Gastrointestinal Cancers Symposium 2016

SAN FRANCISCO – Oxaliplatin has substantial neurotoxicity in older adults with colorectal cancer that should be factored into treatment decision making, suggests a study reported at the Gastrointestinal Cancers Symposium.

The Canadian analysis of more than 3,500 patients found that those aged 70 years or older who received oxaliplatin as part of their adjuvant chemotherapy had a doubling of the risk of a new diagnosis of peripheral neuropathy. The 3-year cumulative incidence in this group approached 8%.

Susan London/Frontline Medical News

“Hopefully, this study will allow patients to make more informed decisions with their clinicians,” first author Dr. Michael J. Raphael said in an interview. “We are able to say to patients that there is a significant risk of developing a neuropathy. Patients need to consider this in terms of their quality of life because as we are curing more and more people with colorectal cancer, even in the elderly, survivorship is becoming a very big issue. And it becomes an individual choice for the patient, if they survive, what level of toxicity are they willing to accept?”

The study didn’t look at oxaliplatin’s efficacy in older adults, he noted. However, some research has called into question the drug’s benefit in this population as well.

“We know that fluorouracil-based chemotherapy is the standard of care for patients with colorectal cancer stage II high risk and stage III, and the addition of oxaliplatin has provided significant survival benefits for the majority of the colon cancer population,” elaborated Dr. Raphael, who is a resident in the Department of Medicine, University of Toronto, and an investigator with the Institute for Clinical Evaluative Sciences, also in Toronto. “But retrospective subgroup analyses of some of the major trials – MOSAIC and NSABP C-07 – suggest that there may not be a benefit of giving oxaliplatin to patients over the age of 70.”

For the study, the investigators used a population-based database to capture all cases of colorectal cancer diagnosed in Ontario between 2007 and 2011. They restricted analyses to 3,607 patients aged 66 years or older with stage II or III disease and adjusted for potential confounders and the competing risk of death, which is important in an older population, he noted. Overall, 43% received oxaliplatin, Dr. Raphael reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Urologic Oncology.

Results showed that in the 66 to 69 age-group, patients given oxaliplatin as part of their chemotherapy did not have a significantly elevated adjusted risk of a new diagnosis of peripheral neuropathy, but they did have an elevated risk of a new prescription for a neuropathic pain medication (hazard ratio, 1.92; P = .005).

In the 70 and older age-group, those given oxaliplatin had elevated adjusted risks of both a new diagnosis of peripheral neuropathy (HR, 2.07; P less than .001) and a new prescription for a neuropathic pain medication (HR, 1.86; P less than .001).

The 3-year cumulative incidence of neuropathy among those 66 to 69 years old was 5.17% with oxaliplatin and 5.06% without it. But among those 70 years old and older, it was 7.65% with the drug and 3.70% without it.

The clinical impact of the observed neuropathy is not yet known, noted Dr. Raphael. The investigators have therefore undertaken another study looking at possible correlates in this population, such as an uptick in visits to the emergency department for falls or fractures.

SAN FRANCISCO – Oxaliplatin has substantial neurotoxicity in older adults with colorectal cancer that should be factored into treatment decision making, suggests a study reported at the Gastrointestinal Cancers Symposium.

The Canadian analysis of more than 3,500 patients found that those aged 70 years or older who received oxaliplatin as part of their adjuvant chemotherapy had a doubling of the risk of a new diagnosis of peripheral neuropathy. The 3-year cumulative incidence in this group approached 8%.

Susan London/Frontline Medical News

“Hopefully, this study will allow patients to make more informed decisions with their clinicians,” first author Dr. Michael J. Raphael said in an interview. “We are able to say to patients that there is a significant risk of developing a neuropathy. Patients need to consider this in terms of their quality of life because as we are curing more and more people with colorectal cancer, even in the elderly, survivorship is becoming a very big issue. And it becomes an individual choice for the patient, if they survive, what level of toxicity are they willing to accept?”

The study didn’t look at oxaliplatin’s efficacy in older adults, he noted. However, some research has called into question the drug’s benefit in this population as well.

