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Democratic Lawmakers Press Pfizer on Chemotherapy Drug Shortages
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
In a statement about their February 21 action, the legislators, led by Rep. Jamie Raskin (D-Md.), the committee’s ranking minority member, described their work as a follow up to an earlier investigation into price hikes of generic drugs. While the committee members queried Pfizer over the three oncology medications only, they also sent letters to drugmakers Teva and Sandoz with respect to shortages in other drug classes.
A representative for Pfizer confirmed to MDedge Oncology that the company had received the representatives’ letter but said “we have no further details to provide at this time.”
What is the basis for concern?
All three generic chemotherapy drugs are mainstay treatments used across a broad array of cancers. Though shortages have been reported for several years, they became especially acute after December 2022, when an inspection by the US Food and Drug Administration (FDA) led to regulatory action against an Indian manufacturer, Intas, that produced up to half of the platinum-based therapies supplied globally. The National Comprehensive Cancer Care Network reported in October 2023 that more than 90% of its member centers were struggling to maintain adequate supplies of carboplatin, and 70% had trouble obtaining cisplatin, while the American Society of Clinical Oncology published clinical guidance on alternative treatment strategies.
What has the government done in response to the recent shortages?
The White House and the FDA announced in September that they were working with several manufacturers to help increase supplies of the platinum-based chemotherapies and of methotrexate, and taking measures that included relaxing rules on imports. Recent guidance under a pandemic-era federal law, the 2020 CARES Act, strengthened manufacturer reporting requirements related to drug shortages, and other measures have been proposed. While federal regulators have many tools with which to address drug shortages, they cannot legally oblige a manufacturer to increase production of a drug.
What can the lawmakers expect to achieve with their letter?
By pressuring Pfizer publicly, the lawmakers may be able to nudge the company to take measures to assure more consistent supplies of the three drugs. The lawmakers also said they hoped to glean from Pfizer more insight into the root causes of the shortages and potential remedies. They noted that, in a May 2023 letter by Pfizer to customers, the company had warned of depleted and limited supplies of the three drugs and said it was “working diligently” to increase output. However, the lawmakers wrote, “the root cause is not yet resolved and carboplatin, cisplatin, and methotrexate continue to experience residual delays.”
Why did the committee target Pfizer specifically?
Pfizer and its subsidiaries are among the major manufacturers of the three generic chemotherapy agents mentioned in the letter. The legislators noted that “pharmaceutical companies may not be motivated to produce generic drugs like carboplatin, cisplatin, and methotrexate, because they are not as lucrative as producing patented brand name drugs,” and that “as a principal supplier of carboplatin, cisplatin, and methotrexate, it is critical that Pfizer continues to increase production of these life-sustaining cancer medications, even amidst potential lower profitability.”
The committee members also made reference to news reports of price-gouging with these medications, as smaller hospitals or oncology centers are forced to turn to unscrupulous third-party suppliers.
What is being demanded of Pfizer?
Pfizer was given until March 6 to respond, in writing and in a briefing with committee staff, to a six questions. These queries concern what specific steps the company has taken to increase supplies of the three generic oncology drugs, what Pfizer is doing to help avert price-gouging, whether further oncology drug shortages are anticipated, and how the company is working with the FDA on the matter.
Unleashing Our Immune Response to Quash Cancer
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”
It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.
Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.
Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.
And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.
As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.
Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.
An Ever-Expanding Armamentarium
Immune Checkpoint Inhibitors
The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.
But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.
Therapeutic Cancer Vaccines
There are many therapeutic cancer vaccines in the works, as reviewed in depth here.
Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.
An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.
Antibody-Drug Conjugates (ADC)
There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.
A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.
This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.
Oncolytic Viruses
Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.
After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.
Engineering T Cells (Chimeric Antigen Receptor [CAR-T])
As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.
As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.
Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.
Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.
Summary
Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.
Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.
Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.
Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.
Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.
A version of this article appeared on Medscape.com.
Mantle Cell Lymphoma: Drug Combo Improves PFS
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
Still, “in the countries where ibrutinib is indicated, this combination should be a new standard therapy for relapsed/refractory mantle cell lymphoma,” Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in a media briefing at the annual meeting of the American Society of Hematology.
Its use would be off label, according to the authors of the industry-funded trial, because no nation has approved the combination therapy for MCL, a rare, aggressive form of non-Hodgkin lymphoma.
As Dr. Wang noted, ibrutinib (a Bruton tyrosine kinase inhibitor) is approved by the Food and Drug Administration to treat MCL, while venetoclax (a BCL-2 inhibitor) is approved for chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. “The combination of these two agents leverages complementary modes of action and has demonstrated synergistic anti-tumor activity in preclinical models of mantle cell lymphoma,” he said. And “in patients with relapsed/refractory mantle cell lymphoma, promising clinical activity has also been observed in early-phase studies.”
For the multinational, randomized, phase 3, double-blind SYMPATICO study, researchers assigned 267 adults with relapsed/refractory MCL after 1-5 prior therapies 1:1 to receive oral ibrutinib 560 mg daily with oral venetoclax (standard 5-wk ramp-up to a target dose of 400 mg once daily) or placebo for 2 years. Then they continued with ibrutinib alone until progressive disease or unacceptable toxicity.
The study began in 2017. The median age of patients was 68, and the numbers of patients in each group were 134 (both drugs) and 133 (ibrutinib plus placebo).
At a median of 51.2 months, median PFS — the primary endpoint — was higher in the combination group vs. ibrutinib alone (31.9 vs. 22.1 months, hazard ratio [HR]=0.65, 95% CI, 0.47–0.88, P = .0052). While overall survival was higher in the combination group vs. ibrutinib alone, an interim analysis found that the difference was not statistically significant (44.9 months vs. 38.6 months, 95% CI, HR = 0.85, 0.62-1.19, P = .3465).
When questioned about this finding at the ASH news briefing, Dr. Wang said that 170 events are needed for a full overall survival analysis, and there are just 144 now. The study may reach that point in early 2025, he said.
Over a median treatment duration of 22.0 months for the combination treatment and 17.7 months for ibrutinib alone, grade ≥ 3 adverse events occurred in 84% and 76% of patients, respectively. At 60%, the level of serious adverse events was the same in both groups.
In an interview, Brian T. Hill, MD, PhD, of Cleveland Clinic, noted that in general, MCL “has a pretty relentless pattern of relapses and disease progression without an easy cure in the vast majority of patients.”
Ibrutinib has revolutionized treatment over the past decade with generally manageable side effects, and clinicians are now turning to other Bruton tyrosine kinase inhibitors, he said. Still, “there is a need for improving the durability and the response rates second-line treatment or beyond,” Dr. Hill said.
The new study is important since it’s the first randomized trial “that demonstrates that additional venetoclax significantly improves not only response rates, but also progression-free survival with a trend toward overall survival,” he said. “The toxicity profile doesn’t really seem to be significantly more worse than what we might expect with each agent given individually.”
However, Dr. Hill noted that “it’s a relatively small study and relatively short follow-up.”
It may be difficult to get an ibrutinib-venetoclax combination approved today since ibrutinib is no longer the preferred Bruton tyrosine kinase inhibitor for clinicians, he said.
