you slice it, these patients have done fantastically well,” Dr. Radich said.
The two other, newer therapies, nilotinib and dasatinib, have yielded significantly better short-term cytogenetic response and major molecular response rates in numerous trials. “But curiously enough, if you look at overall survival, there is no difference,” he commented. “We don’t know why the short-term efficacy of the second generations hasn’t translated into long-term efficacy yet.”
In the guidelines, the three front-line TKIs are nearly identical with respect to their Evidence Blocks, a new tool added to facilitate treatment comparisons and decision making.
But specific toxicities differ across the agents, which may tilt the decision one way or another. “If somebody has a history of really bad atherosclerotic events previously, then imatinib is probably not the best drug for them. If somebody has a history of pulmonary issues, then dasatinib may not be the best drug for them. And if somebody has diabetes, nilotinib probably isn’t the best drug for them,” Dr. Radich elaborated.
Costs for the three drugs are the same at present, he said. But imatinib will likely become available as a generic next year, which may make that drug the most attractive from the financial perspective.
When do you switch therapies?
There is some debate about how long to persevere with a front-line therapy when monitoring suggests the response is suboptimal, according to Dr. Radich.
Data have identified the BCR-ABL1 transcript level at 3 months to be a good predictor of long-term survival (J Clin Oncol. 2012;30:232-8). “We in the NCCN have said at 3 months or 6 months, you should consider changing [if the response is suboptimal]. You don’t have to, but you should consider changing because there are some other [therapies] that get rid of that,” he said.
However, he cautioned, a true assessment of response hinges critically on patients’ compliance with therapy. Studies using electronic monitors hidden in the caps of pill bottles suggest that even though the majority of patients say they take their TKI daily, only about 15% actually do.
Studies out of Europe and Australia have shown that some patients with a suboptimal response will have progression to accelerated phase/blast crisis in the interim between 3 months and 6 months, Dr. Radich noted. “So if you think that your patient is really, really religiously taking their drug, and if they still have not responded very well at 3 months, that might be an indication that you can consider changing therapy.”
Which second-line TKI should patients get?
The options for second-line TKI therapy include nilotinib and dasatinib, as well as bosutinib (Bosulif) and ponatinib (Iclusig).
About half of patients who experience progression on or become resistant to their first-line TKI have mutations, according to Dr. Radich. Here, a mutational analysis is warranted as the second-line agents differ somewhat with respect to the mutations they act against, which may guide the choice of agent. And toxicity profile may again dictate drugs that can and can’t be used for a specific patient.
Patients who have genuine resistance are unlikely to achieve a cure although they may have a cytogenetic response. “Most of us think that resistance might be forever and if we have a patient who has genuinely become resistant, you don’t need to transplant them necessarily [right away]. But that’s the time you have to have a conversation about doing transplantation and start doing HLA typing and the like,” he said.
Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).
“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”
In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”
Can you discontinue therapy?
“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.
“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”
“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.
A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.
“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.
“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.
Take-home message
The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.
“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”
Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.
EXPERT ANALYSIS FROM NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
New systemic therapies altering management of melanoma brain metastases
SEATTLE – Targeted therapies for melanoma are improving outcomes for patients with brain metastases and changing management of this dreaded complication, according to Dr. John A. Thompson, codirector of the Melanoma Clinic at the Seattle Cancer Care Alliance and a professor in the medical oncology division at the University of Washington, both in Seattle.
“We are in a new era of treatment of brain metastasis. It’s no longer just surgery and radiation therapy, but a multidisciplinary approach involving medical oncology, radiation oncology, and surgery,” he told attendees of the World Cutaneous Malignancies Congress.
Without question, surgery and radiation therapy techniques have advanced over time, and these modalities remain helpful in achieving local control of disease. Additionally, greater experience with them has improved patient selection.
For example, research has identified several predictors of benefit from stereotactic radiosurgery, such as fewer brain metastases and better performance status (J Neurosurg. 2011;114:769-79). But overall survival was fairly poor given disease elsewhere in the body. “Here’s where I think the new developments in systemic therapy may hopefully be able to start improving this curve,” Dr. Thompson said.
Toxicity of some forms of radiation therapy also remains problematic. For example, a recent randomized phase III trial in patients with up to three brain metastases showed that addition of whole-brain radiation therapy to radiosurgery improved intracranial tumor control, but at the expense of more rapid cognitive decline (ASCO 2015. Abstract LBA4). And there was no gain in overall survival.
“The changes that have happened in systemic therapy over the past 5-10 years have been very exciting,” Dr. Thompson said. By way of example, he pointed to a phase II trial that tested ipilimumab (Yervoy), an antibody to the T-cell receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA4), as induction therapy and then maintenance therapy among patients with melanoma who had brain metastases (Lancet Oncol. 2012;13:459-65).
The subset of patients who were neurologically stable and not on systemic steroids had a disease control rate of 24%, with some having objective responses, including ones in the CNS; the value was lower, at 10%, among patients who were neurologically symptomatic and on steroids, indicating more advanced disease. The 2-year overall survival rate was 26%.
“I think this is encouraging if you compare [these patients] to historical control patients with brain metastases,” said Dr. Thompson, who disclosed that he performs contracted research with Agensys, BMS, Merck, Novartis, and Pfizer.
Another phase II trial, CheckMate 204, which is currently enrolling patients, is taking the concept further, testing the combination of ipilimumab and nivolumab (Opdivo), an antibody to the cell surface receptor programmed death-1 (PD-1), as induction therapy followed by nivolumab maintenance therapy among patients with melanoma who have brain metastases. “This is I think a high-priority trial,” he asserted.
Discussing some cases from his own practice, Dr. Thompson described patient-tailored integration of the new systemic therapies with surgery and radiation therapy.
Oncologists must often deal with toxicities of these therapies as well, such as the colitis and hypophysitis related to ipilimumab therapy, and the development of resistance over time, Dr. Thompson acknowledged.
Nonetheless, the multimodality approach has led to regression and elimination of brain metastases, and even allowed some patients to achieve remission, he reported.
SEATTLE – Targeted therapies for melanoma are improving outcomes for patients with brain metastases and changing management of this dreaded complication, according to Dr. John A. Thompson, codirector of the Melanoma Clinic at the Seattle Cancer Care Alliance and a professor in the medical oncology division at the University of Washington, both in Seattle.
“We are in a new era of treatment of brain metastasis. It’s no longer just surgery and radiation therapy, but a multidisciplinary approach involving medical oncology, radiation oncology, and surgery,” he told attendees of the World Cutaneous Malignancies Congress.
Without question, surgery and radiation therapy techniques have advanced over time, and these modalities remain helpful in achieving local control of disease. Additionally, greater experience with them has improved patient selection.
For example, research has identified several predictors of benefit from stereotactic radiosurgery, such as fewer brain metastases and better performance status (J Neurosurg. 2011;114:769-79). But overall survival was fairly poor given disease elsewhere in the body. “Here’s where I think the new developments in systemic therapy may hopefully be able to start improving this curve,” Dr. Thompson said.
Toxicity of some forms of radiation therapy also remains problematic. For example, a recent randomized phase III trial in patients with up to three brain metastases showed that addition of whole-brain radiation therapy to radiosurgery improved intracranial tumor control, but at the expense of more rapid cognitive decline (ASCO 2015. Abstract LBA4). And there was no gain in overall survival.
“The changes that have happened in systemic therapy over the past 5-10 years have been very exciting,” Dr. Thompson said. By way of example, he pointed to a phase II trial that tested ipilimumab (Yervoy), an antibody to the T-cell receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA4), as induction therapy and then maintenance therapy among patients with melanoma who had brain metastases (Lancet Oncol. 2012;13:459-65).
The subset of patients who were neurologically stable and not on systemic steroids had a disease control rate of 24%, with some having objective responses, including ones in the CNS; the value was lower, at 10%, among patients who were neurologically symptomatic and on steroids, indicating more advanced disease. The 2-year overall survival rate was 26%.
“I think this is encouraging if you compare [these patients] to historical control patients with brain metastases,” said Dr. Thompson, who disclosed that he performs contracted research with Agensys, BMS, Merck, Novartis, and Pfizer.
Another phase II trial, CheckMate 204, which is currently enrolling patients, is taking the concept further, testing the combination of ipilimumab and nivolumab (Opdivo), an antibody to the cell surface receptor programmed death-1 (PD-1), as induction therapy followed by nivolumab maintenance therapy among patients with melanoma who have brain metastases. “This is I think a high-priority trial,” he asserted.
Discussing some cases from his own practice, Dr. Thompson described patient-tailored integration of the new systemic therapies with surgery and radiation therapy.
Oncologists must often deal with toxicities of these therapies as well, such as the colitis and hypophysitis related to ipilimumab therapy, and the development of resistance over time, Dr. Thompson acknowledged.
Nonetheless, the multimodality approach has led to regression and elimination of brain metastases, and even allowed some patients to achieve remission, he reported.
SEATTLE – Targeted therapies for melanoma are improving outcomes for patients with brain metastases and changing management of this dreaded complication, according to Dr. John A. Thompson, codirector of the Melanoma Clinic at the Seattle Cancer Care Alliance and a professor in the medical oncology division at the University of Washington, both in Seattle.
“We are in a new era of treatment of brain metastasis. It’s no longer just surgery and radiation therapy, but a multidisciplinary approach involving medical oncology, radiation oncology, and surgery,” he told attendees of the World Cutaneous Malignancies Congress.
Without question, surgery and radiation therapy techniques have advanced over time, and these modalities remain helpful in achieving local control of disease. Additionally, greater experience with them has improved patient selection.
For example, research has identified several predictors of benefit from stereotactic radiosurgery, such as fewer brain metastases and better performance status (J Neurosurg. 2011;114:769-79). But overall survival was fairly poor given disease elsewhere in the body. “Here’s where I think the new developments in systemic therapy may hopefully be able to start improving this curve,” Dr. Thompson said.
Toxicity of some forms of radiation therapy also remains problematic. For example, a recent randomized phase III trial in patients with up to three brain metastases showed that addition of whole-brain radiation therapy to radiosurgery improved intracranial tumor control, but at the expense of more rapid cognitive decline (ASCO 2015. Abstract LBA4). And there was no gain in overall survival.
“The changes that have happened in systemic therapy over the past 5-10 years have been very exciting,” Dr. Thompson said. By way of example, he pointed to a phase II trial that tested ipilimumab (Yervoy), an antibody to the T-cell receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA4), as induction therapy and then maintenance therapy among patients with melanoma who had brain metastases (Lancet Oncol. 2012;13:459-65).
The subset of patients who were neurologically stable and not on systemic steroids had a disease control rate of 24%, with some having objective responses, including ones in the CNS; the value was lower, at 10%, among patients who were neurologically symptomatic and on steroids, indicating more advanced disease. The 2-year overall survival rate was 26%.
“I think this is encouraging if you compare [these patients] to historical control patients with brain metastases,” said Dr. Thompson, who disclosed that he performs contracted research with Agensys, BMS, Merck, Novartis, and Pfizer.
Another phase II trial, CheckMate 204, which is currently enrolling patients, is taking the concept further, testing the combination of ipilimumab and nivolumab (Opdivo), an antibody to the cell surface receptor programmed death-1 (PD-1), as induction therapy followed by nivolumab maintenance therapy among patients with melanoma who have brain metastases. “This is I think a high-priority trial,” he asserted.
Discussing some cases from his own practice, Dr. Thompson described patient-tailored integration of the new systemic therapies with surgery and radiation therapy.
Oncologists must often deal with toxicities of these therapies as well, such as the colitis and hypophysitis related to ipilimumab therapy, and the development of resistance over time, Dr. Thompson acknowledged.
Nonetheless, the multimodality approach has led to regression and elimination of brain metastases, and even allowed some patients to achieve remission, he reported.
EXPERT ANALYSIS FROM THE WORLD CUTANEOUS MALIGNANCIES CONGRESS
In ALL, early treatment decisions have “irrevocable” implications
SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.
Cytogenetics and genomics help risk-adapt therapy
“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.
Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.
“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.
Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).
Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.
A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.
“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”
Demographics can guide treatment choices as well
Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.
“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”
AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).
“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”
At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.
He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).
“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.
At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.
“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”
Immunotherapy shows promise in the salvage setting
“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.
“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).
This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.
The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.
Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”
Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.
Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.
“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”
SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.
Cytogenetics and genomics help risk-adapt therapy
“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.
Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.
“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.
Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).
Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.
A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.
“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”
Demographics can guide treatment choices as well
Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.
“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”
AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).
“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”
At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.
He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).
“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.
At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.
“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”
Immunotherapy shows promise in the salvage setting
“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.
“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).
This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.
The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.
Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”
Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.
Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.
“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”
SAN FRANCISCO – “The best opportunity to improve acute lymphoblastic leukemia (ALL) outcomes is to make the best evidence-based choices early at the time of diagnosis or early at the time of relapse. This is a disease where early choices are irrevocable, and if you make the wrong choices, patients suffer,” Dr. Joseph C. Alvarnas asserted at the National Comprehensive Cancer Network 10th Annual Congress: Hematologic Malignancies.
Hematologists must also stay up on novel agents being added to the ALL treatment armamentarium, he stressed. “The state of the art is one that evolves over the course of months, not over the course of years. So maintaining current [knowledge] in this is essential. And many of these patients benefit from being referred quickly to an expert institution,” he said.
Cytogenetics and genomics help risk-adapt therapy
“Cytogenetic, molecular, and genomic data are essential to making great early choices,” maintained Dr. Alvarnas, who is an associate clinical professor in the department of hematology & hematopoietic cell transplantation, and director of Value Based Analytics, at the City of Hope Comprehensive Cancer Center in Duarte, California.
Patients with Philadelphia chromosome (Ph)-positive ALL should receive tyrosine kinase inhibitors (TKIs) concomitantly with age-adapted induction and consolidation therapy, he recommended. In those with a poor response, a mutational analysis is key to guiding next steps.