“We know that fluorouracil-based chemotherapy is the standard of care for patients with colorectal cancer stage II high risk and stage III, and the addition of oxaliplatin has provided significant survival benefits for the majority of the colon cancer population,” elaborated Dr. Raphael, who is a resident in the Department of Medicine, University of Toronto, and an investigator with the Institute for Clinical Evaluative Sciences, also in Toronto. “But retrospective subgroup analyses of some of the major trials – MOSAIC and NSABP C-07 – suggest that there may not be a benefit of giving oxaliplatin to patients over the age of 70.”

For the study, the investigators used a population-based database to capture all cases of colorectal cancer diagnosed in Ontario between 2007 and 2011. They restricted analyses to 3,607 patients aged 66 years or older with stage II or III disease and adjusted for potential confounders and the competing risk of death, which is important in an older population, he noted. Overall, 43% received oxaliplatin, Dr. Raphael reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Urologic Oncology.

Results showed that in the 66 to 69 age-group, patients given oxaliplatin as part of their chemotherapy did not have a significantly elevated adjusted risk of a new diagnosis of peripheral neuropathy, but they did have an elevated risk of a new prescription for a neuropathic pain medication (hazard ratio, 1.92; P = .005).

In the 70 and older age-group, those given oxaliplatin had elevated adjusted risks of both a new diagnosis of peripheral neuropathy (HR, 2.07; P less than .001) and a new prescription for a neuropathic pain medication (HR, 1.86; P less than .001).

The 3-year cumulative incidence of neuropathy among those 66 to 69 years old was 5.17% with oxaliplatin and 5.06% without it. But among those 70 years old and older, it was 7.65% with the drug and 3.70% without it.

The clinical impact of the observed neuropathy is not yet known, noted Dr. Raphael. The investigators have therefore undertaken another study looking at possible correlates in this population, such as an uptick in visits to the emergency department for falls or fractures.

SAN FRANCISCO – Oxaliplatin has substantial neurotoxicity in older adults with colorectal cancer that should be factored into treatment decision making, suggests a study reported at the Gastrointestinal Cancers Symposium.

The Canadian analysis of more than 3,500 patients found that those aged 70 years or older who received oxaliplatin as part of their adjuvant chemotherapy had a doubling of the risk of a new diagnosis of peripheral neuropathy. The 3-year cumulative incidence in this group approached 8%.

Susan London/Frontline Medical News

“Hopefully, this study will allow patients to make more informed decisions with their clinicians,” first author Dr. Michael J. Raphael said in an interview. “We are able to say to patients that there is a significant risk of developing a neuropathy. Patients need to consider this in terms of their quality of life because as we are curing more and more people with colorectal cancer, even in the elderly, survivorship is becoming a very big issue. And it becomes an individual choice for the patient, if they survive, what level of toxicity are they willing to accept?”

The study didn’t look at oxaliplatin’s efficacy in older adults, he noted. However, some research has called into question the drug’s benefit in this population as well.

“We know that fluorouracil-based chemotherapy is the standard of care for patients with colorectal cancer stage II high risk and stage III, and the addition of oxaliplatin has provided significant survival benefits for the majority of the colon cancer population,” elaborated Dr. Raphael, who is a resident in the Department of Medicine, University of Toronto, and an investigator with the Institute for Clinical Evaluative Sciences, also in Toronto. “But retrospective subgroup analyses of some of the major trials – MOSAIC and NSABP C-07 – suggest that there may not be a benefit of giving oxaliplatin to patients over the age of 70.”

For the study, the investigators used a population-based database to capture all cases of colorectal cancer diagnosed in Ontario between 2007 and 2011. They restricted analyses to 3,607 patients aged 66 years or older with stage II or III disease and adjusted for potential confounders and the competing risk of death, which is important in an older population, he noted. Overall, 43% received oxaliplatin, Dr. Raphael reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Urologic Oncology.

Results showed that in the 66 to 69 age-group, patients given oxaliplatin as part of their chemotherapy did not have a significantly elevated adjusted risk of a new diagnosis of peripheral neuropathy, but they did have an elevated risk of a new prescription for a neuropathic pain medication (hazard ratio, 1.92; P = .005).

In the 70 and older age-group, those given oxaliplatin had elevated adjusted risks of both a new diagnosis of peripheral neuropathy (HR, 2.07; P less than .001) and a new prescription for a neuropathic pain medication (HR, 1.86; P less than .001).

The 3-year cumulative incidence of neuropathy among those 66 to 69 years old was 5.17% with oxaliplatin and 5.06% without it. But among those 70 years old and older, it was 7.65% with the drug and 3.70% without it.