Pharmacyclics, maker of ibrutinib, is the study sponsor and Janssen is a collaborator.
Dr. Wang reports research funding Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Other authors report multiple and various relationships with industry. Dr. Hill discloses research funding and consulting relationships with Pharmacyclics, AbbVie, BeiGene, and AstraZeneca.
FROM ASH 2023
FDA approves pirtobrutinib for previously treated CLL/SLL
The agent was initially approved in January 2023 for patients with mantle cell lymphoma who had previously received a BTK inhibitor.
Like the mantle cell approval, the CLL/SLL approval was based on findings from the open-label, single-arm, phase 1/2 BRUIN study that included adults with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
The trial included 108 patients with either CLL or SLL. Overall, patients demonstrated an overall response rate of 72%, all of which were partial responses, and median duration of response of 12.2 months.
Before starting pirtobrutinib, 77% of patients with CLL or SLL had discontinued their last BTK inhibitor for refractory or progressive disease.
“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients,” William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, said in an Eli Lilly press release.
Treatment during the study included the recommended dose of 200 mg given orally once daily until disease progression or unacceptable toxicity. Common adverse reactions that occurred in at least 20% of patients included fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. Grade 3 or 4 laboratory abnormalities occurring in more than 10% of patients included decreased neutrophil counts, anemia, and decreased platelet counts.
Serious infections occurred in 32% of patients, including fatal infections in 10% of patients. The prescribing information for pirtobrutinib includes warnings about infections, hemorrhage, cytopenias, cardiac arrhythmias, and secondary primary malignancies.
A version of this article first appeared on Medscape.com.
The agent was initially approved in January 2023 for patients with mantle cell lymphoma who had previously received a BTK inhibitor.
Like the mantle cell approval, the CLL/SLL approval was based on findings from the open-label, single-arm, phase 1/2 BRUIN study that included adults with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
The trial included 108 patients with either CLL or SLL. Overall, patients demonstrated an overall response rate of 72%, all of which were partial responses, and median duration of response of 12.2 months.
Before starting pirtobrutinib, 77% of patients with CLL or SLL had discontinued their last BTK inhibitor for refractory or progressive disease.
“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients,” William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, said in an Eli Lilly press release.
Treatment during the study included the recommended dose of 200 mg given orally once daily until disease progression or unacceptable toxicity. Common adverse reactions that occurred in at least 20% of patients included fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. Grade 3 or 4 laboratory abnormalities occurring in more than 10% of patients included decreased neutrophil counts, anemia, and decreased platelet counts.
Serious infections occurred in 32% of patients, including fatal infections in 10% of patients. The prescribing information for pirtobrutinib includes warnings about infections, hemorrhage, cytopenias, cardiac arrhythmias, and secondary primary malignancies.
A version of this article first appeared on Medscape.com.
The agent was initially approved in January 2023 for patients with mantle cell lymphoma who had previously received a BTK inhibitor.
Like the mantle cell approval, the CLL/SLL approval was based on findings from the open-label, single-arm, phase 1/2 BRUIN study that included adults with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
The trial included 108 patients with either CLL or SLL. Overall, patients demonstrated an overall response rate of 72%, all of which were partial responses, and median duration of response of 12.2 months.
Before starting pirtobrutinib, 77% of patients with CLL or SLL had discontinued their last BTK inhibitor for refractory or progressive disease.
“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients,” William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, said in an Eli Lilly press release.
Treatment during the study included the recommended dose of 200 mg given orally once daily until disease progression or unacceptable toxicity. Common adverse reactions that occurred in at least 20% of patients included fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. Grade 3 or 4 laboratory abnormalities occurring in more than 10% of patients included decreased neutrophil counts, anemia, and decreased platelet counts.
Serious infections occurred in 32% of patients, including fatal infections in 10% of patients. The prescribing information for pirtobrutinib includes warnings about infections, hemorrhage, cytopenias, cardiac arrhythmias, and secondary primary malignancies.
A version of this article first appeared on Medscape.com.
FDA OKs new agent to block chemotherapy-induced neutropenia
Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.
The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.
The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.
The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.
During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.
The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.
The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.
A version of this article first appeared on Medscape.com.
Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.
The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.
The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.
The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.
During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.
The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.
The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.
A version of this article first appeared on Medscape.com.
Efbemalenograstim joins other agents already on the U.S. market, including pegfilgrastim (Neulasta), that aim to reduce the incidence of chemotherapy-induced febrile neutropenia.
The approval of efbemalenograstim was based on two randomized trials. The first included 122 women with either metastatic or nonmetastatic breast cancer who were receiving doxorubicin and docetaxel. These patients were randomly assigned to receive either one subcutaneous injection of efbemalenograstim or placebo on the second day of their first chemotherapy cycle. All patients received efbemalenograstim on the second day of cycles two through four.
The mean duration of grade 4 neutropenia in the first cycle was 1.4 days with efbemalenograstim versus 4.3 days with placebo. Only 4.8% of patients who received efbemalenograstim experienced chemotherapy-induced febrile neutropenia, compared with 25.6% who received the placebo.
The new agent went up against pegfilgrastim in the second trial, which included 393 women who received docetaxel and cyclophosphamide as treatment for nonmetastatic breast cancer. These patients were randomly assigned to receive either a single subcutaneous injection of efbemalenograstim or pegfilgrastim on the second day of each cycle.
During the first cycle, patients in both arms of the trial experienced a mean of 0.2 days of grade 4 neutropenia.
The most common side effects associated with efbemalenograstim were nausea, anemia, and thrombocytopenia. Similar to pegfilgrastim’s label, efbemalenograstim’s label warns of possible splenic rupture, respiratory distress syndrome, sickle cell crisis, and other serious adverse events.
The FDA recommends a dose of 20 mg subcutaneous once per chemotherapy cycle.
A version of this article first appeared on Medscape.com.
FDA’s Project Optimus aims to transform early cancer research
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
SAN DIEGO –
The goal is “to better identify and characterize optimized doses” in early stages of research and move away from the default of the traditional maximum tolerated dose strategy, hematologist-oncologist Marc R. Theoret, MD, deputy director of the FDA’s Oncology Center of Excellence, said in a presentation at the 2023 Society for Immunotherapy of Cancer annual meeting.
Earlier this year, the FDA released a draft guidance regarding the changes it hopes to see. The agency supported randomized, parallel dose-response trials when feasible, and “strong rationale for choice of dosage should be provided before initiating a registration trial(s) to support a subsequent indication and usage.”
The goal of controlling toxicity is “very highly important” in hematology research since blood cancer drugs can cause significant adverse effects in areas such as the lungs and heart, said Cecilia Yeung, MD, who led the SITC session about Project Optimus. Dr. Yeung is a clinical pathologist who works on investigational trials at Fred Hutchinson Cancer Research Center in Seattle.
In an interview, Dr. Yeung, who has a subspecialty in hematopathology, explained why the foundations of cancer research are changing and what hematologist-oncologists can expect to see on the horizon.
Q: Project Optimus aims to move beyond the traditional dose-escalation approach to the development of cancer drugs. How does that strategy work?