“While in the young pediatric population – we are talking ages 5-10 years – there is a trend away from offering transplant to patients with Ph-positive disease because some of them are actually cured through the combination of induction pediatric regimens followed by TKI-based therapy, for adults, the standard of care until demonstrated otherwise is prompt referral for transplant,” he said.
Indeed, long-term survival is nearly doubled for Ph-positive patients if they have a transplant in a first complete remission versus later (54% vs 29%) (Blood. 2008;112;903-9).
Patients with the high-risk MLL rearrangement are likely to fare poorly and should also be considered for early transplant in first complete remission, according to Dr. Alvarnas.
A novel genetic subtype of ALL identified by looking at networks of genes – Ph-like ALL – has a poor prognosis, especially when affected patients are young adults as compared with children or adolescents (N Engl J Med. 2014;371:1005-15). Analyses have identified the presence of a cluster of genetic abnormalities involving ABL, JAK2, and RAS, among others.
“If you think strategically about how we might be able to better treat these patients … targeted agents like ruxolitinib (Jakafi), dasatinib (Sprycel), and crizotinib (Xalkori) may all play a role,” he said. “Now this is not ready for prime time yet – I’m not ready to advocate that you begin treating patients with targeted therapies. I think in fact this patient population should be referred to an academic cancer center for treatment on protocol. But as we look at what’s likely to change over the next year to 5 years, genomic alterations may make these patients better candidates for treatment with TKIs.”
Demographics can guide treatment choices as well
Patient demographics, especially age, should also be used to risk-adapt ALL therapy, according to Dr. Alvarnas. The adolescent and young adult (AYA) subset of patients – aged 15-39 – tend to be fitter and can therefore benefit from pediatric or pediatric-inspired regimens.
“These regimens don’t use novel therapeutics, for the most part; they increase the dose density or dose intensity of existing agents, particularly L-asparaginase. And a lot of adult doctors used to treating older patients don’t like L-asparaginase because of the significant morbidities, particularly pancreatitis, that can arise with this agent,” he said. “But when you get a younger, fitter group of patients, you can use very intensive doses of L-asparaginase not only with impunity, but with greater cure rates.”
AYA patients have superior event-free and overall survival when treated with a pediatric or pediatric-inspired regimen than when treated with an adult regimen (Blood. 2008;112:1646-54).
“So think of it this way: patients 15-39 years of age are receiving inferior therapy if they are receiving adult regimens,” Dr. Alvarnas said. “Now the caveat there is they have to be … physiologically fit, and there may be specific contraindications to these pediatric regimens. But this should be an opt out, not an opt in. The pediatric-inspired regimens are, I would say, the standard care for this population.”
At the other end of the age spectrum, patients 65 years and older with ALL have poorer outcomes, which may be due to both biology of disease and physiology. “We need to be very mindful and think carefully of how best to treat these patients in a patient-centric fashion,” he said.
He recommended consideration of comorbidities and use of a comprehensive geriatric assessment when contemplating care options for this age group. “We want to make sure that the therapy used matches the patient before us,” he added, pointing to an algorithm that is helpful in this setting (Blood. 2013;122:1366-75).
“Where it’s possible, I would encourage the use of clinical trials, particularly geared to the older age population. And that said, in the older, fitter patient with a good initial response to therapy, do not discount the appropriateness of allogeneic stem cell transplant,” Dr. Alvarnas advised.
At the same time, hematologists should have a frank discussion with these older patients about the goals of care and advanced directives, and should involve supportive care early.
“NCCN has an absolutely beautiful document on the care of older oncology patients as well as a beautiful set of guidelines regarding supportive care,” he added. “Please look at those. I think are an invaluable resource.”
Immunotherapy shows promise in the salvage setting
“At the time of salvage, immunotherapy-based approaches are very powerful, so don’t overtreat the patient with modalities that aren’t going to work,” Dr. Alvarnas recommended.
“Immunotherapeutic approaches are going to play an increasingly important role in patients with ALL, and we see these novel therapeutics completely upending what we knew about this disease even a year or two ago,” he said. A variety of monoclonal antibodies against CD20, CD19, CD22, and CD52 have shown promise when tested in various patient populations (Blood. 2015;125:4010-6).
This concept has been taken a step further with blinatumomab (Blincyto), an antibody having two antigen recognition sites that brings CD19-positive tumor cells in contact with T lymphocytes. It is the first such agent to be approved by the FDA for an ALL indication (currently for refractory or relapsed Ph-negative B-cell ALL). “It has nonoverlapping activity with cytotoxic chemotherapy, which makes it an ideal agent,” Dr. Alvarnas noted.
The main risk with blinatumomab is a cytokine release syndrome, which is most common in patients with a high disease burden and requires drug discontinuation and treatment with high-dose dexamethasone. Neurotoxicity is also noteworthy as it can be fatal.
Responses to blinatumomab tend to be dramatic and deep, but brief, according to Dr. Alvarnas. “Even though it’s profoundly powerful, it’s not a curative agent. It really provides a bridge towards cure, with that cure coming through the use of allogeneic stem cell transplant,” he elaborated. “So if someone relapses and you begin blinatumomab, get them referred very quickly to a transplant center.”
Another promising immunotherapy is inotuzumab ozagamicin, an antibody-drug conjugate that targets CD22-expressing cells. It has been associated with a complete response rate of 19%, although veno-occlusive toxicity has been problematic (Cancer. 2013;119:2728-36). “This agent has not yet received FDA approval, but it’s one that we are awaiting expectantly,” he said.
Finally, phase 1 trials from various academic centers have shown that chimeric antigen receptor (CAR) T-cell therapy achieves complete response rates of 67%-90% in patients with high-risk refractory disease, according to Dr. Alvarnas, who disclosed that he had no relevant financial relationships.
“This has lead to culmination in phase 2 trials, and I really do see this as an important component in the management of patients with relapsed and refractory ALL,” he concluded. “It’s not something that is available at every center. Right now it’s restricted largely to academic centers capable of producing these therapeutics in their own GLP [Good Laboratory Practice] facility.”
EXPERT ANALYSIS AT NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
New guidelines address multiple myeloma–related complications
New guidelines on managing the complications of multiple myeloma and its treatment recommend whole-body, low-dose computed tomography over conventional radiography because of its superior sensitivity for detecting osteolytic lesions. The guidelines, drafted by the European Myeloma Network, also provide an imaging algorithm to address various clinical scenarios.
This is just one of the recommendations from the interdisciplinary panel that reviewed published randomized trials, guidelines, meta-analyses, systematic reviews, observational studies, and case reports on the topic. They graded their recommendations according to the strength of the evidence and, when evidence was insufficient, expert consensus.
“Multiple myeloma … is characterized by bone destruction, anemia, renal and immunological impairment. These complications may lead to severe impairment of the quality of life of myeloma patients and may deteriorate their life expectancy,” note the authors, who were led by Dr. Evangelos Terpos of the department of clinical therapeutics, National and Kapodistrian University of Athens (Haematologica. 2015;100:1254-66).
The panel endorsed addition of zoledronic acid (Zometa) or pamidronate (Aredia) to specific antimyeloma therapy for patients with adequate renal function who have bone disease at diagnosis. Although evidence is weaker, they note that symptomatic patients who do not have lytic lesions on conventional radiography can be treated with zoledronic acid; however, its use in patients with no bone involvement on computed tomography or magnetic resonance imaging has uncertain benefit. Additionally, they do not recommend use of bisphosphonates in asymptomatic patients.
The panel recommends that zoledronic acid be given continuously, although they add that benefit of continuous use is not clear in patients who achieve at least a very good partial response.
Treatment can be initiated with erythropoiesis-stimulating agents such as epoetin alfa (various brand names) and darbepoetin (Aranesp) in patients who have persistent symptomatic anemia (defined as a hemoglobin level of less than 10 g/dL) without any other apparent cause. However, these agents should be stopped after 6 to 8 weeks if hemoglobin response has not been adequate.
The panel notes that bortezomib(Velcade)-based regimens are the standard of care for patients with multiple myeloma who have renal impairment. Lenalidomide is an option, albeit with weaker evidence, in cases of mild to moderate renal impairment.
In patients who experience treatment-induced peripheral neuropathy, therapy should be modified by either altering the schedule or route of administration (as appropriate) or reducing the dose, according to the guidelines.
Patients with multiple myeloma (and their contacts) should be vaccinated against influenza, the panel recommends; vaccination against Streptococcus pneumonia and Haemophilus influenzae is “appropriate,” although efficacy is not guaranteed as patients are immunologically compromised.
The panel endorsed acyclovir (Zovirax) or valacyclovir (Valtrex) for herpes zoster virus prophylaxis in patients receiving proteasome inhibitors or undergoing autologous or allogeneic transplantation, mainly directed to patients who are seropositive.
Finally, clinicians should assess risk of venous thromboembolism in patients who are due to start immunomodulatory drug therapy and should use appropriate risk-based antiplatelet or anticoagulation therapy throughout treatment, according to the guidelines.
Dr. Terpos reported having no relevant disclosures.
New guidelines on managing the complications of multiple myeloma and its treatment recommend whole-body, low-dose computed tomography over conventional radiography because of its superior sensitivity for detecting osteolytic lesions. The guidelines, drafted by the European Myeloma Network, also provide an imaging algorithm to address various clinical scenarios.
This is just one of the recommendations from the interdisciplinary panel that reviewed published randomized trials, guidelines, meta-analyses, systematic reviews, observational studies, and case reports on the topic. They graded their recommendations according to the strength of the evidence and, when evidence was insufficient, expert consensus.
“Multiple myeloma … is characterized by bone destruction, anemia, renal and immunological impairment. These complications may lead to severe impairment of the quality of life of myeloma patients and may deteriorate their life expectancy,” note the authors, who were led by Dr. Evangelos Terpos of the department of clinical therapeutics, National and Kapodistrian University of Athens (Haematologica. 2015;100:1254-66).
The panel endorsed addition of zoledronic acid (Zometa) or pamidronate (Aredia) to specific antimyeloma therapy for patients with adequate renal function who have bone disease at diagnosis. Although evidence is weaker, they note that symptomatic patients who do not have lytic lesions on conventional radiography can be treated with zoledronic acid; however, its use in patients with no bone involvement on computed tomography or magnetic resonance imaging has uncertain benefit. Additionally, they do not recommend use of bisphosphonates in asymptomatic patients.
The panel recommends that zoledronic acid be given continuously, although they add that benefit of continuous use is not clear in patients who achieve at least a very good partial response.
Treatment can be initiated with erythropoiesis-stimulating agents such as epoetin alfa (various brand names) and darbepoetin (Aranesp) in patients who have persistent symptomatic anemia (defined as a hemoglobin level of less than 10 g/dL) without any other apparent cause. However, these agents should be stopped after 6 to 8 weeks if hemoglobin response has not been adequate.
The panel notes that bortezomib(Velcade)-based regimens are the standard of care for patients with multiple myeloma who have renal impairment. Lenalidomide is an option, albeit with weaker evidence, in cases of mild to moderate renal impairment.
In patients who experience treatment-induced peripheral neuropathy, therapy should be modified by either altering the schedule or route of administration (as appropriate) or reducing the dose, according to the guidelines.
Patients with multiple myeloma (and their contacts) should be vaccinated against influenza, the panel recommends; vaccination against Streptococcus pneumonia and Haemophilus influenzae is “appropriate,” although efficacy is not guaranteed as patients are immunologically compromised.
The panel endorsed acyclovir (Zovirax) or valacyclovir (Valtrex) for herpes zoster virus prophylaxis in patients receiving proteasome inhibitors or undergoing autologous or allogeneic transplantation, mainly directed to patients who are seropositive.
Finally, clinicians should assess risk of venous thromboembolism in patients who are due to start immunomodulatory drug therapy and should use appropriate risk-based antiplatelet or anticoagulation therapy throughout treatment, according to the guidelines.
Dr. Terpos reported having no relevant disclosures.
New guidelines on managing the complications of multiple myeloma and its treatment recommend whole-body, low-dose computed tomography over conventional radiography because of its superior sensitivity for detecting osteolytic lesions. The guidelines, drafted by the European Myeloma Network, also provide an imaging algorithm to address various clinical scenarios.
This is just one of the recommendations from the interdisciplinary panel that reviewed published randomized trials, guidelines, meta-analyses, systematic reviews, observational studies, and case reports on the topic. They graded their recommendations according to the strength of the evidence and, when evidence was insufficient, expert consensus.
“Multiple myeloma … is characterized by bone destruction, anemia, renal and immunological impairment. These complications may lead to severe impairment of the quality of life of myeloma patients and may deteriorate their life expectancy,” note the authors, who were led by Dr. Evangelos Terpos of the department of clinical therapeutics, National and Kapodistrian University of Athens (Haematologica. 2015;100:1254-66).
The panel endorsed addition of zoledronic acid (Zometa) or pamidronate (Aredia) to specific antimyeloma therapy for patients with adequate renal function who have bone disease at diagnosis. Although evidence is weaker, they note that symptomatic patients who do not have lytic lesions on conventional radiography can be treated with zoledronic acid; however, its use in patients with no bone involvement on computed tomography or magnetic resonance imaging has uncertain benefit. Additionally, they do not recommend use of bisphosphonates in asymptomatic patients.
The panel recommends that zoledronic acid be given continuously, although they add that benefit of continuous use is not clear in patients who achieve at least a very good partial response.
Treatment can be initiated with erythropoiesis-stimulating agents such as epoetin alfa (various brand names) and darbepoetin (Aranesp) in patients who have persistent symptomatic anemia (defined as a hemoglobin level of less than 10 g/dL) without any other apparent cause. However, these agents should be stopped after 6 to 8 weeks if hemoglobin response has not been adequate.
The panel notes that bortezomib(Velcade)-based regimens are the standard of care for patients with multiple myeloma who have renal impairment. Lenalidomide is an option, albeit with weaker evidence, in cases of mild to moderate renal impairment.
In patients who experience treatment-induced peripheral neuropathy, therapy should be modified by either altering the schedule or route of administration (as appropriate) or reducing the dose, according to the guidelines.