The clinical impact of the observed neuropathy is not yet known, noted Dr. Raphael. The investigators have therefore undertaken another study looking at possible correlates in this population, such as an uptick in visits to the emergency department for falls or fractures.

SAN FRANCISCO – A variety of commonly used medications may improve survival of pancreatic cancer, reducing the risk of death by up to one-fourth, according to a pair of national retrospective cohort studies reported in a poster session at the Gastrointestinal Cancers Symposium.

In the first study, Dr. Muhammad S. Beg and his colleagues analyzed data from Surveillance, Epidemiology and End Results (SEER)-Medicare Part D beneficiaries with pancreatic cancer for the years 2006-2009. Patients were defined as using a medication if they filled at least two prescriptions within a year of the diagnosis.

“There is mounting preclinical evidence that medications conventionally used for noncancer indications may have an effect on pancreatic cancer biology and can potentially impart an effect on cancer outcome,” Dr. Beg said in an interview.

However, “validating each of these findings in the clinic in the form of prospective clinical trials is not feasible due to constraints related to resources and time. Historically, institutional cancer registries lack details on patient comorbidity and medication usage. As a result, prior studies are limited to small database analysis and results have been mixed,” he added. “Availability of large clinical datasets allows the impact of these medications to be evaluated on large numbers of cancer patients.”

Multivariate analyses based on 13,702 patients with pancreatic adenocarcinoma showed that the adjusted risk of death was significantly lower for users of beta-blockers (hazard ratio, 0.92), warfarin (HR, 0.90), insulin (HR, 0.89), and heparin (HR, 0.76).

The findings are most noteworthy for warfarin, which appears to act through inhibition of the gas6-axl pathway, according to Dr. Beg of UT Southwestern Medical Center, Simmons Cancer Center, Dallas.

“Warfarin is an old drug, cheap and no one really likes it as it is tough for patients to take,” he elaborated. But “we have a potential mechanism of action and a new class of drugs, AXL inhibitors, which given this information should be explored in pancreatic cancer.”

In contrast, risk of death was not affected by use of statins, thiazolidinediones, or metformin. “That metformin did not have an effect goes against a large number of studies [that] suggested metformin could be very active in pancreatic cancer,” Dr. Beg said.

“In a cancer [that] has such dismal outcome as pancreatic cancer, understanding how to best use concurrent medications may have significant impact on patients’ outcomes and our understanding of the cancer biology,” he concluded.

Susan London/Frontline Medical News

In the second study, Dr. Aimee Lucas and her colleagues analyzed data from SEER-Medicare Part D beneficiaries with pancreatic cancer for the years 2007-2011. They excluded those receiving a diabetes diagnosis in the year before their cancer diagnosis to minimize the effect of reverse causation, whereby the cancer led to diabetes.

Analyses were based on 1,916 patients with pancreatic adenocarcinoma who were taking medications for diabetes before their cancer diagnosis. Overall, 57% used metformin, with or without other medications.

In propensity-adjusted analyses, mean survival was longer for metformin users than for nonusers (5.5 vs. 4.2 months; P less than .01), reported Dr. Lucas of the Icahn School of Medicine at Mount Sinai, New York. The difference was significant across stages, except for stage I.

In multivariate analysis, metformin users still had a reduced risk of death (hazard ratio, 0.88; P less than .01). The association was consistent across subgroups of patients stratified by Charlson comorbidity score, diabetic complications severity index score, presence of chronic kidney disease, and use of insulin or other hypoglycemic agents.

On the other hand, insulin users had poorer survival than nonusers (4.3 vs. 5.5 months; P less than .01). And survival did not differ significantly according to use of sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase 4 (DPP-4) inhibitors, or alpha-glucosidase inhibitors.

“We think that this study provides growing evidence for a survival benefit for diabetics who are on metformin at the time of diagnosis, and we would be interested in further work to try to figure out why,” Dr. Lucas said in an interview at the symposium, which was sponsored by the ASCO, ASTRO, the American Gastroenterological Association, and the Society of Urologic Oncology.

More research will be needed in particular to determine whether the findings for metformin represent a true protective effect of the drug or, rather, a harmful effect of other medications such as insulin, she added.