Dr. Yeung: Prior to Project Optimus, they’d use a 3+3 strategy in phase 1 trials: They’d give a dose to three fairly healthy patients, then they’d go up by escalating doses in more patients. They’d keep going up until two-thirds of patients at a specific dose suffered from bad side effects, then they’d back off to the last dose.
Q: This approach, which aims to identify the “maximum tolerated dose,” seemed to work well over decades of research into chemotherapy drugs. But worries arose as targeted therapies appeared in oncology areas such as blood cancer. Why did things change?
Dr. Yeung: With 3+3, you could tell pretty quickly how toxic chemotherapy was. But in targeted therapy, we were finding that these studies are not representative of actual toxicity. You’re not treating these patients for a very long time in phase 1, while patients on targeted therapy may be on these drugs for years. Concerns actually started with the first targeted drugs to treat leukemias and lymphomas. They were shown to have unexpected toxicity. A 2016 study found that drug developers had to reduce the original phase 1 dose in 45% of phase 3 trials [of small molecule and monoclonal antibody targeted agents] approved by the FDA over 12 years because of toxicity.
Q: What is FDA’s goal for Project Optimus?
Dr. Yeung: They want to have a second piece, to balance that maximum tolerated dose with a safe and tolerable dose for most people.
Q: What kind of resistance is the FDA getting from drug companies?
Dr. Yeung: The FDA makes a good argument that the system wasn’t working. But drug companies say this will drive up the cost of clinical trials and won’t allow them to treat patients with the maximal doses they could give them. I see arguments from both sides. There has to be a balance between the two.
Q: How will all this affect drug development?
Dr. Yeung: Drugs may become more expensive because much more testing will happen during clinical trials.
Q: Could this reduce the number of investigational drugs?
Dr. Yeung: Hopefully not, but this is huge endeavor for smaller companies that are strapped for funding.
Q: What do you think the future holds?
Dr. Yeung: Ultimately, this is a good thing because if everything works out, we’ll have fewer toxic side effects. But we’re going to have to go through a period of growing pains.
AT SITC 2023
DLBCL treatment options: CAR T outperforms ASCT
NEW YORK – according to evidence presented at the 2023 Lymphoma, Leukemia, and Myeloma Congress.
DLBCL is characterized by the National Institutes of Health as an aggressive malignancy and the most common lymphoma. Research presented at the conference indicated that 60%70% of patients were cured with six to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP).
“In the past, if a relapsed of refractory DLBCL patient couldn’t get a transplant, they were likely headed for palliative care. CAR T-cell therapy is no longer experimental. Not only can we offer it to patients who are ineligible for transplant (and manage the side effects), the treatment has proven to offer better overall survival and cure rates, even in patients who eligible for ASCT,” said presenter Jason Westin, MD, director of the lymphoma clinical research program at the University of Texas MD Anderson Cancer Center, Houston.
The ZUMA-7 phase 3trial among patients with early r/r DLBCL demonstrated the superiority of CAR T-cell therapy with the agent, axicabtagene ciloleucel (YESCARTA, Kita Pharma) versus standard of care (chemoimmunotherapy followed by high-dose chemotherapy and ASCT). Those in the axicabtagene ciloleucel (axi-cel) group had a median progression free survival (PFS) of 14.7 months and an estimated 4-year overall survival (OS) rate of 54.6% compared to 3.7 months and 46% in the control group.
Patients treated with axi-cel experienced a higher rate of adverse events (AE) grade 3 of higher, compared with the ACST group (91% vs. 83%) Furthermore, patients who received axi-cel had cytokine release syndrome (6%) and neurologic events in (21%) grade 3 or higher, compared with 0% and less than 1% in the ASCT group.
At the conference, Dr. Westin’s copanelist Jennifer Amengual, MD, of Columbia University Irving Medical Center, New York, interpreted the data on adverse events (AEs) from ZUMA-7 to mean that if a patient is especially susceptible to CAR T side effects, then ASCT could be preferred. She also outlined a second strategy that shows promise when a patient has either failed CAR T and ASCT or whose frailty demands an approach that avoids AEs.
Dr. Amengual cited a study in which patients with r/r DLBCL were treated with the bispecific antibody glofitamab (Columvi/Roche), which induced a complete response in 39% of patients at a median follow-up of 12.6 months and a 12-month PFS rate of 37%. Those treated with the agent experienced cytokine release syndrome and neurologic events grade 3 or higher, at a rate of 4% and 3% respectively.
“Efforts to make off-the-shelf CAR T therapy are ongoing. With some fine-tuning the PFS and OS with bispecific antibodies will likely approach or exceed both CAR T and ACST. The fact that they could come right off the shelf, rather than having to be tailor made for each patient, gives them a huge advantage in terms of cost and availability, while maintaining what appears to be an excellent safety profile” said Morton Colman, MD, professor of medicine at Weill Cornell Medicine, New York, and chair of the 2023 Lymphoma, Leukemia, and Myeloma Congress.
Dr. Amengual disclosed ties with Astra Zeneca and Incyte. Dr. Westin reported ties with Abbie, ADC therapeutics, AstraZeneca, Bristol-Myers Squibb, Genentech, GenMad, Hanssen, Kite/Gilead, Morphosys/Incyte, Novartis, Nurix, Regeneron, and SeaGen. Dr. Coleman had no disclosures.
NEW YORK – according to evidence presented at the 2023 Lymphoma, Leukemia, and Myeloma Congress.
DLBCL is characterized by the National Institutes of Health as an aggressive malignancy and the most common lymphoma. Research presented at the conference indicated that 60%70% of patients were cured with six to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP).
“In the past, if a relapsed of refractory DLBCL patient couldn’t get a transplant, they were likely headed for palliative care. CAR T-cell therapy is no longer experimental. Not only can we offer it to patients who are ineligible for transplant (and manage the side effects), the treatment has proven to offer better overall survival and cure rates, even in patients who eligible for ASCT,” said presenter Jason Westin, MD, director of the lymphoma clinical research program at the University of Texas MD Anderson Cancer Center, Houston.
The ZUMA-7 phase 3trial among patients with early r/r DLBCL demonstrated the superiority of CAR T-cell therapy with the agent, axicabtagene ciloleucel (YESCARTA, Kita Pharma) versus standard of care (chemoimmunotherapy followed by high-dose chemotherapy and ASCT). Those in the axicabtagene ciloleucel (axi-cel) group had a median progression free survival (PFS) of 14.7 months and an estimated 4-year overall survival (OS) rate of 54.6% compared to 3.7 months and 46% in the control group.
Patients treated with axi-cel experienced a higher rate of adverse events (AE) grade 3 of higher, compared with the ACST group (91% vs. 83%) Furthermore, patients who received axi-cel had cytokine release syndrome (6%) and neurologic events in (21%) grade 3 or higher, compared with 0% and less than 1% in the ASCT group.
At the conference, Dr. Westin’s copanelist Jennifer Amengual, MD, of Columbia University Irving Medical Center, New York, interpreted the data on adverse events (AEs) from ZUMA-7 to mean that if a patient is especially susceptible to CAR T side effects, then ASCT could be preferred. She also outlined a second strategy that shows promise when a patient has either failed CAR T and ASCT or whose frailty demands an approach that avoids AEs.