Patients with multiple myeloma (and their contacts) should be vaccinated against influenza, the panel recommends; vaccination against Streptococcus pneumonia and Haemophilus influenzae is “appropriate,” although efficacy is not guaranteed as patients are immunologically compromised.
The panel endorsed acyclovir (Zovirax) or valacyclovir (Valtrex) for herpes zoster virus prophylaxis in patients receiving proteasome inhibitors or undergoing autologous or allogeneic transplantation, mainly directed to patients who are seropositive.
Finally, clinicians should assess risk of venous thromboembolism in patients who are due to start immunomodulatory drug therapy and should use appropriate risk-based antiplatelet or anticoagulation therapy throughout treatment, according to the guidelines.
Dr. Terpos reported having no relevant disclosures.
FROM HAEMATOLOGICA
PD-L1 status of NSCLC consistent across primary, nodes, and metastases
DENVER – In patients with non–small cell lung cancer (NSCLC), the programmed death-ligand 1 (PD-L1) status of the primary tumor is generally a reliable predictor of the status of tumor elsewhere the body, suggest a pair of retrospective cohort studies presented at a world conference on lung cancer.
Results showed a high rate of concordance of PD-L1 immunohistochemical (IHC) staining, whether comparing primary with nodes (81%-89%) or primary with metastasis (77%), investigators reported.
These findings are relevant in that some studies have suggested that high PD-L1 expression is a biomarker for benefit from agents that inhibit the programmed cell death 1 (PD-1) signaling pathway. Thus, being able to use archival primary tumor to assess PD-L1 status might help guide decisions about treatment options in the metastatic setting.
“This is pretty good concordance, especially considering that our assays only have about 75% concordance [among them], depending on how you measure it and what cutpoints you use and which antibodies you use,” said invited discussant Dr. David Rimm, professor of pathology and of medicine, director of pathology tissue services, and director of translational pathology at Yale University in New Haven, Conn.
“The take-home message is, is the glass half full or is the glass half empty? And the real message is that maybe the glass is twice as big as it needs to be,” he said. “That is, what we really need to do is come up with a uniform assay here that’s standardized so that we can actually do studies like this a little more carefully.”
In the first study, Dr. Brandon S. Sheffield, of the pathology office at BC Cancer Agency, Vancouver, studied 78 patients who underwent resection of a primary nonsquamous NSCLC and were found to have nodal involvement.
For each patient, they compared PD-L1 staining between the primary tumor and the matched nodal tumor, simultaneously testing various antibodies; Bristol-Myers Squibb Canada performed some of the IHC. Tumors were considered positive if at least 1% of cells stained with any intensity.
Results showed an 81% rate of concordance of PD-L1 staining between the primary and node; in about 8% of cases, only the primary was positive, and in about 9%, only the node was positive.
Study results also showed good concordance across the three different antibodies: SP142 (Spring Bioscience), E1L3N (Cell Signaling Technology), and 28-8 (Dako). In 76% of cases, all three antibodies were in agreement.
In some cases, clusters of infiltrating macrophages stained for PD-L1. “This could represent a possible pitfall, especially using a cutoff as low as 1%, although with some practice, one can appreciate that the staining of macrophages is somewhat different than the crisp membranous staining seen in tumor cells,” Dr. Sheffield.
“PD-L1 IHC is feasible and it can be done in your laboratory. There are small but very relevant differences in testing primary tumor tissue and lymph node metastasis, and that will need to be explored with a bias toward testing more, not less, tissue,” he concluded. “Multiple methods for PD-L1 IHC appear to be equivalent, and we should be able to have some freedom in choosing the best PD-L1 IHC assay for our own laboratories.”
In the second study, Dr. Paul Mitchell of Austin Health, Melbourne, and colleagues assessed PD-L1 staining among 433 sequential patients who underwent resection of primary NSCLC between 1992 and 2010. Bristol-Myers Squibb performed the IHC staining and some of the scoring.
In one set of assays, the investigators used the 28.8 antibody and considered tumors to be positive if at least 5% of cells showed membranous staining of any intensity.
Results here showed that 28% of primaries were PD-L1 positive. The rate was similar for men and women, but higher in squamous tumors than in adenocarcinomas (39% vs. 18%). It was merely 14% in patients having an epidermal growth factor receptor (EGFR) mutation. The rate of positivity increased with the number of pack-years of smoking and, starting 5 years after cessation, decreased over time.
A total of 57 patients had paired primary tumor and metastatic tumor (most commonly from brain metastases). The median time from primary to metastasis was 1.3 years; in eight patients, metastasis was synchronous.
In this cohort, there was a 77% rate of concordance of PD-L1 staining between the primary and metastasis (r = 0.37, P = .0049); in 11% of cases, only the primary was positive, and in 12%, only the metastasis was positive. Also, among the eight patients having multiple metastases, all samples were concordant in six patients.
In another set of assays, the investigators used the E11340 XP antibody (Cell Signaling Technology) and considered tumors to be strongly positive if more than 50% of cells stained with intensity of 2 or higher (ASCO 2015, abstract 11051).
Here, 24% of primaries were strongly positive. In a multivariate analysis, patients with stage III disease who had high PD-L1 expression in both the primary and node had better disease-free survival (hazard ratio, 0.49; P = .031) and overall survival (HR, 0.46; P = .006).
Among the 53 patients who had paired primary and nodal tumor, PD-L1 staining was concordant in these sites in 89% of patients.
“These data do suggest that PD-L1 status in general in the primary NSCLC predicts the PD-L1 status in metastases as well as in the nodes,” Dr. Mitchell said. “However, if the PD-L1 expression status is critical in the decision to treat metastatic NSCLC with a PD-1 pathway inhibitor, then rebiopsy of a metastasis may be warranted,” he added.
Dr. Sheffield reported that he had no relevant disclosures; Bristol-Myers Squibb Canada performed some of the IHC staining. Dr. Mitchell disclosed ties with AstraZeneca, Roche, Boehringer-Ingelheim, Bristol-Myers Squibb, and MSD. Bristol-Myers Squibb performed IHC staining and some of the scoring.
The conference was sponsored by the International Association for the Study of Lung Cancer.
DENVER – In patients with non–small cell lung cancer (NSCLC), the programmed death-ligand 1 (PD-L1) status of the primary tumor is generally a reliable predictor of the status of tumor elsewhere the body, suggest a pair of retrospective cohort studies presented at a world conference on lung cancer.
Results showed a high rate of concordance of PD-L1 immunohistochemical (IHC) staining, whether comparing primary with nodes (81%-89%) or primary with metastasis (77%), investigators reported.
These findings are relevant in that some studies have suggested that high PD-L1 expression is a biomarker for benefit from agents that inhibit the programmed cell death 1 (PD-1) signaling pathway. Thus, being able to use archival primary tumor to assess PD-L1 status might help guide decisions about treatment options in the metastatic setting.
“This is pretty good concordance, especially considering that our assays only have about 75% concordance [among them], depending on how you measure it and what cutpoints you use and which antibodies you use,” said invited discussant Dr. David Rimm, professor of pathology and of medicine, director of pathology tissue services, and director of translational pathology at Yale University in New Haven, Conn.
“The take-home message is, is the glass half full or is the glass half empty? And the real message is that maybe the glass is twice as big as it needs to be,” he said. “That is, what we really need to do is come up with a uniform assay here that’s standardized so that we can actually do studies like this a little more carefully.”
In the first study, Dr. Brandon S. Sheffield, of the pathology office at BC Cancer Agency, Vancouver, studied 78 patients who underwent resection of a primary nonsquamous NSCLC and were found to have nodal involvement.
For each patient, they compared PD-L1 staining between the primary tumor and the matched nodal tumor, simultaneously testing various antibodies; Bristol-Myers Squibb Canada performed some of the IHC. Tumors were considered positive if at least 1% of cells stained with any intensity.
Results showed an 81% rate of concordance of PD-L1 staining between the primary and node; in about 8% of cases, only the primary was positive, and in about 9%, only the node was positive.
Study results also showed good concordance across the three different antibodies: SP142 (Spring Bioscience), E1L3N (Cell Signaling Technology), and 28-8 (Dako). In 76% of cases, all three antibodies were in agreement.
In some cases, clusters of infiltrating macrophages stained for PD-L1. “This could represent a possible pitfall, especially using a cutoff as low as 1%, although with some practice, one can appreciate that the staining of macrophages is somewhat different than the crisp membranous staining seen in tumor cells,” Dr. Sheffield.
“PD-L1 IHC is feasible and it can be done in your laboratory. There are small but very relevant differences in testing primary tumor tissue and lymph node metastasis, and that will need to be explored with a bias toward testing more, not less, tissue,” he concluded. “Multiple methods for PD-L1 IHC appear to be equivalent, and we should be able to have some freedom in choosing the best PD-L1 IHC assay for our own laboratories.”
In the second study, Dr. Paul Mitchell of Austin Health, Melbourne, and colleagues assessed PD-L1 staining among 433 sequential patients who underwent resection of primary NSCLC between 1992 and 2010. Bristol-Myers Squibb performed the IHC staining and some of the scoring.
In one set of assays, the investigators used the 28.8 antibody and considered tumors to be positive if at least 5% of cells showed membranous staining of any intensity.
Results here showed that 28% of primaries were PD-L1 positive. The rate was similar for men and women, but higher in squamous tumors than in adenocarcinomas (39% vs. 18%). It was merely 14% in patients having an epidermal growth factor receptor (EGFR) mutation. The rate of positivity increased with the number of pack-years of smoking and, starting 5 years after cessation, decreased over time.
A total of 57 patients had paired primary tumor and metastatic tumor (most commonly from brain metastases). The median time from primary to metastasis was 1.3 years; in eight patients, metastasis was synchronous.
In this cohort, there was a 77% rate of concordance of PD-L1 staining between the primary and metastasis (r = 0.37, P = .0049); in 11% of cases, only the primary was positive, and in 12%, only the metastasis was positive. Also, among the eight patients having multiple metastases, all samples were concordant in six patients.
In another set of assays, the investigators used the E11340 XP antibody (Cell Signaling Technology) and considered tumors to be strongly positive if more than 50% of cells stained with intensity of 2 or higher (ASCO 2015, abstract 11051).
Here, 24% of primaries were strongly positive. In a multivariate analysis, patients with stage III disease who had high PD-L1 expression in both the primary and node had better disease-free survival (hazard ratio, 0.49; P = .031) and overall survival (HR, 0.46; P = .006).
Among the 53 patients who had paired primary and nodal tumor, PD-L1 staining was concordant in these sites in 89% of patients.
“These data do suggest that PD-L1 status in general in the primary NSCLC predicts the PD-L1 status in metastases as well as in the nodes,” Dr. Mitchell said. “However, if the PD-L1 expression status is critical in the decision to treat metastatic NSCLC with a PD-1 pathway inhibitor, then rebiopsy of a metastasis may be warranted,” he added.
Dr. Sheffield reported that he had no relevant disclosures; Bristol-Myers Squibb Canada performed some of the IHC staining. Dr. Mitchell disclosed ties with AstraZeneca, Roche, Boehringer-Ingelheim, Bristol-Myers Squibb, and MSD. Bristol-Myers Squibb performed IHC staining and some of the scoring.
The conference was sponsored by the International Association for the Study of Lung Cancer.
DENVER – In patients with non–small cell lung cancer (NSCLC), the programmed death-ligand 1 (PD-L1) status of the primary tumor is generally a reliable predictor of the status of tumor elsewhere the body, suggest a pair of retrospective cohort studies presented at a world conference on lung cancer.
Results showed a high rate of concordance of PD-L1 immunohistochemical (IHC) staining, whether comparing primary with nodes (81%-89%) or primary with metastasis (77%), investigators reported.
These findings are relevant in that some studies have suggested that high PD-L1 expression is a biomarker for benefit from agents that inhibit the programmed cell death 1 (PD-1) signaling pathway. Thus, being able to use archival primary tumor to assess PD-L1 status might help guide decisions about treatment options in the metastatic setting.
“This is pretty good concordance, especially considering that our assays only have about 75% concordance [among them], depending on how you measure it and what cutpoints you use and which antibodies you use,” said invited discussant Dr. David Rimm, professor of pathology and of medicine, director of pathology tissue services, and director of translational pathology at Yale University in New Haven, Conn.
“The take-home message is, is the glass half full or is the glass half empty? And the real message is that maybe the glass is twice as big as it needs to be,” he said. “That is, what we really need to do is come up with a uniform assay here that’s standardized so that we can actually do studies like this a little more carefully.”
In the first study, Dr. Brandon S. Sheffield, of the pathology office at BC Cancer Agency, Vancouver, studied 78 patients who underwent resection of a primary nonsquamous NSCLC and were found to have nodal involvement.
For each patient, they compared PD-L1 staining between the primary tumor and the matched nodal tumor, simultaneously testing various antibodies; Bristol-Myers Squibb Canada performed some of the IHC. Tumors were considered positive if at least 1% of cells stained with any intensity.
Results showed an 81% rate of concordance of PD-L1 staining between the primary and node; in about 8% of cases, only the primary was positive, and in about 9%, only the node was positive.
Study results also showed good concordance across the three different antibodies: SP142 (Spring Bioscience), E1L3N (Cell Signaling Technology), and 28-8 (Dako). In 76% of cases, all three antibodies were in agreement.
In some cases, clusters of infiltrating macrophages stained for PD-L1. “This could represent a possible pitfall, especially using a cutoff as low as 1%, although with some practice, one can appreciate that the staining of macrophages is somewhat different than the crisp membranous staining seen in tumor cells,” Dr. Sheffield.
“PD-L1 IHC is feasible and it can be done in your laboratory. There are small but very relevant differences in testing primary tumor tissue and lymph node metastasis, and that will need to be explored with a bias toward testing more, not less, tissue,” he concluded. “Multiple methods for PD-L1 IHC appear to be equivalent, and we should be able to have some freedom in choosing the best PD-L1 IHC assay for our own laboratories.”