Dr. Lucas likewise noted the power of being able to tap into a large database that captures medication use and comorbidities when studying these associations in pancreatic cancer.

Smaller and single-institution cohorts studies have been done, she commented. But “no one has really been able to control for severity of diabetes and comorbidities in the same way that we were able to. And that’s just because we have the SEER-Medicare database and such a large sample size.”

SAN FRANCISCO – A variety of commonly used medications may improve survival of pancreatic cancer, reducing the risk of death by up to one-fourth, according to a pair of national retrospective cohort studies reported in a poster session at the Gastrointestinal Cancers Symposium.

In the first study, Dr. Muhammad S. Beg and his colleagues analyzed data from Surveillance, Epidemiology and End Results (SEER)-Medicare Part D beneficiaries with pancreatic cancer for the years 2006-2009. Patients were defined as using a medication if they filled at least two prescriptions within a year of the diagnosis.

“There is mounting preclinical evidence that medications conventionally used for noncancer indications may have an effect on pancreatic cancer biology and can potentially impart an effect on cancer outcome,” Dr. Beg said in an interview.

However, “validating each of these findings in the clinic in the form of prospective clinical trials is not feasible due to constraints related to resources and time. Historically, institutional cancer registries lack details on patient comorbidity and medication usage. As a result, prior studies are limited to small database analysis and results have been mixed,” he added. “Availability of large clinical datasets allows the impact of these medications to be evaluated on large numbers of cancer patients.”

Multivariate analyses based on 13,702 patients with pancreatic adenocarcinoma showed that the adjusted risk of death was significantly lower for users of beta-blockers (hazard ratio, 0.92), warfarin (HR, 0.90), insulin (HR, 0.89), and heparin (HR, 0.76).

The findings are most noteworthy for warfarin, which appears to act through inhibition of the gas6-axl pathway, according to Dr. Beg of UT Southwestern Medical Center, Simmons Cancer Center, Dallas.

“Warfarin is an old drug, cheap and no one really likes it as it is tough for patients to take,” he elaborated. But “we have a potential mechanism of action and a new class of drugs, AXL inhibitors, which given this information should be explored in pancreatic cancer.”

In contrast, risk of death was not affected by use of statins, thiazolidinediones, or metformin. “That metformin did not have an effect goes against a large number of studies [that] suggested metformin could be very active in pancreatic cancer,” Dr. Beg said.

“In a cancer [that] has such dismal outcome as pancreatic cancer, understanding how to best use concurrent medications may have significant impact on patients’ outcomes and our understanding of the cancer biology,” he concluded.

Susan London/Frontline Medical News

In the second study, Dr. Aimee Lucas and her colleagues analyzed data from SEER-Medicare Part D beneficiaries with pancreatic cancer for the years 2007-2011. They excluded those receiving a diabetes diagnosis in the year before their cancer diagnosis to minimize the effect of reverse causation, whereby the cancer led to diabetes.

Analyses were based on 1,916 patients with pancreatic adenocarcinoma who were taking medications for diabetes before their cancer diagnosis. Overall, 57% used metformin, with or without other medications.

In propensity-adjusted analyses, mean survival was longer for metformin users than for nonusers (5.5 vs. 4.2 months; P less than .01), reported Dr. Lucas of the Icahn School of Medicine at Mount Sinai, New York. The difference was significant across stages, except for stage I.

In multivariate analysis, metformin users still had a reduced risk of death (hazard ratio, 0.88; P less than .01). The association was consistent across subgroups of patients stratified by Charlson comorbidity score, diabetic complications severity index score, presence of chronic kidney disease, and use of insulin or other hypoglycemic agents.

On the other hand, insulin users had poorer survival than nonusers (4.3 vs. 5.5 months; P less than .01). And survival did not differ significantly according to use of sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase 4 (DPP-4) inhibitors, or alpha-glucosidase inhibitors.

“We think that this study provides growing evidence for a survival benefit for diabetics who are on metformin at the time of diagnosis, and we would be interested in further work to try to figure out why,” Dr. Lucas said in an interview at the symposium, which was sponsored by the ASCO, ASTRO, the American Gastroenterological Association, and the Society of Urologic Oncology.

More research will be needed in particular to determine whether the findings for metformin represent a true protective effect of the drug or, rather, a harmful effect of other medications such as insulin, she added.