Dr. Amengual cited a study in which patients with r/r DLBCL were treated with the bispecific antibody glofitamab (Columvi/Roche), which induced a complete response in 39% of patients at a median follow-up of 12.6 months and a 12-month PFS rate of 37%. Those treated with the agent experienced cytokine release syndrome and neurologic events grade 3 or higher, at a rate of 4% and 3% respectively.
“Efforts to make off-the-shelf CAR T therapy are ongoing. With some fine-tuning the PFS and OS with bispecific antibodies will likely approach or exceed both CAR T and ACST. The fact that they could come right off the shelf, rather than having to be tailor made for each patient, gives them a huge advantage in terms of cost and availability, while maintaining what appears to be an excellent safety profile” said Morton Colman, MD, professor of medicine at Weill Cornell Medicine, New York, and chair of the 2023 Lymphoma, Leukemia, and Myeloma Congress.
Dr. Amengual disclosed ties with Astra Zeneca and Incyte. Dr. Westin reported ties with Abbie, ADC therapeutics, AstraZeneca, Bristol-Myers Squibb, Genentech, GenMad, Hanssen, Kite/Gilead, Morphosys/Incyte, Novartis, Nurix, Regeneron, and SeaGen. Dr. Coleman had no disclosures.
NEW YORK – according to evidence presented at the 2023 Lymphoma, Leukemia, and Myeloma Congress.
DLBCL is characterized by the National Institutes of Health as an aggressive malignancy and the most common lymphoma. Research presented at the conference indicated that 60%70% of patients were cured with six to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP).
“In the past, if a relapsed of refractory DLBCL patient couldn’t get a transplant, they were likely headed for palliative care. CAR T-cell therapy is no longer experimental. Not only can we offer it to patients who are ineligible for transplant (and manage the side effects), the treatment has proven to offer better overall survival and cure rates, even in patients who eligible for ASCT,” said presenter Jason Westin, MD, director of the lymphoma clinical research program at the University of Texas MD Anderson Cancer Center, Houston.
The ZUMA-7 phase 3trial among patients with early r/r DLBCL demonstrated the superiority of CAR T-cell therapy with the agent, axicabtagene ciloleucel (YESCARTA, Kita Pharma) versus standard of care (chemoimmunotherapy followed by high-dose chemotherapy and ASCT). Those in the axicabtagene ciloleucel (axi-cel) group had a median progression free survival (PFS) of 14.7 months and an estimated 4-year overall survival (OS) rate of 54.6% compared to 3.7 months and 46% in the control group.
Patients treated with axi-cel experienced a higher rate of adverse events (AE) grade 3 of higher, compared with the ACST group (91% vs. 83%) Furthermore, patients who received axi-cel had cytokine release syndrome (6%) and neurologic events in (21%) grade 3 or higher, compared with 0% and less than 1% in the ASCT group.
At the conference, Dr. Westin’s copanelist Jennifer Amengual, MD, of Columbia University Irving Medical Center, New York, interpreted the data on adverse events (AEs) from ZUMA-7 to mean that if a patient is especially susceptible to CAR T side effects, then ASCT could be preferred. She also outlined a second strategy that shows promise when a patient has either failed CAR T and ASCT or whose frailty demands an approach that avoids AEs.
Dr. Amengual cited a study in which patients with r/r DLBCL were treated with the bispecific antibody glofitamab (Columvi/Roche), which induced a complete response in 39% of patients at a median follow-up of 12.6 months and a 12-month PFS rate of 37%. Those treated with the agent experienced cytokine release syndrome and neurologic events grade 3 or higher, at a rate of 4% and 3% respectively.
“Efforts to make off-the-shelf CAR T therapy are ongoing. With some fine-tuning the PFS and OS with bispecific antibodies will likely approach or exceed both CAR T and ACST. The fact that they could come right off the shelf, rather than having to be tailor made for each patient, gives them a huge advantage in terms of cost and availability, while maintaining what appears to be an excellent safety profile” said Morton Colman, MD, professor of medicine at Weill Cornell Medicine, New York, and chair of the 2023 Lymphoma, Leukemia, and Myeloma Congress.
Dr. Amengual disclosed ties with Astra Zeneca and Incyte. Dr. Westin reported ties with Abbie, ADC therapeutics, AstraZeneca, Bristol-Myers Squibb, Genentech, GenMad, Hanssen, Kite/Gilead, Morphosys/Incyte, Novartis, Nurix, Regeneron, and SeaGen. Dr. Coleman had no disclosures.
AT LLM CONGRESS 2023
PD-1 inhibitor improves outcomes in NHL subtype
, while pretreatment mutational profiles offer clues as to which patients may respond to such anti-PD-1 treatments, according to studies presented at the European Society of Medical Oncology (ESMO) Congress 2023.
“We found that toripalimab combined with radiotherapy is safe and has promising efficacy for stage I/II extranodal NK/T cell lymphoma [patients] who have poor response after previous standard chemotherapy,” said first author Ming Jiang, MD, of the department of medical oncology, Cancer Center, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China.
“This combined strategy can not only improve patient efficacy but also avoid unnecessary medication, and is worth further exploration,” she said in a presentation at ESMO on Oct. 27 in Madrid. The current standard of care for extranodal NK/T cell lymphoma, a subtype of non-Hodgkin lymphoma, is L-asparaginase or pegaspargase-based multi-agent chemotherapy combined with radiotherapy.
However, for patients who fail to respond to first-line treatment, the prognosis is poor: The median progression-free survival of those patients is approximately 4.5 months, with a median overall survival of about 6.4 months, Dr. Jiang explained.
“There is a need to establish a better first-line treatment for this group of patients,” she said.
In the prospective, single-arm, multicenter phase 2 study, Dr. Jiang and her colleagues enrolled patients with stage 1 and 2 extranodal NK/T cell lymphoma who had failed to achieve a complete response following 2-3 cycles of multi-agent chemotherapy.
Of the patients, eight (36.4%) had partial response, eight (36.2%) had stable disease, and six (27.2%) had progressive disease after the chemotherapy.
The patients were treated with toripalimab at 240 mg, once every 3 weeks, plus radiotherapy at a dose of 56 Gy, sequentially with or without two to four cycles of chemotherapy.
Patients who did not have disease progression were then continued with toripalimab for 1 year or until disease progression or intolerable toxicity.
The 22 patients had a median age of 45 (range 26-64) and 14 were male. Most were stage 1 (77.3%; 17) and the remaining were stage 2, while 81% had primary tumor invasion.
For the primary endpoint, at 3 months following radiotherapy, the overall response rate was 90.9%, with 17 patients (77.3%) having a complete response, 3 (13.6%) a partial response, and 2 (9.1%) having progressive disease.
Eight who had responded to previous chemotherapy received two additional chemotherapy cycles after completion of radiotherapy, while the others were treated with toripalimab alone.
With a median follow-up of 23 months (range 3-78), the 2-year progression-free survival was 81.6%, and overall survival was 95.0%.