In the second study, Dr. Paul Mitchell of Austin Health, Melbourne, and colleagues assessed PD-L1 staining among 433 sequential patients who underwent resection of primary NSCLC between 1992 and 2010. Bristol-Myers Squibb performed the IHC staining and some of the scoring.
In one set of assays, the investigators used the 28.8 antibody and considered tumors to be positive if at least 5% of cells showed membranous staining of any intensity.
Results here showed that 28% of primaries were PD-L1 positive. The rate was similar for men and women, but higher in squamous tumors than in adenocarcinomas (39% vs. 18%). It was merely 14% in patients having an epidermal growth factor receptor (EGFR) mutation. The rate of positivity increased with the number of pack-years of smoking and, starting 5 years after cessation, decreased over time.
A total of 57 patients had paired primary tumor and metastatic tumor (most commonly from brain metastases). The median time from primary to metastasis was 1.3 years; in eight patients, metastasis was synchronous.
In this cohort, there was a 77% rate of concordance of PD-L1 staining between the primary and metastasis (r = 0.37, P = .0049); in 11% of cases, only the primary was positive, and in 12%, only the metastasis was positive. Also, among the eight patients having multiple metastases, all samples were concordant in six patients.
In another set of assays, the investigators used the E11340 XP antibody (Cell Signaling Technology) and considered tumors to be strongly positive if more than 50% of cells stained with intensity of 2 or higher (ASCO 2015, abstract 11051).
Here, 24% of primaries were strongly positive. In a multivariate analysis, patients with stage III disease who had high PD-L1 expression in both the primary and node had better disease-free survival (hazard ratio, 0.49; P = .031) and overall survival (HR, 0.46; P = .006).
Among the 53 patients who had paired primary and nodal tumor, PD-L1 staining was concordant in these sites in 89% of patients.
“These data do suggest that PD-L1 status in general in the primary NSCLC predicts the PD-L1 status in metastases as well as in the nodes,” Dr. Mitchell said. “However, if the PD-L1 expression status is critical in the decision to treat metastatic NSCLC with a PD-1 pathway inhibitor, then rebiopsy of a metastasis may be warranted,” he added.
Dr. Sheffield reported that he had no relevant disclosures; Bristol-Myers Squibb Canada performed some of the IHC staining. Dr. Mitchell disclosed ties with AstraZeneca, Roche, Boehringer-Ingelheim, Bristol-Myers Squibb, and MSD. Bristol-Myers Squibb performed IHC staining and some of the scoring.
The conference was sponsored by the International Association for the Study of Lung Cancer.
AT THE IASLC WORLD CONFERENCE
Key clinical point: PD-L1 status of the primary in NSCLC generally predicts that of nodal tumor and metastases.
Major finding: The rate of concordance for PD-L1 staining comparing primary with lymph nodes was 81%-89% and comparing primary with metastasis was 77%.
Data source: A pair of retrospective cohort studies of 78 patients with nonsquamous NSCLC and 433 patients with NSCLC.
Disclosures: Dr. Sheffield reported that he had no relevant disclosures; Bristol-Myers Squibb Canada performed some of the IHC staining. Dr. Mitchell disclosed ties with AstraZeneca, Roche, Boehringer-Ingelheim, Bristol-Myers Squibb, and MSD. Bristol-Myers Squibb performed IHC staining and some of the scoring.
Actionable mutations are highly prevalent in young lung cancer patients
DENVER – Genomic testing in young patients with lung cancer is critical, as the majority have adenocarcinomas harboring driver alterations that can be targeted with drugs available today, suggested a trio of cohort studies presented at a conference sponsored by the International Association for the Study of Lung Cancer.
More than three-fourths of patients aged 40 years or younger with adenocarcinoma were found to have driver alterations in genes such as those for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1), investigators reported in a session and related press conference.
“Lung cancer under 40 is a group of patients who are enriched for actionable mutations,” commented invited discussant Dr. Benjamin Levy, assistant professor of medicine, Mount Sinai School of Medicine; medical director of the thoracic oncology program for the Mount Sinai Health System; and associate director of the cancer clinical trials office at Mount Sinai Hospital – all in New York. “I think that if there was ever a clinical circumstance in which next-generation sequencing should be performed routinely outside a clinical trial, it’s for these patients under 40.”
Of note, in two of the three studies, the majority of patients had some history of smoking, “suggesting that this lung cancer in patients under 40 is not necessarily a nonsmoking disease,” he said. “It’s wonderful to have great drugs for those patients who do develop lung cancer, but instituting preventive measures for tobacco control and education does wonders.”
New study design expands enrollment options
In the first study, a team led by Dr. Barbara J. Gitlitz, associate professor of clinical medicine at the University of Southern California in Los Angeles, analyzed data from the Genomics of Young Lung Cancer Study, the first to prospectively assess clinical characteristics and genomic alterations of this population.
The study is open to patients younger than 40 years at diagnosis. All are tested for alterations of EGFR, BRAF, HER2, KRAS, ALK, ROS1, and RET, and those negative for alterations in these genes have additional testing.
“One interesting point of our study is that people can enter either through coming to a [brick and mortar] site that has IRB approval or through a website (https://www.openmednet.org/site/alcmi-goyl) where people can remotely consent anywhere in the world and participate in our clinical trial,” Dr. Gitlitz noted.
In fact, of the 68 patients enrolled in the first year, 44% did so through the website, including some from as far away as Australia, Norway, and Turkey. The patients ranged in age from 16 to 39 years at diagnosis (median, 35 years), and 52% were female. They tended to be never-smokers, Dr. Gitlitz reported.
Fifty of the patients had stage IV adenocarcinoma at diagnosis. In this group, 76% were found to have known actionable driver alterations – most commonly in ALK (44%), EGFR (26%), or ROS1 (6%). The prevalence was higher among women than men (95% vs 74%), “so there might be a different genomic spectrum of females to males,” she said.
Another 14% had other driver mutations identified, most of which also were targetable. Of note, this group included a young man found to have a previously unknown EGFR kinase domain duplication who had a response to afatinib (Cancer Discov. 2015 Aug. 18. doi: 10.1158/2159-8290.CD-15-0654). “So a new, actionable EGFR mutation has been discovered through looking at young-emergent lung cancer,” noted Dr. Gitlitz.
“We hypothesized that this cohort may be a special population enriched for driver mutations, but we have far exceeded our statistical expectations, with the majority having an actionable mutation for which they are on targeted therapy, greater than 76%,” she said. “A website allowing for virtual consenting so that patients can participate remotely and use social networking to share trial information is a novel, feasible way to conduct research across continents.”
“We will continue accrual for at least another year, and my plea at this international congress is that we would very much love more international participation,” she concluded. “Ultimately, we plan a follow-up study, Epidemiology of Young Lung Cancer, to build upon our unique web-based, patient-engaged trial design.”
Dr. Levy, the discussant, commented, “This study should be lauded … for taking the additional steps to look at both somatic and germline mutations via whole-exome next-generation sequencing, and also pushing the envelope for those who have no matching mutation in evaluating relevant alterations via next-generation sequencing and cell-free DNA.”
He also commended the novel web-based recruitment and consenting design, saying, “We have to put this in the context that only 5% of all lung cancer patients go on clinical trials. Anything we can do that’s novel or outside the box, as done here, is a welcome change.”
ALK translocations predominate
In the second study, Dr. Kosuke Tanaka of the department of thoracic oncology at Aichi Cancer Center Hospital in Nagoya, Japan, performed retrospective genomic screening of 67 consecutive patients who received a diagnosis of lung adenocarcinoma when aged 40 years or younger.
All patients had evaluation for EGFR and KRAS mutations, and most had evaluation for ALK translocations. Those negative for all three had additional testing.
The patients had a median age of 36 years, 60% were female, and 68% had stage IV disease, Dr. Tanaka reported. The majority, 61%, were former or current smokers.
Overall, 82% of the patients were found to have targetable alterations of driver oncogenes. The most common were ALK translocation (seen in 45%) and EGFR mutation (27%); KRAS mutation was uncommon (3%). Among 15 patients known to be negative for all of these, analyses identified HER2 mutations in three and RET mutations in two.
Driver mutations were more common among patients who had no or only a light smoking history, compared with peers who smoked (89% vs. 72%, P = .069). ALK translocation was more common in patients with stage IV disease (58% vs. 18%, P = .002).
“Early-emerging adenocarcinoma has a very high possibility of having some targetable driver oncogenes,” Dr. Tanaka concluded. “Among younger populations, examination of all known oncogenes, including minor ones, is strongly recommended.”
Data finger genes involved in cell adhesion
In the third study, investigators performed genomic analysis in 20 patients from the Cleveland Clinic who underwent surgery for non–small-cell lung cancer (NSCLC) that was diagnosed at age 45 years or younger.
Overall, 60% were female and 65% had smoked at some time, reported lead author Dr. Patrick C. Ma of the Mary Babb Randolph Cancer Center at West Virginia University, Morgantown, and the Sun Yat-sen University Cancer Center’s State Key Laboratory of Oncology in South China and the Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Some 55% of patients had adenocarcinomas, and 20% had stage IV disease. Of note, 25% had a history of some other type of cancer and 60% had a first-degree relative with a cancer diagnosis.
The somatic mutation rate was much higher in ever-smokers than never-smokers (3.47 vs. 0.76 per megabase). The former value “is a relatively high mutational burden, standing shoulder to shoulder with melanoma and bladder cancer,” Dr. Ma pointed out.
Mutations of key driver genes such as TP53 and KRAS were seen exclusively in smokers, but EGFR mutations were more often seen in never-smokers.
Further analyses indicated that genes involved in cell adhesion and epithelial-mesenchymal transition (EMT) showed a sevenfold enrichment in mutation frequency in the cohort, compared with that seen in the lung cancer data set of the Cancer Genome Atlas.
“Our study nominated novel candidate genes and pathways especially related to cell adhesion and EMT process that potentially may play a role in early-onset NSCLC, whether in smokers or nonsmokers,” Dr. Ma said.
“Further analysis and validation of our findings will improve our understanding of lung cancer pathogenesis, especially in younger patients, and eventually lead to precision therapies to benefit these younger patients,” he concluded.
Dr. Gitlitz disclosed that she is on the speakers bureaus of Genentech and Eli Lilly. Dr. Tanaka and Dr. Ma disclosed that they had no relevant conflicts of interest.
DENVER – Genomic testing in young patients with lung cancer is critical, as the majority have adenocarcinomas harboring driver alterations that can be targeted with drugs available today, suggested a trio of cohort studies presented at a conference sponsored by the International Association for the Study of Lung Cancer.
More than three-fourths of patients aged 40 years or younger with adenocarcinoma were found to have driver alterations in genes such as those for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1), investigators reported in a session and related press conference.
“Lung cancer under 40 is a group of patients who are enriched for actionable mutations,” commented invited discussant Dr. Benjamin Levy, assistant professor of medicine, Mount Sinai School of Medicine; medical director of the thoracic oncology program for the Mount Sinai Health System; and associate director of the cancer clinical trials office at Mount Sinai Hospital – all in New York. “I think that if there was ever a clinical circumstance in which next-generation sequencing should be performed routinely outside a clinical trial, it’s for these patients under 40.”
Of note, in two of the three studies, the majority of patients had some history of smoking, “suggesting that this lung cancer in patients under 40 is not necessarily a nonsmoking disease,” he said. “It’s wonderful to have great drugs for those patients who do develop lung cancer, but instituting preventive measures for tobacco control and education does wonders.”
New study design expands enrollment options
In the first study, a team led by Dr. Barbara J. Gitlitz, associate professor of clinical medicine at the University of Southern California in Los Angeles, analyzed data from the Genomics of Young Lung Cancer Study, the first to prospectively assess clinical characteristics and genomic alterations of this population.
The study is open to patients younger than 40 years at diagnosis. All are tested for alterations of EGFR, BRAF, HER2, KRAS, ALK, ROS1, and RET, and those negative for alterations in these genes have additional testing.
“One interesting point of our study is that people can enter either through coming to a [brick and mortar] site that has IRB approval or through a website (https://www.openmednet.org/site/alcmi-goyl) where people can remotely consent anywhere in the world and participate in our clinical trial,” Dr. Gitlitz noted.
In fact, of the 68 patients enrolled in the first year, 44% did so through the website, including some from as far away as Australia, Norway, and Turkey. The patients ranged in age from 16 to 39 years at diagnosis (median, 35 years), and 52% were female. They tended to be never-smokers, Dr. Gitlitz reported.
Fifty of the patients had stage IV adenocarcinoma at diagnosis. In this group, 76% were found to have known actionable driver alterations – most commonly in ALK (44%), EGFR (26%), or ROS1 (6%). The prevalence was higher among women than men (95% vs 74%), “so there might be a different genomic spectrum of females to males,” she said.
Another 14% had other driver mutations identified, most of which also were targetable. Of note, this group included a young man found to have a previously unknown EGFR kinase domain duplication who had a response to afatinib (Cancer Discov. 2015 Aug. 18. doi: 10.1158/2159-8290.CD-15-0654). “So a new, actionable EGFR mutation has been discovered through looking at young-emergent lung cancer,” noted Dr. Gitlitz.
“We hypothesized that this cohort may be a special population enriched for driver mutations, but we have far exceeded our statistical expectations, with the majority having an actionable mutation for which they are on targeted therapy, greater than 76%,” she said. “A website allowing for virtual consenting so that patients can participate remotely and use social networking to share trial information is a novel, feasible way to conduct research across continents.”
“We will continue accrual for at least another year, and my plea at this international congress is that we would very much love more international participation,” she concluded. “Ultimately, we plan a follow-up study, Epidemiology of Young Lung Cancer, to build upon our unique web-based, patient-engaged trial design.”
Dr. Levy, the discussant, commented, “This study should be lauded … for taking the additional steps to look at both somatic and germline mutations via whole-exome next-generation sequencing, and also pushing the envelope for those who have no matching mutation in evaluating relevant alterations via next-generation sequencing and cell-free DNA.”