Dr. Lucas likewise noted the power of being able to tap into a large database that captures medication use and comorbidities when studying these associations in pancreatic cancer.

Smaller and single-institution cohorts studies have been done, she commented. But “no one has really been able to control for severity of diabetes and comorbidities in the same way that we were able to. And that’s just because we have the SEER-Medicare database and such a large sample size.”

SAN FRANCISCO – A variety of commonly used medications may improve survival of pancreatic cancer, reducing the risk of death by up to one-fourth, according to a pair of national retrospective cohort studies reported in a poster session at the Gastrointestinal Cancers Symposium.

In the first study, Dr. Muhammad S. Beg and his colleagues analyzed data from Surveillance, Epidemiology and End Results (SEER)-Medicare Part D beneficiaries with pancreatic cancer for the years 2006-2009. Patients were defined as using a medication if they filled at least two prescriptions within a year of the diagnosis.

“There is mounting preclinical evidence that medications conventionally used for noncancer indications may have an effect on pancreatic cancer biology and can potentially impart an effect on cancer outcome,” Dr. Beg said in an interview.

However, “validating each of these findings in the clinic in the form of prospective clinical trials is not feasible due to constraints related to resources and time. Historically, institutional cancer registries lack details on patient comorbidity and medication usage. As a result, prior studies are limited to small database analysis and results have been mixed,” he added. “Availability of large clinical datasets allows the impact of these medications to be evaluated on large numbers of cancer patients.”

Multivariate analyses based on 13,702 patients with pancreatic adenocarcinoma showed that the adjusted risk of death was significantly lower for users of beta-blockers (hazard ratio, 0.92), warfarin (HR, 0.90), insulin (HR, 0.89), and heparin (HR, 0.76).

The findings are most noteworthy for warfarin, which appears to act through inhibition of the gas6-axl pathway, according to Dr. Beg of UT Southwestern Medical Center, Simmons Cancer Center, Dallas.

“Warfarin is an old drug, cheap and no one really likes it as it is tough for patients to take,” he elaborated. But “we have a potential mechanism of action and a new class of drugs, AXL inhibitors, which given this information should be explored in pancreatic cancer.”

In contrast, risk of death was not affected by use of statins, thiazolidinediones, or metformin. “That metformin did not have an effect goes against a large number of studies [that] suggested metformin could be very active in pancreatic cancer,” Dr. Beg said.

“In a cancer [that] has such dismal outcome as pancreatic cancer, understanding how to best use concurrent medications may have significant impact on patients’ outcomes and our understanding of the cancer biology,” he concluded.

Susan London/Frontline Medical News

In the second study, Dr. Aimee Lucas and her colleagues analyzed data from SEER-Medicare Part D beneficiaries with pancreatic cancer for the years 2007-2011. They excluded those receiving a diabetes diagnosis in the year before their cancer diagnosis to minimize the effect of reverse causation, whereby the cancer led to diabetes.

Analyses were based on 1,916 patients with pancreatic adenocarcinoma who were taking medications for diabetes before their cancer diagnosis. Overall, 57% used metformin, with or without other medications.

In propensity-adjusted analyses, mean survival was longer for metformin users than for nonusers (5.5 vs. 4.2 months; P less than .01), reported Dr. Lucas of the Icahn School of Medicine at Mount Sinai, New York. The difference was significant across stages, except for stage I.

In multivariate analysis, metformin users still had a reduced risk of death (hazard ratio, 0.88; P less than .01). The association was consistent across subgroups of patients stratified by Charlson comorbidity score, diabetic complications severity index score, presence of chronic kidney disease, and use of insulin or other hypoglycemic agents.

On the other hand, insulin users had poorer survival than nonusers (4.3 vs. 5.5 months; P less than .01). And survival did not differ significantly according to use of sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase 4 (DPP-4) inhibitors, or alpha-glucosidase inhibitors.

“We think that this study provides growing evidence for a survival benefit for diabetics who are on metformin at the time of diagnosis, and we would be interested in further work to try to figure out why,” Dr. Lucas said in an interview at the symposium, which was sponsored by the ASCO, ASTRO, the American Gastroenterological Association, and the Society of Urologic Oncology.

More research will be needed in particular to determine whether the findings for metformin represent a true protective effect of the drug or, rather, a harmful effect of other medications such as insulin, she added.