Two of three patients with a partial response had a recurrence after radiotherapy at 5 and 10 months; one of the complete-response patients had a recurrence at 60 months, and two patients with progressive disease died at 9 months after radiotherapy.
In terms of safety, the most common adverse events during and after radiotherapy included oral mucositis and hypothyroidism. No adverse events of grade 3 or higher were reported.
Dr. Jiang speculated that “radiotherapy could synergize PD-1 inhibitors,” and she urged that “optimal radiotherapy and PD-1 inhibitor administration plans should be further explored.”
Genetic factors
Additional research presented in that ESMO session offered insights into the genetic factors that may play key roles in either response or resistance to anti-PD-1 therapy in peripheral T cell lymphoma (PTCL), of which extranodal NK/T cell lymphoma is a subtype.
The findings are from a genetic analysis of a phase 2 trial that demonstrated benefits the PD-1 inhibitor geptanolimab in patients with PTCL who failed initial chemotherapy.
Specifically, geptanolimab treatment was associated with an objective response rate of 40.4%, a complete response rate of 14.6%, and partial response rate of 25.8%.
Of 44 patients who had been treated with geptanolimab and had next-generation sequencing genetic data available, PD-L1 expression was found to be significantly elevated among those who had a complete or partial response, whereas PD-L1 expression was lower among those who had disease progression, which is consistent with previous research suggesting that low PD-L1 expression is linked to poorer response to anti-PD-1 therapies.
Tumor mutation burden did not exhibit significant prognostic value. However, the authors noted that this may be confounded by variation across PTCL subtypes.
Among other key findings were that JAK3 and EZH2 mutations, which are among the top genes frequently mutated in PTCL and extranodal NK/T cell lymphoma, were consistently associated with low PD-L1 expression (P < .05) and shorter progression-free survival (HR 5.97; P = .027, JAK3, and HR 4.76; P = .027 EZH2).
“Notably, we found JAK3 mutations, which are vital and prevalent in PTCL, reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense,” said the study’s first author, Ning Lou, MD, of the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing.
Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand in Dijon, France, said that the findings are especially notable in relation to extranodal NK/T cell lymphoma.
“The clinical relevance of anti PD1 is mainly observed in relapsing/recurrent extranodal NK/T cell lymphoma, and much less in other T-cell lymphoma subtypes,” he told this news organization.
“So identifying molecular events associated with the chance of response to a PD1 blocker in relapsing extranodal NK/T cell lymphoma is important as PD1-blockers are recommended to treat [those] patients,” Dr. Casasnovas added.
Furthermore, “the interest of next-generation sequencing to identify JAK3 mutations associated with low level of PDL1 expression and weak response to anti PD1 blockers is important as JAK3 mutated tumors are potentially targetable by JAK inhibitors such as tofacitinib,” he said.
“Obviously this assumption has to be tested in clinical trials but it’s an interesting lead.”
The research on toripalimab additionally shows that “the combination of radiotherapy and PD1 blockers provides a high response rate in patients who are nonresponders to asparaginase-based chemotherapy on the basis of PET evaluation and could be a new option for optimizing the first line treatment of extranodal NK/T cell lymphoma patients,” Dr. Casasnovas added.
The authors and Dr. Casasnovas had no disclosures to report.
, while pretreatment mutational profiles offer clues as to which patients may respond to such anti-PD-1 treatments, according to studies presented at the European Society of Medical Oncology (ESMO) Congress 2023.
“We found that toripalimab combined with radiotherapy is safe and has promising efficacy for stage I/II extranodal NK/T cell lymphoma [patients] who have poor response after previous standard chemotherapy,” said first author Ming Jiang, MD, of the department of medical oncology, Cancer Center, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China.
“This combined strategy can not only improve patient efficacy but also avoid unnecessary medication, and is worth further exploration,” she said in a presentation at ESMO on Oct. 27 in Madrid. The current standard of care for extranodal NK/T cell lymphoma, a subtype of non-Hodgkin lymphoma, is L-asparaginase or pegaspargase-based multi-agent chemotherapy combined with radiotherapy.
However, for patients who fail to respond to first-line treatment, the prognosis is poor: The median progression-free survival of those patients is approximately 4.5 months, with a median overall survival of about 6.4 months, Dr. Jiang explained.
“There is a need to establish a better first-line treatment for this group of patients,” she said.
In the prospective, single-arm, multicenter phase 2 study, Dr. Jiang and her colleagues enrolled patients with stage 1 and 2 extranodal NK/T cell lymphoma who had failed to achieve a complete response following 2-3 cycles of multi-agent chemotherapy.
Of the patients, eight (36.4%) had partial response, eight (36.2%) had stable disease, and six (27.2%) had progressive disease after the chemotherapy.
The patients were treated with toripalimab at 240 mg, once every 3 weeks, plus radiotherapy at a dose of 56 Gy, sequentially with or without two to four cycles of chemotherapy.
Patients who did not have disease progression were then continued with toripalimab for 1 year or until disease progression or intolerable toxicity.
The 22 patients had a median age of 45 (range 26-64) and 14 were male. Most were stage 1 (77.3%; 17) and the remaining were stage 2, while 81% had primary tumor invasion.
For the primary endpoint, at 3 months following radiotherapy, the overall response rate was 90.9%, with 17 patients (77.3%) having a complete response, 3 (13.6%) a partial response, and 2 (9.1%) having progressive disease.
Eight who had responded to previous chemotherapy received two additional chemotherapy cycles after completion of radiotherapy, while the others were treated with toripalimab alone.
With a median follow-up of 23 months (range 3-78), the 2-year progression-free survival was 81.6%, and overall survival was 95.0%.
Two of three patients with a partial response had a recurrence after radiotherapy at 5 and 10 months; one of the complete-response patients had a recurrence at 60 months, and two patients with progressive disease died at 9 months after radiotherapy.
In terms of safety, the most common adverse events during and after radiotherapy included oral mucositis and hypothyroidism. No adverse events of grade 3 or higher were reported.
Dr. Jiang speculated that “radiotherapy could synergize PD-1 inhibitors,” and she urged that “optimal radiotherapy and PD-1 inhibitor administration plans should be further explored.”
Genetic factors
Additional research presented in that ESMO session offered insights into the genetic factors that may play key roles in either response or resistance to anti-PD-1 therapy in peripheral T cell lymphoma (PTCL), of which extranodal NK/T cell lymphoma is a subtype.
The findings are from a genetic analysis of a phase 2 trial that demonstrated benefits the PD-1 inhibitor geptanolimab in patients with PTCL who failed initial chemotherapy.
Specifically, geptanolimab treatment was associated with an objective response rate of 40.4%, a complete response rate of 14.6%, and partial response rate of 25.8%.
Of 44 patients who had been treated with geptanolimab and had next-generation sequencing genetic data available, PD-L1 expression was found to be significantly elevated among those who had a complete or partial response, whereas PD-L1 expression was lower among those who had disease progression, which is consistent with previous research suggesting that low PD-L1 expression is linked to poorer response to anti-PD-1 therapies.