He also commended the novel web-based recruitment and consenting design, saying, “We have to put this in the context that only 5% of all lung cancer patients go on clinical trials. Anything we can do that’s novel or outside the box, as done here, is a welcome change.”
ALK translocations predominate
In the second study, Dr. Kosuke Tanaka of the department of thoracic oncology at Aichi Cancer Center Hospital in Nagoya, Japan, performed retrospective genomic screening of 67 consecutive patients who received a diagnosis of lung adenocarcinoma when aged 40 years or younger.
All patients had evaluation for EGFR and KRAS mutations, and most had evaluation for ALK translocations. Those negative for all three had additional testing.
The patients had a median age of 36 years, 60% were female, and 68% had stage IV disease, Dr. Tanaka reported. The majority, 61%, were former or current smokers.
Overall, 82% of the patients were found to have targetable alterations of driver oncogenes. The most common were ALK translocation (seen in 45%) and EGFR mutation (27%); KRAS mutation was uncommon (3%). Among 15 patients known to be negative for all of these, analyses identified HER2 mutations in three and RET mutations in two.
Driver mutations were more common among patients who had no or only a light smoking history, compared with peers who smoked (89% vs. 72%, P = .069). ALK translocation was more common in patients with stage IV disease (58% vs. 18%, P = .002).
“Early-emerging adenocarcinoma has a very high possibility of having some targetable driver oncogenes,” Dr. Tanaka concluded. “Among younger populations, examination of all known oncogenes, including minor ones, is strongly recommended.”
Data finger genes involved in cell adhesion
In the third study, investigators performed genomic analysis in 20 patients from the Cleveland Clinic who underwent surgery for non–small-cell lung cancer (NSCLC) that was diagnosed at age 45 years or younger.
Overall, 60% were female and 65% had smoked at some time, reported lead author Dr. Patrick C. Ma of the Mary Babb Randolph Cancer Center at West Virginia University, Morgantown, and the Sun Yat-sen University Cancer Center’s State Key Laboratory of Oncology in South China and the Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Some 55% of patients had adenocarcinomas, and 20% had stage IV disease. Of note, 25% had a history of some other type of cancer and 60% had a first-degree relative with a cancer diagnosis.
The somatic mutation rate was much higher in ever-smokers than never-smokers (3.47 vs. 0.76 per megabase). The former value “is a relatively high mutational burden, standing shoulder to shoulder with melanoma and bladder cancer,” Dr. Ma pointed out.
Mutations of key driver genes such as TP53 and KRAS were seen exclusively in smokers, but EGFR mutations were more often seen in never-smokers.
Further analyses indicated that genes involved in cell adhesion and epithelial-mesenchymal transition (EMT) showed a sevenfold enrichment in mutation frequency in the cohort, compared with that seen in the lung cancer data set of the Cancer Genome Atlas.
“Our study nominated novel candidate genes and pathways especially related to cell adhesion and EMT process that potentially may play a role in early-onset NSCLC, whether in smokers or nonsmokers,” Dr. Ma said.
“Further analysis and validation of our findings will improve our understanding of lung cancer pathogenesis, especially in younger patients, and eventually lead to precision therapies to benefit these younger patients,” he concluded.
Dr. Gitlitz disclosed that she is on the speakers bureaus of Genentech and Eli Lilly. Dr. Tanaka and Dr. Ma disclosed that they had no relevant conflicts of interest.
DENVER – Genomic testing in young patients with lung cancer is critical, as the majority have adenocarcinomas harboring driver alterations that can be targeted with drugs available today, suggested a trio of cohort studies presented at a conference sponsored by the International Association for the Study of Lung Cancer.
More than three-fourths of patients aged 40 years or younger with adenocarcinoma were found to have driver alterations in genes such as those for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1), investigators reported in a session and related press conference.
“Lung cancer under 40 is a group of patients who are enriched for actionable mutations,” commented invited discussant Dr. Benjamin Levy, assistant professor of medicine, Mount Sinai School of Medicine; medical director of the thoracic oncology program for the Mount Sinai Health System; and associate director of the cancer clinical trials office at Mount Sinai Hospital – all in New York. “I think that if there was ever a clinical circumstance in which next-generation sequencing should be performed routinely outside a clinical trial, it’s for these patients under 40.”
Of note, in two of the three studies, the majority of patients had some history of smoking, “suggesting that this lung cancer in patients under 40 is not necessarily a nonsmoking disease,” he said. “It’s wonderful to have great drugs for those patients who do develop lung cancer, but instituting preventive measures for tobacco control and education does wonders.”
New study design expands enrollment options
In the first study, a team led by Dr. Barbara J. Gitlitz, associate professor of clinical medicine at the University of Southern California in Los Angeles, analyzed data from the Genomics of Young Lung Cancer Study, the first to prospectively assess clinical characteristics and genomic alterations of this population.
The study is open to patients younger than 40 years at diagnosis. All are tested for alterations of EGFR, BRAF, HER2, KRAS, ALK, ROS1, and RET, and those negative for alterations in these genes have additional testing.
“One interesting point of our study is that people can enter either through coming to a [brick and mortar] site that has IRB approval or through a website (https://www.openmednet.org/site/alcmi-goyl) where people can remotely consent anywhere in the world and participate in our clinical trial,” Dr. Gitlitz noted.
In fact, of the 68 patients enrolled in the first year, 44% did so through the website, including some from as far away as Australia, Norway, and Turkey. The patients ranged in age from 16 to 39 years at diagnosis (median, 35 years), and 52% were female. They tended to be never-smokers, Dr. Gitlitz reported.
Fifty of the patients had stage IV adenocarcinoma at diagnosis. In this group, 76% were found to have known actionable driver alterations – most commonly in ALK (44%), EGFR (26%), or ROS1 (6%). The prevalence was higher among women than men (95% vs 74%), “so there might be a different genomic spectrum of females to males,” she said.
Another 14% had other driver mutations identified, most of which also were targetable. Of note, this group included a young man found to have a previously unknown EGFR kinase domain duplication who had a response to afatinib (Cancer Discov. 2015 Aug. 18. doi: 10.1158/2159-8290.CD-15-0654). “So a new, actionable EGFR mutation has been discovered through looking at young-emergent lung cancer,” noted Dr. Gitlitz.
“We hypothesized that this cohort may be a special population enriched for driver mutations, but we have far exceeded our statistical expectations, with the majority having an actionable mutation for which they are on targeted therapy, greater than 76%,” she said. “A website allowing for virtual consenting so that patients can participate remotely and use social networking to share trial information is a novel, feasible way to conduct research across continents.”
“We will continue accrual for at least another year, and my plea at this international congress is that we would very much love more international participation,” she concluded. “Ultimately, we plan a follow-up study, Epidemiology of Young Lung Cancer, to build upon our unique web-based, patient-engaged trial design.”
Dr. Levy, the discussant, commented, “This study should be lauded … for taking the additional steps to look at both somatic and germline mutations via whole-exome next-generation sequencing, and also pushing the envelope for those who have no matching mutation in evaluating relevant alterations via next-generation sequencing and cell-free DNA.”
He also commended the novel web-based recruitment and consenting design, saying, “We have to put this in the context that only 5% of all lung cancer patients go on clinical trials. Anything we can do that’s novel or outside the box, as done here, is a welcome change.”
ALK translocations predominate
In the second study, Dr. Kosuke Tanaka of the department of thoracic oncology at Aichi Cancer Center Hospital in Nagoya, Japan, performed retrospective genomic screening of 67 consecutive patients who received a diagnosis of lung adenocarcinoma when aged 40 years or younger.
All patients had evaluation for EGFR and KRAS mutations, and most had evaluation for ALK translocations. Those negative for all three had additional testing.
The patients had a median age of 36 years, 60% were female, and 68% had stage IV disease, Dr. Tanaka reported. The majority, 61%, were former or current smokers.
Overall, 82% of the patients were found to have targetable alterations of driver oncogenes. The most common were ALK translocation (seen in 45%) and EGFR mutation (27%); KRAS mutation was uncommon (3%). Among 15 patients known to be negative for all of these, analyses identified HER2 mutations in three and RET mutations in two.
Driver mutations were more common among patients who had no or only a light smoking history, compared with peers who smoked (89% vs. 72%, P = .069). ALK translocation was more common in patients with stage IV disease (58% vs. 18%, P = .002).
“Early-emerging adenocarcinoma has a very high possibility of having some targetable driver oncogenes,” Dr. Tanaka concluded. “Among younger populations, examination of all known oncogenes, including minor ones, is strongly recommended.”
Data finger genes involved in cell adhesion
In the third study, investigators performed genomic analysis in 20 patients from the Cleveland Clinic who underwent surgery for non–small-cell lung cancer (NSCLC) that was diagnosed at age 45 years or younger.
Overall, 60% were female and 65% had smoked at some time, reported lead author Dr. Patrick C. Ma of the Mary Babb Randolph Cancer Center at West Virginia University, Morgantown, and the Sun Yat-sen University Cancer Center’s State Key Laboratory of Oncology in South China and the Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Some 55% of patients had adenocarcinomas, and 20% had stage IV disease. Of note, 25% had a history of some other type of cancer and 60% had a first-degree relative with a cancer diagnosis.
The somatic mutation rate was much higher in ever-smokers than never-smokers (3.47 vs. 0.76 per megabase). The former value “is a relatively high mutational burden, standing shoulder to shoulder with melanoma and bladder cancer,” Dr. Ma pointed out.
Mutations of key driver genes such as TP53 and KRAS were seen exclusively in smokers, but EGFR mutations were more often seen in never-smokers.
Further analyses indicated that genes involved in cell adhesion and epithelial-mesenchymal transition (EMT) showed a sevenfold enrichment in mutation frequency in the cohort, compared with that seen in the lung cancer data set of the Cancer Genome Atlas.
“Our study nominated novel candidate genes and pathways especially related to cell adhesion and EMT process that potentially may play a role in early-onset NSCLC, whether in smokers or nonsmokers,” Dr. Ma said.
“Further analysis and validation of our findings will improve our understanding of lung cancer pathogenesis, especially in younger patients, and eventually lead to precision therapies to benefit these younger patients,” he concluded.
Dr. Gitlitz disclosed that she is on the speakers bureaus of Genentech and Eli Lilly. Dr. Tanaka and Dr. Ma disclosed that they had no relevant conflicts of interest.
AT THE IASLC WORLD CONFERENCE
Key clinical point: The majority of young patients with lung cancer have mutations for which targeted therapies are available.
Major finding: Actionable mutations were found in more than 76% of patients with stage IV adenocarcinoma and in 82% of patients with any-stage adenocarcinoma. Sizable proportions of patients had a smoking history.
Data source: Three cohort studies in 68 patients younger than 40 years, 67 patients aged 40 or younger, and 20 patients aged 45 or younger at lung cancer diagnosis.
Disclosures: Dr. Gitlitz reported that she is on the speakers bureaus of Genentech and Eli Lilly. Dr. Tanaka reported that he had no relevant conflicts of interest. Dr. Ma reported that he had no relevant conflicts of interest.
SWITCH 1 supports carboplatin-vinorelbine regimen in early NSCLC
DENVER – An adjuvant regimen of carboplatin plus vinorelbine is well tolerated and efficacious in patients who have undergone complete resection of early non–small cell lung cancer (NSCLC), results from a multicenter phase II trial suggested.
The 74 patients in SWITCH 1 received carboplatin plus intravenous vinorelbine on day 1, with a switch to oral vinorelbine on day 8. A total of four cycles of a 21-day regimen were planned.
Main results reported at a world lung cancer conference sponsored by the International Association for the Study of Lung Cancer showed that the regimen was well tolerated, with higher-grade neutropenia seen in only about a quarter of patients and no deaths because of toxicity. More than four-fifths of patients completed all of the planned treatment, and median survival was nearly 6 years.
“Adjuvant chemotherapy with carboplatin and vinorelbine given [intravenously] and switched to oral formula is feasible, tolerable, and effective in early-stage NSCLC,” commented first author Dr. Vitezslav Kolek, a pulmonary oncologist at University Hospital in Olomouc, Czech Republic.
Although comparison with large phase III adjuvant trials is problematic, he acknowledged, “this regimen gives better comfort to the patients, and provides high dose intensity and more completed treatments, compared with cisplatin-based trials. And the present regimen achieved comparable survival to cisplatin-based therapy.”
“The take-home message could be that we don’t have reliable, routinely used predictors in the adjuvant setting. Under these conditions, probably the most intensive [therapy] doesn’t mean the best,” he concluded.
Invited discussant Dr. Giorgio V. Scagliotti of the department of oncology at the University of Torino (Italy), expressed some reservations about the trial. He took issue with the lack of presentation of a statistical hypothesis and with the cross-trial comparison, and he noted that the study population differed somewhat from that typically seen in the clinic.
“The most proven regimen is cisplatin-vinorelbine. … Cisplatin doublets with proven efficacy in advanced disease remain the standard of care for adjuvant chemotherapy,” he contended. “For elderly or unfit patients, carboplatin may be considered in individual cases.”
Introducing the trial, Dr. Kolek noted that carboplatin and cisplatin have not been directly compared in the adjuvant setting. The combination of cisplatin and vinorelbine, however, is known to result in some deaths due to toxicity, and a large share of patients are unable to complete the therapy. In addition, oral vinorelbine seems to perform as well as the intravenous formulation, and patients generally prefer oral therapy, he said.
The patients enrolled in SWITCH 1 had undergone complete resection of stage IB, II, or IIIA NSCLC. The median age was 64 years, and 72% were male. Sixty-two percent had squamous histology.
The mean relative dose intensity was 83% for oral vinorelbine, 93% for intravenous vinorelbine, and 89% for carboplatin, Dr. Kolek reported. The mean number of cycles of chemotherapy received was 3.8 per patient and, overall, 82% of patients completed the planned therapy.
With a median follow-up of 4.7 years, median disease-free and overall survival were 4.4 years and 5.9 years, respectively. Corresponding 5-year rates were 48% and 56%.
The most common grade 3 or 4 toxicities per cycle were neutropenia (seen in 26% of patients), leukopenia (16%), alopecia (12%), and anemia (8%). None of the patients died from treatment toxicity.
Dr. Kolek reported that he receives honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Pierre Fabre, and Roche.
DENVER – An adjuvant regimen of carboplatin plus vinorelbine is well tolerated and efficacious in patients who have undergone complete resection of early non–small cell lung cancer (NSCLC), results from a multicenter phase II trial suggested.
The 74 patients in SWITCH 1 received carboplatin plus intravenous vinorelbine on day 1, with a switch to oral vinorelbine on day 8. A total of four cycles of a 21-day regimen were planned.
Main results reported at a world lung cancer conference sponsored by the International Association for the Study of Lung Cancer showed that the regimen was well tolerated, with higher-grade neutropenia seen in only about a quarter of patients and no deaths because of toxicity. More than four-fifths of patients completed all of the planned treatment, and median survival was nearly 6 years.
“Adjuvant chemotherapy with carboplatin and vinorelbine given [intravenously] and switched to oral formula is feasible, tolerable, and effective in early-stage NSCLC,” commented first author Dr. Vitezslav Kolek, a pulmonary oncologist at University Hospital in Olomouc, Czech Republic.
Although comparison with large phase III adjuvant trials is problematic, he acknowledged, “this regimen gives better comfort to the patients, and provides high dose intensity and more completed treatments, compared with cisplatin-based trials. And the present regimen achieved comparable survival to cisplatin-based therapy.”
“The take-home message could be that we don’t have reliable, routinely used predictors in the adjuvant setting. Under these conditions, probably the most intensive [therapy] doesn’t mean the best,” he concluded.
Invited discussant Dr. Giorgio V. Scagliotti of the department of oncology at the University of Torino (Italy), expressed some reservations about the trial. He took issue with the lack of presentation of a statistical hypothesis and with the cross-trial comparison, and he noted that the study population differed somewhat from that typically seen in the clinic.
“The most proven regimen is cisplatin-vinorelbine. … Cisplatin doublets with proven efficacy in advanced disease remain the standard of care for adjuvant chemotherapy,” he contended. “For elderly or unfit patients, carboplatin may be considered in individual cases.”
Introducing the trial, Dr. Kolek noted that carboplatin and cisplatin have not been directly compared in the adjuvant setting. The combination of cisplatin and vinorelbine, however, is known to result in some deaths due to toxicity, and a large share of patients are unable to complete the therapy. In addition, oral vinorelbine seems to perform as well as the intravenous formulation, and patients generally prefer oral therapy, he said.
The patients enrolled in SWITCH 1 had undergone complete resection of stage IB, II, or IIIA NSCLC. The median age was 64 years, and 72% were male. Sixty-two percent had squamous histology.
The mean relative dose intensity was 83% for oral vinorelbine, 93% for intravenous vinorelbine, and 89% for carboplatin, Dr. Kolek reported. The mean number of cycles of chemotherapy received was 3.8 per patient and, overall, 82% of patients completed the planned therapy.
With a median follow-up of 4.7 years, median disease-free and overall survival were 4.4 years and 5.9 years, respectively. Corresponding 5-year rates were 48% and 56%.
The most common grade 3 or 4 toxicities per cycle were neutropenia (seen in 26% of patients), leukopenia (16%), alopecia (12%), and anemia (8%). None of the patients died from treatment toxicity.
Dr. Kolek reported that he receives honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Pierre Fabre, and Roche.
DENVER – An adjuvant regimen of carboplatin plus vinorelbine is well tolerated and efficacious in patients who have undergone complete resection of early non–small cell lung cancer (NSCLC), results from a multicenter phase II trial suggested.
The 74 patients in SWITCH 1 received carboplatin plus intravenous vinorelbine on day 1, with a switch to oral vinorelbine on day 8. A total of four cycles of a 21-day regimen were planned.
Main results reported at a world lung cancer conference sponsored by the International Association for the Study of Lung Cancer showed that the regimen was well tolerated, with higher-grade neutropenia seen in only about a quarter of patients and no deaths because of toxicity. More than four-fifths of patients completed all of the planned treatment, and median survival was nearly 6 years.
“Adjuvant chemotherapy with carboplatin and vinorelbine given [intravenously] and switched to oral formula is feasible, tolerable, and effective in early-stage NSCLC,” commented first author Dr. Vitezslav Kolek, a pulmonary oncologist at University Hospital in Olomouc, Czech Republic.
Although comparison with large phase III adjuvant trials is problematic, he acknowledged, “this regimen gives better comfort to the patients, and provides high dose intensity and more completed treatments, compared with cisplatin-based trials. And the present regimen achieved comparable survival to cisplatin-based therapy.”
“The take-home message could be that we don’t have reliable, routinely used predictors in the adjuvant setting. Under these conditions, probably the most intensive [therapy] doesn’t mean the best,” he concluded.
Invited discussant Dr. Giorgio V. Scagliotti of the department of oncology at the University of Torino (Italy), expressed some reservations about the trial. He took issue with the lack of presentation of a statistical hypothesis and with the cross-trial comparison, and he noted that the study population differed somewhat from that typically seen in the clinic.
“The most proven regimen is cisplatin-vinorelbine. … Cisplatin doublets with proven efficacy in advanced disease remain the standard of care for adjuvant chemotherapy,” he contended. “For elderly or unfit patients, carboplatin may be considered in individual cases.”
Introducing the trial, Dr. Kolek noted that carboplatin and cisplatin have not been directly compared in the adjuvant setting. The combination of cisplatin and vinorelbine, however, is known to result in some deaths due to toxicity, and a large share of patients are unable to complete the therapy. In addition, oral vinorelbine seems to perform as well as the intravenous formulation, and patients generally prefer oral therapy, he said.
The patients enrolled in SWITCH 1 had undergone complete resection of stage IB, II, or IIIA NSCLC. The median age was 64 years, and 72% were male. Sixty-two percent had squamous histology.
The mean relative dose intensity was 83% for oral vinorelbine, 93% for intravenous vinorelbine, and 89% for carboplatin, Dr. Kolek reported. The mean number of cycles of chemotherapy received was 3.8 per patient and, overall, 82% of patients completed the planned therapy.
With a median follow-up of 4.7 years, median disease-free and overall survival were 4.4 years and 5.9 years, respectively. Corresponding 5-year rates were 48% and 56%.
The most common grade 3 or 4 toxicities per cycle were neutropenia (seen in 26% of patients), leukopenia (16%), alopecia (12%), and anemia (8%). None of the patients died from treatment toxicity.
Dr. Kolek reported that he receives honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Pierre Fabre, and Roche.
AT THE IASLC WORLD CONFERENCE
Key clinical point: Adjuvant carboplatin plus vinorelbine (intravenous then oral) is well tolerated and efficacious.
Major finding: The rate of grade 3/4 neutropenia was 26%, there were no deaths due to toxicity, and median survival was 5.9 years.
Data source: A single-arm phase II trial among 74 patients with completely resected early NSCLC.
Disclosures: Dr. Kolek reported that he receives honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Pierre Fabre, and Roche.
MAPS: Bevacizumab prolongs survival in mesothelioma
DENVER – Adding the antiangiogenic antibody bevacizumab to chemotherapy improves outcomes in patients who have unresectable mesothelioma, with little downside, according to results of MAPS (the Mesothelioma Avastin Plus Pemetrexed-Cisplatin Study).
Median overall survival in the multicenter randomized phase III trial was 2.75 months longer for patients given bevacizumab in addition to the doublet of pemetrexed plus cisplatin, first author Dr. Arnaud Scherpereel reported at a world conference on lung cancer. This benefit was achieved with only a small increase in the rate of grade 3 or 4 toxicity and no detriment to quality of life.
“We feel that the treatment of pemetrexed-cisplatin with bevacizumab is a new treatment paradigm for mesothelioma patients eligible for bevacizumab and not candidates for curative surgery. And I think that most of them may be eligible for this drug because these patients are not so often smokers and [have] lung conservation, they have less comorbidities,” he said. “Perhaps this treatment may be accepted as a new standard of care for these patients.”
The control arm had much better survival than had been seen historically with this chemotherapy, noted Dr. Scherpereel, who is head of the pulmonary and thoracic oncology department and a professor at the University Hospital (CHRU) of Lille, France. This may have been because of the trial’s eligibility criteria, chosen to ensure that patients could receive bevacizumab, or to the facts that patients had to be fit enough to undergo thoracoscopy and that some received pleurodesis before enrollment.
Bevacizumab benefit may therefore differ in other patients, he acknowledged. “We will see in the real life. I hope first to have the drug [available] for this indication,” he said an the conference sponsored by the International Association for the Study of Lung Cancer.
Press conference moderator Dr. James R. Jett, conference cochair and a professor of medicine at National Jewish Health in Denver, noted that pemetrexed-cisplatin remains the standard of care in the United States. “We don’t have bevacizumab as the standard, but this [trial] may very well change that,” he said.
He wondered if the unusually good outcomes in the control arm were related to earlier diagnosis, but said that regardless, bevacizumab still showed a benefit. “I think the main message here is that it’s important to do concurrent controls because if we were comparing to a historic control, it would be very difficult,” he said.
MAPS was sponsored by the French Cooperative Thoracic Intergroup and was open to patients with mesothelioma who were not candidates for surgery and had not received chemotherapy. Those who had pleural effusion were allowed to undergo a talc pleurodesis at the time of diagnostic thoracoscopy.
A total of 448 patients were randomized to open-label cisplatin and pemetrexed, with versus without bevacizumab (Avastin). The bevacizumab group additionally received the drug alone as maintenance therapy after completing chemotherapy. Cross-over was not allowed.
With a median follow-up of 39.4 months, the bevacizumab arm had better median overall survival (18.82 vs. 16.07 months; hazard ratio, 0.76; P = .015)—the trial’s primary endpoint—and progression-free survival (9.59 vs. 7.48 months; hazard ratio, 0.61; P less than .0001).
“Usually the progression-free survival in the trials with best medical treatment was between 6 and 7 months,” Dr. Scherpereel pointed out. Similarly, “the best [overall survival] results with the standard treatment is close to 13 months.”
“There was no significant difference between the two arms in the percentage of drug delivery or the percentage of patients having second-line treatment which could explain the increase of survival in the bevacizumab arm,” he reported.
The proportion of patients experiencing grade 3 or 4 toxicity was higher with bevacizumab (71.2% vs. 62.1%; P = .04), largely because of more nonhematologic toxicity such as hypertension and venous thromboembolism. However, this additional toxicity was manageable, according to Dr. Scherpereel.
Furthermore, in terms of quality of life measures, patients in the bevacizumab arm had a greater improvement in fatigue from baseline (P = .046) and scores for other measures did not differ between arms.
“We did not find some predictive clinical or biological marker [of bevacizumab benefit] for this study,” he said. In particular, patients’ pretreatment levels of vascular endothelial growth factor (VEGF) did not identify a group more likely to benefit. But an ongoing companion study is still evaluating other biomarkers, such as mesothelin and endocan, he added.
Dr. Scherpereel disclosed that he and coinvestigators had affiliations with Roche and other companies. Roche supplied bevacizumab and a research grant for the biomarker studies.
DENVER – Adding the antiangiogenic antibody bevacizumab to chemotherapy improves outcomes in patients who have unresectable mesothelioma, with little downside, according to results of MAPS (the Mesothelioma Avastin Plus Pemetrexed-Cisplatin Study).
Median overall survival in the multicenter randomized phase III trial was 2.75 months longer for patients given bevacizumab in addition to the doublet of pemetrexed plus cisplatin, first author Dr. Arnaud Scherpereel reported at a world conference on lung cancer. This benefit was achieved with only a small increase in the rate of grade 3 or 4 toxicity and no detriment to quality of life.
“We feel that the treatment of pemetrexed-cisplatin with bevacizumab is a new treatment paradigm for mesothelioma patients eligible for bevacizumab and not candidates for curative surgery. And I think that most of them may be eligible for this drug because these patients are not so often smokers and [have] lung conservation, they have less comorbidities,” he said. “Perhaps this treatment may be accepted as a new standard of care for these patients.”
The control arm had much better survival than had been seen historically with this chemotherapy, noted Dr. Scherpereel, who is head of the pulmonary and thoracic oncology department and a professor at the University Hospital (CHRU) of Lille, France. This may have been because of the trial’s eligibility criteria, chosen to ensure that patients could receive bevacizumab, or to the facts that patients had to be fit enough to undergo thoracoscopy and that some received pleurodesis before enrollment.
Bevacizumab benefit may therefore differ in other patients, he acknowledged. “We will see in the real life. I hope first to have the drug [available] for this indication,” he said an the conference sponsored by the International Association for the Study of Lung Cancer.
Press conference moderator Dr. James R. Jett, conference cochair and a professor of medicine at National Jewish Health in Denver, noted that pemetrexed-cisplatin remains the standard of care in the United States. “We don’t have bevacizumab as the standard, but this [trial] may very well change that,” he said.
He wondered if the unusually good outcomes in the control arm were related to earlier diagnosis, but said that regardless, bevacizumab still showed a benefit. “I think the main message here is that it’s important to do concurrent controls because if we were comparing to a historic control, it would be very difficult,” he said.
MAPS was sponsored by the French Cooperative Thoracic Intergroup and was open to patients with mesothelioma who were not candidates for surgery and had not received chemotherapy. Those who had pleural effusion were allowed to undergo a talc pleurodesis at the time of diagnostic thoracoscopy.
A total of 448 patients were randomized to open-label cisplatin and pemetrexed, with versus without bevacizumab (Avastin). The bevacizumab group additionally received the drug alone as maintenance therapy after completing chemotherapy. Cross-over was not allowed.