Tumor mutation burden did not exhibit significant prognostic value. However, the authors noted that this may be confounded by variation across PTCL subtypes.
Among other key findings were that JAK3 and EZH2 mutations, which are among the top genes frequently mutated in PTCL and extranodal NK/T cell lymphoma, were consistently associated with low PD-L1 expression (P < .05) and shorter progression-free survival (HR 5.97; P = .027, JAK3, and HR 4.76; P = .027 EZH2).
“Notably, we found JAK3 mutations, which are vital and prevalent in PTCL, reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense,” said the study’s first author, Ning Lou, MD, of the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing.
Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand in Dijon, France, said that the findings are especially notable in relation to extranodal NK/T cell lymphoma.
“The clinical relevance of anti PD1 is mainly observed in relapsing/recurrent extranodal NK/T cell lymphoma, and much less in other T-cell lymphoma subtypes,” he told this news organization.
“So identifying molecular events associated with the chance of response to a PD1 blocker in relapsing extranodal NK/T cell lymphoma is important as PD1-blockers are recommended to treat [those] patients,” Dr. Casasnovas added.
Furthermore, “the interest of next-generation sequencing to identify JAK3 mutations associated with low level of PDL1 expression and weak response to anti PD1 blockers is important as JAK3 mutated tumors are potentially targetable by JAK inhibitors such as tofacitinib,” he said.
“Obviously this assumption has to be tested in clinical trials but it’s an interesting lead.”
The research on toripalimab additionally shows that “the combination of radiotherapy and PD1 blockers provides a high response rate in patients who are nonresponders to asparaginase-based chemotherapy on the basis of PET evaluation and could be a new option for optimizing the first line treatment of extranodal NK/T cell lymphoma patients,” Dr. Casasnovas added.
The authors and Dr. Casasnovas had no disclosures to report.
, while pretreatment mutational profiles offer clues as to which patients may respond to such anti-PD-1 treatments, according to studies presented at the European Society of Medical Oncology (ESMO) Congress 2023.
“We found that toripalimab combined with radiotherapy is safe and has promising efficacy for stage I/II extranodal NK/T cell lymphoma [patients] who have poor response after previous standard chemotherapy,” said first author Ming Jiang, MD, of the department of medical oncology, Cancer Center, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China.
“This combined strategy can not only improve patient efficacy but also avoid unnecessary medication, and is worth further exploration,” she said in a presentation at ESMO on Oct. 27 in Madrid. The current standard of care for extranodal NK/T cell lymphoma, a subtype of non-Hodgkin lymphoma, is L-asparaginase or pegaspargase-based multi-agent chemotherapy combined with radiotherapy.
However, for patients who fail to respond to first-line treatment, the prognosis is poor: The median progression-free survival of those patients is approximately 4.5 months, with a median overall survival of about 6.4 months, Dr. Jiang explained.
“There is a need to establish a better first-line treatment for this group of patients,” she said.
In the prospective, single-arm, multicenter phase 2 study, Dr. Jiang and her colleagues enrolled patients with stage 1 and 2 extranodal NK/T cell lymphoma who had failed to achieve a complete response following 2-3 cycles of multi-agent chemotherapy.
Of the patients, eight (36.4%) had partial response, eight (36.2%) had stable disease, and six (27.2%) had progressive disease after the chemotherapy.
The patients were treated with toripalimab at 240 mg, once every 3 weeks, plus radiotherapy at a dose of 56 Gy, sequentially with or without two to four cycles of chemotherapy.
Patients who did not have disease progression were then continued with toripalimab for 1 year or until disease progression or intolerable toxicity.
The 22 patients had a median age of 45 (range 26-64) and 14 were male. Most were stage 1 (77.3%; 17) and the remaining were stage 2, while 81% had primary tumor invasion.
For the primary endpoint, at 3 months following radiotherapy, the overall response rate was 90.9%, with 17 patients (77.3%) having a complete response, 3 (13.6%) a partial response, and 2 (9.1%) having progressive disease.
Eight who had responded to previous chemotherapy received two additional chemotherapy cycles after completion of radiotherapy, while the others were treated with toripalimab alone.
With a median follow-up of 23 months (range 3-78), the 2-year progression-free survival was 81.6%, and overall survival was 95.0%.
Two of three patients with a partial response had a recurrence after radiotherapy at 5 and 10 months; one of the complete-response patients had a recurrence at 60 months, and two patients with progressive disease died at 9 months after radiotherapy.
In terms of safety, the most common adverse events during and after radiotherapy included oral mucositis and hypothyroidism. No adverse events of grade 3 or higher were reported.
Dr. Jiang speculated that “radiotherapy could synergize PD-1 inhibitors,” and she urged that “optimal radiotherapy and PD-1 inhibitor administration plans should be further explored.”
Genetic factors
Additional research presented in that ESMO session offered insights into the genetic factors that may play key roles in either response or resistance to anti-PD-1 therapy in peripheral T cell lymphoma (PTCL), of which extranodal NK/T cell lymphoma is a subtype.
The findings are from a genetic analysis of a phase 2 trial that demonstrated benefits the PD-1 inhibitor geptanolimab in patients with PTCL who failed initial chemotherapy.
Specifically, geptanolimab treatment was associated with an objective response rate of 40.4%, a complete response rate of 14.6%, and partial response rate of 25.8%.
Of 44 patients who had been treated with geptanolimab and had next-generation sequencing genetic data available, PD-L1 expression was found to be significantly elevated among those who had a complete or partial response, whereas PD-L1 expression was lower among those who had disease progression, which is consistent with previous research suggesting that low PD-L1 expression is linked to poorer response to anti-PD-1 therapies.
Tumor mutation burden did not exhibit significant prognostic value. However, the authors noted that this may be confounded by variation across PTCL subtypes.
Among other key findings were that JAK3 and EZH2 mutations, which are among the top genes frequently mutated in PTCL and extranodal NK/T cell lymphoma, were consistently associated with low PD-L1 expression (P < .05) and shorter progression-free survival (HR 5.97; P = .027, JAK3, and HR 4.76; P = .027 EZH2).
“Notably, we found JAK3 mutations, which are vital and prevalent in PTCL, reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense,” said the study’s first author, Ning Lou, MD, of the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing.
Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand in Dijon, France, said that the findings are especially notable in relation to extranodal NK/T cell lymphoma.
“The clinical relevance of anti PD1 is mainly observed in relapsing/recurrent extranodal NK/T cell lymphoma, and much less in other T-cell lymphoma subtypes,” he told this news organization.
“So identifying molecular events associated with the chance of response to a PD1 blocker in relapsing extranodal NK/T cell lymphoma is important as PD1-blockers are recommended to treat [those] patients,” Dr. Casasnovas added.
Furthermore, “the interest of next-generation sequencing to identify JAK3 mutations associated with low level of PDL1 expression and weak response to anti PD1 blockers is important as JAK3 mutated tumors are potentially targetable by JAK inhibitors such as tofacitinib,” he said.
“Obviously this assumption has to be tested in clinical trials but it’s an interesting lead.”