With a median follow-up of 39.4 months, the bevacizumab arm had better median overall survival (18.82 vs. 16.07 months; hazard ratio, 0.76; P = .015)—the trial’s primary endpoint—and progression-free survival (9.59 vs. 7.48 months; hazard ratio, 0.61; P less than .0001).
“Usually the progression-free survival in the trials with best medical treatment was between 6 and 7 months,” Dr. Scherpereel pointed out. Similarly, “the best [overall survival] results with the standard treatment is close to 13 months.”
“There was no significant difference between the two arms in the percentage of drug delivery or the percentage of patients having second-line treatment which could explain the increase of survival in the bevacizumab arm,” he reported.
The proportion of patients experiencing grade 3 or 4 toxicity was higher with bevacizumab (71.2% vs. 62.1%; P = .04), largely because of more nonhematologic toxicity such as hypertension and venous thromboembolism. However, this additional toxicity was manageable, according to Dr. Scherpereel.
Furthermore, in terms of quality of life measures, patients in the bevacizumab arm had a greater improvement in fatigue from baseline (P = .046) and scores for other measures did not differ between arms.
“We did not find some predictive clinical or biological marker [of bevacizumab benefit] for this study,” he said. In particular, patients’ pretreatment levels of vascular endothelial growth factor (VEGF) did not identify a group more likely to benefit. But an ongoing companion study is still evaluating other biomarkers, such as mesothelin and endocan, he added.
Dr. Scherpereel disclosed that he and coinvestigators had affiliations with Roche and other companies. Roche supplied bevacizumab and a research grant for the biomarker studies.
DENVER – Adding the antiangiogenic antibody bevacizumab to chemotherapy improves outcomes in patients who have unresectable mesothelioma, with little downside, according to results of MAPS (the Mesothelioma Avastin Plus Pemetrexed-Cisplatin Study).
Median overall survival in the multicenter randomized phase III trial was 2.75 months longer for patients given bevacizumab in addition to the doublet of pemetrexed plus cisplatin, first author Dr. Arnaud Scherpereel reported at a world conference on lung cancer. This benefit was achieved with only a small increase in the rate of grade 3 or 4 toxicity and no detriment to quality of life.
“We feel that the treatment of pemetrexed-cisplatin with bevacizumab is a new treatment paradigm for mesothelioma patients eligible for bevacizumab and not candidates for curative surgery. And I think that most of them may be eligible for this drug because these patients are not so often smokers and [have] lung conservation, they have less comorbidities,” he said. “Perhaps this treatment may be accepted as a new standard of care for these patients.”
The control arm had much better survival than had been seen historically with this chemotherapy, noted Dr. Scherpereel, who is head of the pulmonary and thoracic oncology department and a professor at the University Hospital (CHRU) of Lille, France. This may have been because of the trial’s eligibility criteria, chosen to ensure that patients could receive bevacizumab, or to the facts that patients had to be fit enough to undergo thoracoscopy and that some received pleurodesis before enrollment.
Bevacizumab benefit may therefore differ in other patients, he acknowledged. “We will see in the real life. I hope first to have the drug [available] for this indication,” he said an the conference sponsored by the International Association for the Study of Lung Cancer.
Press conference moderator Dr. James R. Jett, conference cochair and a professor of medicine at National Jewish Health in Denver, noted that pemetrexed-cisplatin remains the standard of care in the United States. “We don’t have bevacizumab as the standard, but this [trial] may very well change that,” he said.
He wondered if the unusually good outcomes in the control arm were related to earlier diagnosis, but said that regardless, bevacizumab still showed a benefit. “I think the main message here is that it’s important to do concurrent controls because if we were comparing to a historic control, it would be very difficult,” he said.
MAPS was sponsored by the French Cooperative Thoracic Intergroup and was open to patients with mesothelioma who were not candidates for surgery and had not received chemotherapy. Those who had pleural effusion were allowed to undergo a talc pleurodesis at the time of diagnostic thoracoscopy.
A total of 448 patients were randomized to open-label cisplatin and pemetrexed, with versus without bevacizumab (Avastin). The bevacizumab group additionally received the drug alone as maintenance therapy after completing chemotherapy. Cross-over was not allowed.
With a median follow-up of 39.4 months, the bevacizumab arm had better median overall survival (18.82 vs. 16.07 months; hazard ratio, 0.76; P = .015)—the trial’s primary endpoint—and progression-free survival (9.59 vs. 7.48 months; hazard ratio, 0.61; P less than .0001).
“Usually the progression-free survival in the trials with best medical treatment was between 6 and 7 months,” Dr. Scherpereel pointed out. Similarly, “the best [overall survival] results with the standard treatment is close to 13 months.”
“There was no significant difference between the two arms in the percentage of drug delivery or the percentage of patients having second-line treatment which could explain the increase of survival in the bevacizumab arm,” he reported.
The proportion of patients experiencing grade 3 or 4 toxicity was higher with bevacizumab (71.2% vs. 62.1%; P = .04), largely because of more nonhematologic toxicity such as hypertension and venous thromboembolism. However, this additional toxicity was manageable, according to Dr. Scherpereel.
Furthermore, in terms of quality of life measures, patients in the bevacizumab arm had a greater improvement in fatigue from baseline (P = .046) and scores for other measures did not differ between arms.
“We did not find some predictive clinical or biological marker [of bevacizumab benefit] for this study,” he said. In particular, patients’ pretreatment levels of vascular endothelial growth factor (VEGF) did not identify a group more likely to benefit. But an ongoing companion study is still evaluating other biomarkers, such as mesothelin and endocan, he added.
Dr. Scherpereel disclosed that he and coinvestigators had affiliations with Roche and other companies. Roche supplied bevacizumab and a research grant for the biomarker studies.
AT THE IASLC WORLD CONFERENCE
Key clinical point: Adding bevacizumab to pemetrexed and cisplatin prolonged overall survival by almost 3 months.
Major finding: Median overall survival was 18.82 months with bevacizumab and 16.07 months without it (P = .015).
Data source: A randomized phase III trial among 448 patients with mesothelioma who were not surgical candidates.
Disclosures: Dr. Scherpereel disclosed that he and his coinvestigators had affiliations with Roche and other companies. Roche supplied bevacizumab and a research grant for the biomarker studies.
Lung adenocarcinomas: mutations you don’t want to miss
SEATTLE – Many advanced non–small cell lung cancer (NSCLC) adenocarcinomas can now be managed with therapies that target driving mutations, but oncologists must look for these mutations and be aware that they can change over time, Dr. Mark A. Socinski said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.
The 2013 College of American Pathology guideline for the molecular testing of lung cancer “was a monumental publication and a beachhead, if you will, for establishing a standard of care [for NSCLC], much like we have in breast cancer for ER, PR, and HER2 measurement,” he said. Furthermore, “we are now in an era where doing subsequent or sequential biopsies with repeat molecular testing is a standard of care in this population.”
Although lung adenocarcinomas are homogeneous histologically, they are diverse with respect to oncogenic drivers (JAMA 2014;311[19]:1998-2006), noted Dr. Socinski, director of the lung cancer section at the University of Pittsburgh Medical Center; clinical associate director of the University of Pittsburgh Lung Cancer SPORE; codirector of the UPMC Lung Cancer Center of Excellence; and coleader of the lung cancer program at the University of Pittsburgh.
“Our major nemesis is KRAS. We still don’t have a good answer for that,” he said. But roughly a third of lung adenocarcinomas have actionable mutations in the genes for EGFR [epidermal growth factor receptor], ALK, ROS1, BRAF, MET, or RET.
“In the year 2015, these are what I look for in our patient population … We test routinely to identify these populations,” he said. “In my clinic this week, I might have had almost all of these patients on targeted TKIs [tyrosine kinase inhibitors] with these sorts of things, getting clinical benefit in this particular setting.”
Common mutations
“The EGFR mutation story really transformed lung cancer,” Dr. Socinski said. In patients whose adenocarcinomas harbor these mutations, targeted therapy with an EGFR inhibitor commonly nets a dramatic response. “If you see this a number of times and you’re a lung cancer doc, you become addicted to oncotype testing. And you certainly don’t want to ever miss this,” he said.
The IPASS trial (First-Line Iressa Versus Carboplatin/Paclitaxel in Asia) comparing the targeted agent gefitinib (Iressa) with chemotherapy in advanced NSCLC adenocarcinoma among never or light smokers was “a transformational trial in lung cancer,” according to Dr. Socinski (N Engl J Med. 2009;361[10]:947-57).
“The lesson from IPASS: phenotype we threw out the door, it’s really about genotype. And if you didn’t have the genotype [EGFR mutation], a TKI was very poor treatment. And if you had the genotype, the TKI was superior to chemotherapy,” with a 52% reduction in the risk of progression or death.
Trials testing the EGFR inhibitors erlotinib (Tarceva) and afatinib (Gilotrif) have likewise shown a progression-free survival benefit in this patient population.
“One of the issues that we struggled with for some time was whether there is any survival benefit,” Dr. Socinski said. A recent combined analysis of two afatinib trials has answered that question affirmatively (Lancet Oncol. 2015;16[2]:141-151), and these agents have therefore become standard of care for EGFR-mutant adenocarcinoma.
“Interestingly, as we say, all EGFR mutants are not created equal, because in the exon 21[–mutated tumors], actually there was no difference relative to chemotherapy, and that survival advantage is really driven by exon 19. So the nature of your mutation is important in this particular analysis,” he cautioned.
When patients on EGFR targeted therapy develop resistance, the cause in about half of cases is emergence of a secondary mutation in exon 20, the T790M mutation (Sci Transl Med. 2011;3(75):75ra26).
“The standard of care is to biopsy at the time of progression,” Dr. Socinski maintained. “The reason why rebiopsy is important and it’s important to diagnose that [new mutation] is that we have a couple of drugs close to [Food and Drug Administration] approval that are highly active in patients with T790M-positive disease after a first- or second-generation TKI.”
Specifically, the investigational third-generation TKIs rociletinib (ASCO 2015. Abstract 8001) and AZD9291 (ASCO 2014. Abstract 8009) have response rates of about 48% and 53%, respectively, in this setting. “This looks quite promising. And these drugs will likely be commercially available between now and the holidays at the end of the year,” he predicted.
The T790M mutation can appear at different times, he said. “I’ve even got several patients whom we’ve rebiopsied three or four times, and there has been T790M negativity and then emergence of positivity on subsequent biopsy. Given the activity of these drugs, that’s important to know.”
Another fairly common actionable mutation in lung adenocarcinoma is ALK, for which oncologists now have crizotinib (Xalkori). Crizotinib has likewise been tested against combination chemotherapy in a phase III trial in which it yielded superior progression-free survival in patients with advanced nonsquamous NSCLC harboring ALK mutations (ASCO 2014. Abstract 8002).
“This is now a second example with a molecular biomarker in which we’ve replaced the standard of care chemotherapy with a molecularly targeted agent,” Dr. Socinski noted.
Second-generation ALK inhibitors such as the investigational agent alectinib are showing promise (ASCO 2015. Abstract 8008). “Even in previously crizotinib-exposed patients, these have a great deal of activity and allow another option for sequential therapy in this population of patients,” he said.
Uncommon mutations
Driving mutations of ROS1 are found in about 1%-2% of lung cancers, most often in younger never-smokers with adenocarcinomas, according to Dr. Socinski.
These tumors respond to crizotinib, which is also a ROS1 inhibitor. “In fact I think it may actually be a better ROS1 drug than an ALK drug,” he said.
The drug yields an impressive median progression-free survival of 19.2 months and overall response rate of 72% in this setting (N Engl J Med. 2014;371[21]:1963-1971), “so ROS1 is another biomarker that we go hunting for in this population, even though you won’t see it very commonly.”
Mutations of BRAF are found in about 2% of metastatic adenocarcinomas (Cancer. 2015;121[3]:448-456). The large majority, about fourth-fifths, are of the V600E type.
The BRAF inhibitor dabrafenib (Tafinlar) has been associated with an overall response rate of 32% in patients with this specific mutation (abstract LBA38, Ann Oncol. 2014;25[Suppl 4]. doi:10.1093/annonc/mdu438.46). And preliminary data suggest efficacy increases when it is combined with the Mek inhibitor trametinib (Mekinist) (ASCO 2015. Abstract 8006), as has been seen in melanoma.
About 4% of lung cancers have an intermediate or high level of MET amplification. In a small sample of patients with these tumors, treatment with crizotinib appeared to be active (ASCO 2014. Abstract 8001). In addition, this agent has efficacy against lung cancers having exon 14 splice mutations in MET (ASCO 2015. Abstract 8021). “So this is another genotype not to miss,” Dr. Socinski said.
Finally, mutation of RET is seen about 1%-2% of unselected NSCLCs, also typically in young never-smokers or former smokers with adenocarcinoma. Cabozantinib (Cometriq), a multitargeted TKI having activity against RET, yields a 28% response rate in RET-rearranged adenocarcinomas (ASCO 2015. Abstract 8007).
A controversial topic for these uncommon mutations in lung adenocarcinomas is how much evidence should be required for new targeted agents to gain FDA approval, Dr. Socinski said.
“For instance, the ROS1 experience: Do we really need a randomized trial in a rare genotype to approve this drug [crizotinib] for ROS1-positive patients? I would say, absolutely not,” he concluded.
Dr. Socinski disclosed that he receives fees from Celgene and Genentech, and performs contracted research for Celgene, Clovis, Genentech, GlaxoSmithKline, Pfizer, and Synta.
SEATTLE – Many advanced non–small cell lung cancer (NSCLC) adenocarcinomas can now be managed with therapies that target driving mutations, but oncologists must look for these mutations and be aware that they can change over time, Dr. Mark A. Socinski said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.
The 2013 College of American Pathology guideline for the molecular testing of lung cancer “was a monumental publication and a beachhead, if you will, for establishing a standard of care [for NSCLC], much like we have in breast cancer for ER, PR, and HER2 measurement,” he said. Furthermore, “we are now in an era where doing subsequent or sequential biopsies with repeat molecular testing is a standard of care in this population.”
Although lung adenocarcinomas are homogeneous histologically, they are diverse with respect to oncogenic drivers (JAMA 2014;311[19]:1998-2006), noted Dr. Socinski, director of the lung cancer section at the University of Pittsburgh Medical Center; clinical associate director of the University of Pittsburgh Lung Cancer SPORE; codirector of the UPMC Lung Cancer Center of Excellence; and coleader of the lung cancer program at the University of Pittsburgh.
“Our major nemesis is KRAS. We still don’t have a good answer for that,” he said. But roughly a third of lung adenocarcinomas have actionable mutations in the genes for EGFR [epidermal growth factor receptor], ALK, ROS1, BRAF, MET, or RET.
“In the year 2015, these are what I look for in our patient population … We test routinely to identify these populations,” he said. “In my clinic this week, I might have had almost all of these patients on targeted TKIs [tyrosine kinase inhibitors] with these sorts of things, getting clinical benefit in this particular setting.”
Common mutations
“The EGFR mutation story really transformed lung cancer,” Dr. Socinski said. In patients whose adenocarcinomas harbor these mutations, targeted therapy with an EGFR inhibitor commonly nets a dramatic response. “If you see this a number of times and you’re a lung cancer doc, you become addicted to oncotype testing. And you certainly don’t want to ever miss this,” he said.
The IPASS trial (First-Line Iressa Versus Carboplatin/Paclitaxel in Asia) comparing the targeted agent gefitinib (Iressa) with chemotherapy in advanced NSCLC adenocarcinoma among never or light smokers was “a transformational trial in lung cancer,” according to Dr. Socinski (N Engl J Med. 2009;361[10]:947-57).
“The lesson from IPASS: phenotype we threw out the door, it’s really about genotype. And if you didn’t have the genotype [EGFR mutation], a TKI was very poor treatment. And if you had the genotype, the TKI was superior to chemotherapy,” with a 52% reduction in the risk of progression or death.
Trials testing the EGFR inhibitors erlotinib (Tarceva) and afatinib (Gilotrif) have likewise shown a progression-free survival benefit in this patient population.
“One of the issues that we struggled with for some time was whether there is any survival benefit,” Dr. Socinski said. A recent combined analysis of two afatinib trials has answered that question affirmatively (Lancet Oncol. 2015;16[2]:141-151), and these agents have therefore become standard of care for EGFR-mutant adenocarcinoma.
“Interestingly, as we say, all EGFR mutants are not created equal, because in the exon 21[–mutated tumors], actually there was no difference relative to chemotherapy, and that survival advantage is really driven by exon 19. So the nature of your mutation is important in this particular analysis,” he cautioned.
When patients on EGFR targeted therapy develop resistance, the cause in about half of cases is emergence of a secondary mutation in exon 20, the T790M mutation (Sci Transl Med. 2011;3(75):75ra26).
“The standard of care is to biopsy at the time of progression,” Dr. Socinski maintained. “The reason why rebiopsy is important and it’s important to diagnose that [new mutation] is that we have a couple of drugs close to [Food and Drug Administration] approval that are highly active in patients with T790M-positive disease after a first- or second-generation TKI.”
Specifically, the investigational third-generation TKIs rociletinib (ASCO 2015. Abstract 8001) and AZD9291 (ASCO 2014. Abstract 8009) have response rates of about 48% and 53%, respectively, in this setting. “This looks quite promising. And these drugs will likely be commercially available between now and the holidays at the end of the year,” he predicted.
The T790M mutation can appear at different times, he said. “I’ve even got several patients whom we’ve rebiopsied three or four times, and there has been T790M negativity and then emergence of positivity on subsequent biopsy. Given the activity of these drugs, that’s important to know.”
Another fairly common actionable mutation in lung adenocarcinoma is ALK, for which oncologists now have crizotinib (Xalkori). Crizotinib has likewise been tested against combination chemotherapy in a phase III trial in which it yielded superior progression-free survival in patients with advanced nonsquamous NSCLC harboring ALK mutations (ASCO 2014. Abstract 8002).
“This is now a second example with a molecular biomarker in which we’ve replaced the standard of care chemotherapy with a molecularly targeted agent,” Dr. Socinski noted.
Second-generation ALK inhibitors such as the investigational agent alectinib are showing promise (ASCO 2015. Abstract 8008). “Even in previously crizotinib-exposed patients, these have a great deal of activity and allow another option for sequential therapy in this population of patients,” he said.
Uncommon mutations
Driving mutations of ROS1 are found in about 1%-2% of lung cancers, most often in younger never-smokers with adenocarcinomas, according to Dr. Socinski.
These tumors respond to crizotinib, which is also a ROS1 inhibitor. “In fact I think it may actually be a better ROS1 drug than an ALK drug,” he said.
The drug yields an impressive median progression-free survival of 19.2 months and overall response rate of 72% in this setting (N Engl J Med. 2014;371[21]:1963-1971), “so ROS1 is another biomarker that we go hunting for in this population, even though you won’t see it very commonly.”
Mutations of BRAF are found in about 2% of metastatic adenocarcinomas (Cancer. 2015;121[3]:448-456). The large majority, about fourth-fifths, are of the V600E type.
The BRAF inhibitor dabrafenib (Tafinlar) has been associated with an overall response rate of 32% in patients with this specific mutation (abstract LBA38, Ann Oncol. 2014;25[Suppl 4]. doi:10.1093/annonc/mdu438.46). And preliminary data suggest efficacy increases when it is combined with the Mek inhibitor trametinib (Mekinist) (ASCO 2015. Abstract 8006), as has been seen in melanoma.
About 4% of lung cancers have an intermediate or high level of MET amplification. In a small sample of patients with these tumors, treatment with crizotinib appeared to be active (ASCO 2014. Abstract 8001). In addition, this agent has efficacy against lung cancers having exon 14 splice mutations in MET (ASCO 2015. Abstract 8021). “So this is another genotype not to miss,” Dr. Socinski said.
Finally, mutation of RET is seen about 1%-2% of unselected NSCLCs, also typically in young never-smokers or former smokers with adenocarcinoma. Cabozantinib (Cometriq), a multitargeted TKI having activity against RET, yields a 28% response rate in RET-rearranged adenocarcinomas (ASCO 2015. Abstract 8007).
A controversial topic for these uncommon mutations in lung adenocarcinomas is how much evidence should be required for new targeted agents to gain FDA approval, Dr. Socinski said.
“For instance, the ROS1 experience: Do we really need a randomized trial in a rare genotype to approve this drug [crizotinib] for ROS1-positive patients? I would say, absolutely not,” he concluded.
Dr. Socinski disclosed that he receives fees from Celgene and Genentech, and performs contracted research for Celgene, Clovis, Genentech, GlaxoSmithKline, Pfizer, and Synta.
SEATTLE – Many advanced non–small cell lung cancer (NSCLC) adenocarcinomas can now be managed with therapies that target driving mutations, but oncologists must look for these mutations and be aware that they can change over time, Dr. Mark A. Socinski said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.
The 2013 College of American Pathology guideline for the molecular testing of lung cancer “was a monumental publication and a beachhead, if you will, for establishing a standard of care [for NSCLC], much like we have in breast cancer for ER, PR, and HER2 measurement,” he said. Furthermore, “we are now in an era where doing subsequent or sequential biopsies with repeat molecular testing is a standard of care in this population.”
Although lung adenocarcinomas are homogeneous histologically, they are diverse with respect to oncogenic drivers (JAMA 2014;311[19]:1998-2006), noted Dr. Socinski, director of the lung cancer section at the University of Pittsburgh Medical Center; clinical associate director of the University of Pittsburgh Lung Cancer SPORE; codirector of the UPMC Lung Cancer Center of Excellence; and coleader of the lung cancer program at the University of Pittsburgh.
“Our major nemesis is KRAS. We still don’t have a good answer for that,” he said. But roughly a third of lung adenocarcinomas have actionable mutations in the genes for EGFR [epidermal growth factor receptor], ALK, ROS1, BRAF, MET, or RET.
“In the year 2015, these are what I look for in our patient population … We test routinely to identify these populations,” he said. “In my clinic this week, I might have had almost all of these patients on targeted TKIs [tyrosine kinase inhibitors] with these sorts of things, getting clinical benefit in this particular setting.”
Common mutations
“The EGFR mutation story really transformed lung cancer,” Dr. Socinski said. In patients whose adenocarcinomas harbor these mutations, targeted therapy with an EGFR inhibitor commonly nets a dramatic response. “If you see this a number of times and you’re a lung cancer doc, you become addicted to oncotype testing. And you certainly don’t want to ever miss this,” he said.
The IPASS trial (First-Line Iressa Versus Carboplatin/Paclitaxel in Asia) comparing the targeted agent gefitinib (Iressa) with chemotherapy in advanced NSCLC adenocarcinoma among never or light smokers was “a transformational trial in lung cancer,” according to Dr. Socinski (N Engl J Med. 2009;361[10]:947-57).
“The lesson from IPASS: phenotype we threw out the door, it’s really about genotype. And if you didn’t have the genotype [EGFR mutation], a TKI was very poor treatment. And if you had the genotype, the TKI was superior to chemotherapy,” with a 52% reduction in the risk of progression or death.
Trials testing the EGFR inhibitors erlotinib (Tarceva) and afatinib (Gilotrif) have likewise shown a progression-free survival benefit in this patient population.
“One of the issues that we struggled with for some time was whether there is any survival benefit,” Dr. Socinski said. A recent combined analysis of two afatinib trials has answered that question affirmatively (Lancet Oncol. 2015;16[2]:141-151), and these agents have therefore become standard of care for EGFR-mutant adenocarcinoma.
“Interestingly, as we say, all EGFR mutants are not created equal, because in the exon 21[–mutated tumors], actually there was no difference relative to chemotherapy, and that survival advantage is really driven by exon 19. So the nature of your mutation is important in this particular analysis,” he cautioned.
When patients on EGFR targeted therapy develop resistance, the cause in about half of cases is emergence of a secondary mutation in exon 20, the T790M mutation (Sci Transl Med. 2011;3(75):75ra26).
“The standard of care is to biopsy at the time of progression,” Dr. Socinski maintained. “The reason why rebiopsy is important and it’s important to diagnose that [new mutation] is that we have a couple of drugs close to [Food and Drug Administration] approval that are highly active in patients with T790M-positive disease after a first- or second-generation TKI.”
Specifically, the investigational third-generation TKIs rociletinib (ASCO 2015. Abstract 8001) and AZD9291 (ASCO 2014. Abstract 8009) have response rates of about 48% and 53%, respectively, in this setting. “This looks quite promising. And these drugs will likely be commercially available between now and the holidays at the end of the year,” he predicted.
The T790M mutation can appear at different times, he said. “I’ve even got several patients whom we’ve rebiopsied three or four times, and there has been T790M negativity and then emergence of positivity on subsequent biopsy. Given the activity of these drugs, that’s important to know.”
Another fairly common actionable mutation in lung adenocarcinoma is ALK, for which oncologists now have crizotinib (Xalkori). Crizotinib has likewise been tested against combination chemotherapy in a phase III trial in which it yielded superior progression-free survival in patients with advanced nonsquamous NSCLC harboring ALK mutations (ASCO 2014. Abstract 8002).
“This is now a second example with a molecular biomarker in which we’ve replaced the standard of care chemotherapy with a molecularly targeted agent,” Dr. Socinski noted.
Second-generation ALK inhibitors such as the investigational agent alectinib are showing promise (ASCO 2015. Abstract 8008). “Even in previously crizotinib-exposed patients, these have a great deal of activity and allow another option for sequential therapy in this population of patients,” he said.
Uncommon mutations
Driving mutations of ROS1 are found in about 1%-2% of lung cancers, most often in younger never-smokers with adenocarcinomas, according to Dr. Socinski.
These tumors respond to crizotinib, which is also a ROS1 inhibitor. “In fact I think it may actually be a better ROS1 drug than an ALK drug,” he said.
The drug yields an impressive median progression-free survival of 19.2 months and overall response rate of 72% in this setting (N Engl J Med. 2014;371[21]:1963-1971), “so ROS1 is another biomarker that we go hunting for in this population, even though you won’t see it very commonly.”
Mutations of BRAF are found in about 2% of metastatic adenocarcinomas (Cancer. 2015;121[3]:448-456). The large majority, about fourth-fifths, are of the V600E type.
The BRAF inhibitor dabrafenib (Tafinlar) has been associated with an overall response rate of 32% in patients with this specific mutation (abstract LBA38, Ann Oncol. 2014;25[Suppl 4]. doi:10.1093/annonc/mdu438.46). And preliminary data suggest efficacy increases when it is combined with the Mek inhibitor trametinib (Mekinist) (ASCO 2015. Abstract 8006), as has been seen in melanoma.
About 4% of lung cancers have an intermediate or high level of MET amplification. In a small sample of patients with these tumors, treatment with crizotinib appeared to be active (ASCO 2014. Abstract 8001). In addition, this agent has efficacy against lung cancers having exon 14 splice mutations in MET (ASCO 2015. Abstract 8021). “So this is another genotype not to miss,” Dr. Socinski said.
Finally, mutation of RET is seen about 1%-2% of unselected NSCLCs, also typically in young never-smokers or former smokers with adenocarcinoma. Cabozantinib (Cometriq), a multitargeted TKI having activity against RET, yields a 28% response rate in RET-rearranged adenocarcinomas (ASCO 2015. Abstract 8007).
A controversial topic for these uncommon mutations in lung adenocarcinomas is how much evidence should be required for new targeted agents to gain FDA approval, Dr. Socinski said.
“For instance, the ROS1 experience: Do we really need a randomized trial in a rare genotype to approve this drug [crizotinib] for ROS1-positive patients? I would say, absolutely not,” he concluded.
Dr. Socinski disclosed that he receives fees from Celgene and Genentech, and performs contracted research for Celgene, Clovis, Genentech, GlaxoSmithKline, Pfizer, and Synta.
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