The research on toripalimab additionally shows that “the combination of radiotherapy and PD1 blockers provides a high response rate in patients who are nonresponders to asparaginase-based chemotherapy on the basis of PET evaluation and could be a new option for optimizing the first line treatment of extranodal NK/T cell lymphoma patients,” Dr. Casasnovas added.
The authors and Dr. Casasnovas had no disclosures to report.
FROM ESMO 2023
High rate of subsequent cancers in MCC
.
In a cohort of 6,146 patients with a first primary MCC, a total of 725 (11.8%) developed subsequent primary cancers. For solid tumors, the risk was highest for cutaneous melanoma and papillary thyroid carcinoma, while for hematologic cancers, the risk was increased for non-Hodgkin lymphoma.
“Our study does confirm that patients with MCC are at higher risk for developing other cancers,” study author Lisa C. Zaba, MD, PhD, associate professor of dermatology and director of the Merkel cell carcinoma multidisciplinary clinic, Stanford (Calif.) Cancer Center, said in an interview. “MCC is a highly malignant cancer with a 40% recurrence risk.”
Because of this high risk, Dr. Zaba noted that patients with MCC get frequent surveillance with both imaging studies (PET-CT and CT) as well as frequent visits in clinic with MCC experts. “Specifically, a patient with MCC is imaged and seen in clinic every 3-6 months for the first 3 years after diagnosis, and every 6-12 months thereafter for up to 5 years,” she said. “Interestingly, this high level of surveillance may be one reason that we find so many cancers in patients who have been diagnosed with MCC, compared to the general population.”
The study was published online in JAMA Dermatology.
With the death of “Margaritaville” singer Jimmy Buffett, who recently died of MCC 4 years after his diagnosis, this rare, aggressive skin cancer has been put in the spotlight. Survival has been increasing, primarily because of the advent of immunotherapy, and the authors note that it is therefore imperative to better understand the risk of subsequent primary tumors to inform screening and treatment recommendations.
In this cohort study, Dr. Zaba and colleagues identified 6,146 patients from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program who had been diagnosed with a first primary cutaneous MCC between 2000 and 2018.
Endpoints were the ratio of observed to expected number of cases of subsequent cancer (Standardized incidence ratio, or SIR) and the excess risk.
Overall, there was an elevated risk of developing a subsequent primary cancer after being diagnosed with MCC (SIR, 1.28; excess risk, 57.25 per 10,000 person-years). This included the risk for all solid tumors including liver (SIR, 1.92; excess risk, 2.77 per 10,000 person-years), pancreas (SIR, 1.65; excess risk, 4.55 per 10,000 person-years), cutaneous melanoma (SIR, 2.36; excess risk, 15.27 per 10,000 person-years), and kidney (SIR, 1.64; excess risk, 3.83 per 10,000 person-years).
There was also a higher risk of developing papillary thyroid carcinoma (PTC) (SIR, 5.26; excess risk, 6.16 per 10,000 person-years).
The risk of developing hematological cancers after MCC was also increased, especially for non-Hodgkin lymphoma (SIR, 2.62; excess risk, 15.48 per 10,000 person-years) and myelodysplastic syndrome (SIR, 2.17; excess risk, 2.73 per 10,000 person-years).
The risk for developing subsequent tumors, including melanoma and non-Hodgkin lymphoma, remained significant for up to 10 years, while the risk for developing PTC and kidney cancers remained for up to 5 years.
“After 3-5 years, when a MCC patient’s risk of MCC recurrence drops below 2%, we do not currently have guidelines in place for additional cancer screening,” Dr. Zaba said. “Regarding patient education, patients with MCC are educated to let us know if they experience any symptoms of cancer between visits, including unintentional weight loss, night sweats, headaches that increasingly worsen, or growing lumps or bumps. These symptoms may occur in a multitude of cancers and not just MCC.”
Weighing in on the study, Jeffrey M. Farma, MD, interim chair, department of surgical oncology at Fox Chase Cancer Center, Philadelphia, noted that MCC is considered to be high risk because of its chances of recurring after surgical resection or spreading to lymph nodes or other areas of the body. “There are approximately 3,000 new cases of melanoma a year in the U.S., and it is 40 times rarer than melanoma,” he said. “Patients are usually diagnosed with Merkel cell carcinoma later in life, and the tumors have been associated with sun exposure and immunosuppression and have also been associated with the polyomavirus.”
That said, however, he emphasized that great strides have been made in treatment. “These tumors are very sensitive to radiation, and we generally treat earlier-stage MCC with a combination of surgery and radiation therapy,” said Dr. Farma. “More recently we have had a lot of success with the use of immunotherapy to treat more advanced MCC.”
Dr. Zaba reported receiving grants from the Kuni Foundation outside the submitted work. No other disclosures were reported. Author Eleni Linos, MD, DrPH, MPH, is supported by grant K24AR075060 from the National Institutes of Health. No other outside funding was reported. Dr. Farma had no disclosures.
.
In a cohort of 6,146 patients with a first primary MCC, a total of 725 (11.8%) developed subsequent primary cancers. For solid tumors, the risk was highest for cutaneous melanoma and papillary thyroid carcinoma, while for hematologic cancers, the risk was increased for non-Hodgkin lymphoma.
“Our study does confirm that patients with MCC are at higher risk for developing other cancers,” study author Lisa C. Zaba, MD, PhD, associate professor of dermatology and director of the Merkel cell carcinoma multidisciplinary clinic, Stanford (Calif.) Cancer Center, said in an interview. “MCC is a highly malignant cancer with a 40% recurrence risk.”
Because of this high risk, Dr. Zaba noted that patients with MCC get frequent surveillance with both imaging studies (PET-CT and CT) as well as frequent visits in clinic with MCC experts. “Specifically, a patient with MCC is imaged and seen in clinic every 3-6 months for the first 3 years after diagnosis, and every 6-12 months thereafter for up to 5 years,” she said. “Interestingly, this high level of surveillance may be one reason that we find so many cancers in patients who have been diagnosed with MCC, compared to the general population.”
The study was published online in JAMA Dermatology.
With the death of “Margaritaville” singer Jimmy Buffett, who recently died of MCC 4 years after his diagnosis, this rare, aggressive skin cancer has been put in the spotlight. Survival has been increasing, primarily because of the advent of immunotherapy, and the authors note that it is therefore imperative to better understand the risk of subsequent primary tumors to inform screening and treatment recommendations.
In this cohort study, Dr. Zaba and colleagues identified 6,146 patients from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program who had been diagnosed with a first primary cutaneous MCC between 2000 and 2018.
Endpoints were the ratio of observed to expected number of cases of subsequent cancer (Standardized incidence ratio, or SIR) and the excess risk.
Overall, there was an elevated risk of developing a subsequent primary cancer after being diagnosed with MCC (SIR, 1.28; excess risk, 57.25 per 10,000 person-years). This included the risk for all solid tumors including liver (SIR, 1.92; excess risk, 2.77 per 10,000 person-years), pancreas (SIR, 1.65; excess risk, 4.55 per 10,000 person-years), cutaneous melanoma (SIR, 2.36; excess risk, 15.27 per 10,000 person-years), and kidney (SIR, 1.64; excess risk, 3.83 per 10,000 person-years).
There was also a higher risk of developing papillary thyroid carcinoma (PTC) (SIR, 5.26; excess risk, 6.16 per 10,000 person-years).
The risk of developing hematological cancers after MCC was also increased, especially for non-Hodgkin lymphoma (SIR, 2.62; excess risk, 15.48 per 10,000 person-years) and myelodysplastic syndrome (SIR, 2.17; excess risk, 2.73 per 10,000 person-years).
The risk for developing subsequent tumors, including melanoma and non-Hodgkin lymphoma, remained significant for up to 10 years, while the risk for developing PTC and kidney cancers remained for up to 5 years.
“After 3-5 years, when a MCC patient’s risk of MCC recurrence drops below 2%, we do not currently have guidelines in place for additional cancer screening,” Dr. Zaba said. “Regarding patient education, patients with MCC are educated to let us know if they experience any symptoms of cancer between visits, including unintentional weight loss, night sweats, headaches that increasingly worsen, or growing lumps or bumps. These symptoms may occur in a multitude of cancers and not just MCC.”
Weighing in on the study, Jeffrey M. Farma, MD, interim chair, department of surgical oncology at Fox Chase Cancer Center, Philadelphia, noted that MCC is considered to be high risk because of its chances of recurring after surgical resection or spreading to lymph nodes or other areas of the body. “There are approximately 3,000 new cases of melanoma a year in the U.S., and it is 40 times rarer than melanoma,” he said. “Patients are usually diagnosed with Merkel cell carcinoma later in life, and the tumors have been associated with sun exposure and immunosuppression and have also been associated with the polyomavirus.”
That said, however, he emphasized that great strides have been made in treatment. “These tumors are very sensitive to radiation, and we generally treat earlier-stage MCC with a combination of surgery and radiation therapy,” said Dr. Farma. “More recently we have had a lot of success with the use of immunotherapy to treat more advanced MCC.”
Dr. Zaba reported receiving grants from the Kuni Foundation outside the submitted work. No other disclosures were reported. Author Eleni Linos, MD, DrPH, MPH, is supported by grant K24AR075060 from the National Institutes of Health. No other outside funding was reported. Dr. Farma had no disclosures.
.
In a cohort of 6,146 patients with a first primary MCC, a total of 725 (11.8%) developed subsequent primary cancers. For solid tumors, the risk was highest for cutaneous melanoma and papillary thyroid carcinoma, while for hematologic cancers, the risk was increased for non-Hodgkin lymphoma.
“Our study does confirm that patients with MCC are at higher risk for developing other cancers,” study author Lisa C. Zaba, MD, PhD, associate professor of dermatology and director of the Merkel cell carcinoma multidisciplinary clinic, Stanford (Calif.) Cancer Center, said in an interview. “MCC is a highly malignant cancer with a 40% recurrence risk.”
Because of this high risk, Dr. Zaba noted that patients with MCC get frequent surveillance with both imaging studies (PET-CT and CT) as well as frequent visits in clinic with MCC experts. “Specifically, a patient with MCC is imaged and seen in clinic every 3-6 months for the first 3 years after diagnosis, and every 6-12 months thereafter for up to 5 years,” she said. “Interestingly, this high level of surveillance may be one reason that we find so many cancers in patients who have been diagnosed with MCC, compared to the general population.”
The study was published online in JAMA Dermatology.
With the death of “Margaritaville” singer Jimmy Buffett, who recently died of MCC 4 years after his diagnosis, this rare, aggressive skin cancer has been put in the spotlight. Survival has been increasing, primarily because of the advent of immunotherapy, and the authors note that it is therefore imperative to better understand the risk of subsequent primary tumors to inform screening and treatment recommendations.
In this cohort study, Dr. Zaba and colleagues identified 6,146 patients from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program who had been diagnosed with a first primary cutaneous MCC between 2000 and 2018.
Endpoints were the ratio of observed to expected number of cases of subsequent cancer (Standardized incidence ratio, or SIR) and the excess risk.
Overall, there was an elevated risk of developing a subsequent primary cancer after being diagnosed with MCC (SIR, 1.28; excess risk, 57.25 per 10,000 person-years). This included the risk for all solid tumors including liver (SIR, 1.92; excess risk, 2.77 per 10,000 person-years), pancreas (SIR, 1.65; excess risk, 4.55 per 10,000 person-years), cutaneous melanoma (SIR, 2.36; excess risk, 15.27 per 10,000 person-years), and kidney (SIR, 1.64; excess risk, 3.83 per 10,000 person-years).
There was also a higher risk of developing papillary thyroid carcinoma (PTC) (SIR, 5.26; excess risk, 6.16 per 10,000 person-years).
The risk of developing hematological cancers after MCC was also increased, especially for non-Hodgkin lymphoma (SIR, 2.62; excess risk, 15.48 per 10,000 person-years) and myelodysplastic syndrome (SIR, 2.17; excess risk, 2.73 per 10,000 person-years).
The risk for developing subsequent tumors, including melanoma and non-Hodgkin lymphoma, remained significant for up to 10 years, while the risk for developing PTC and kidney cancers remained for up to 5 years.
“After 3-5 years, when a MCC patient’s risk of MCC recurrence drops below 2%, we do not currently have guidelines in place for additional cancer screening,” Dr. Zaba said. “Regarding patient education, patients with MCC are educated to let us know if they experience any symptoms of cancer between visits, including unintentional weight loss, night sweats, headaches that increasingly worsen, or growing lumps or bumps. These symptoms may occur in a multitude of cancers and not just MCC.”
Weighing in on the study, Jeffrey M. Farma, MD, interim chair, department of surgical oncology at Fox Chase Cancer Center, Philadelphia, noted that MCC is considered to be high risk because of its chances of recurring after surgical resection or spreading to lymph nodes or other areas of the body. “There are approximately 3,000 new cases of melanoma a year in the U.S., and it is 40 times rarer than melanoma,” he said. “Patients are usually diagnosed with Merkel cell carcinoma later in life, and the tumors have been associated with sun exposure and immunosuppression and have also been associated with the polyomavirus.”
That said, however, he emphasized that great strides have been made in treatment. “These tumors are very sensitive to radiation, and we generally treat earlier-stage MCC with a combination of surgery and radiation therapy,” said Dr. Farma. “More recently we have had a lot of success with the use of immunotherapy to treat more advanced MCC.”
Dr. Zaba reported receiving grants from the Kuni Foundation outside the submitted work. No other disclosures were reported. Author Eleni Linos, MD, DrPH, MPH, is supported by grant K24AR075060 from the National Institutes of Health. No other outside funding was reported. Dr. Farma had no disclosures.
FROM JAMA DERMATOLOGY
Antibody shows promise in preventing GVHD
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.
“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.
“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”
While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.
Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.
With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.
The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.
Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.
Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.
Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.
“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.
Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.
The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.
The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.
“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”
The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.
“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”
The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.
“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.
Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.
There are currently no approved anti-DLL4 antibody drugs for use in humans.
“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”
Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.
FROM SCIENCE TRANSLATIONAL MEDICINE