Dr. Lucas likewise noted the power of being able to tap into a large database that captures medication use and comorbidities when studying these associations in pancreatic cancer.

Smaller and single-institution cohorts studies have been done, she commented. But “no one has really been able to control for severity of diabetes and comorbidities in the same way that we were able to. And that’s just because we have the SEER-Medicare database and such a large sample size.”

SAN FRANCISCO – Sleep duration influences survival in the metastatic colorectal cancer population, according to a cohort study of 236 patients who wore wrist actigraphy devices for the 72 hours leading up to chemotherapy.

Those who slept 7 hours nightly or less had a 45% higher adjusted 5-year risk of death when compared with counterparts who logged more hours, investigators reported in a poster session at the Gastrointestinal Cancers Symposium.

Susan London/Frontline Medical News

“If you’ve got advanced cancer, losing sleep is something to lose sleep over. It would be a good idea to view part of your overall health program as making sure you get an adequate amount of sleep,” first author Dr. David Spiegel said in an interview.

“The nice thing about this is, all of our patients could spend almost a third of their lives in bed asleep, and it’s an easy thing to advise them to do and try and help them to do,” he added. “If we had a chemotherapy that had this kind of effect in this setting, we’d be very happy about that. So it’s something we can do that is low risk, no side effects, that can actually have an effect on outcome.”

The mechanisms at play are still unclear, according to Dr. Spiegel, who is the Jack, Samuel, and Lulu Willson Professor of Medicine, Stanford (Calif.) University.

One possibility is perturbation of cortisol levels. “Cortisol has anti-inflammatory effects. Pro-inflammatory cytokines can trigger [vascular endothelial growth factor], which can provide metastatic tumors with more vascular support,” he elaborated. “Cortisol also affects tumor suppressor gene expression… So it’s conceivable that you are having different levels of cortisol throughout the day and night that may have a subtle effect on inflammation or expression of tumor suppressor genes.”

Alternately, short sleep may be a marker for other lifestyle factors negatively affecting prognosis, he proposed. “People who don’t sleep well don’t exercise as well. They may not eat as well. There are a lot of other systems that kind of get triggered,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In previous research, the investigators found that subjectively reported sleep problems in chemotherapy-naïve patients with metastatic colorectal cancer were associated with increased risks of progression, death, and poor treatment response (Sleep Med. 2015 Mar;16:391-8). Additionally, patients with metastatic colorectal cancer with a longer objectively measured proportion of time in bed had better overall survival (Chronobiol Int. 2014 Oct;31:891-900).

In the new study, the median nightly sleep duration was 7.4 hours per night for the entire cohort. Compared with others, patients sleeping 7 hours nightly or less had poorer median overall survival (14.6 vs. 16.4 months, P = .04), and this association remained significant after adjusting for clinical, disease, and treatment factors (hazard ratio, 1.45; P = .012).

“What’s interesting is it’s not simply, as your disease is progressing, you are more anxious, you don’t sleep as well. You are dying anyway, so you are not sleeping well,” Dr. Spiegel commented. “This is a 5-year prediction of subsequent survival. And if you look at the curves, they stay separated pretty much throughout the ensuing 5 years. So it seems to be a strong and independent predictor of mortality.”

In contrast, short sleep duration was not significantly associated with progression-free survival, objective response rate, or grade 3 or 4 toxicity.

The findings are generally consistent with those of a study among women with metastatic breast cancer showing an impact of sleep on survival (Sleep. 2014 May 1;37:837-42). However, in that study, sleep efficiency, not duration, was associated with survival.

“My colleague Oxana Palesh has a brief behavioral intervention for sleep, and it is effective for improving sleep in the short term,” commented Dr. Spiegel. “The next thing would be to do a randomized trial to see if we can get them [short sleepers] to sleep longer and if that has an effect on outcome.”

SAN FRANCISCO – Sleep duration influences survival in the metastatic colorectal cancer population, according to a cohort study of 236 patients who wore wrist actigraphy devices for the 72 hours leading up to chemotherapy.

Those who slept 7 hours nightly or less had a 45% higher adjusted 5-year risk of death when compared with counterparts who logged more hours, investigators reported in a poster session at the Gastrointestinal Cancers Symposium.

Susan London/Frontline Medical News

“If you’ve got advanced cancer, losing sleep is something to lose sleep over. It would be a good idea to view part of your overall health program as making sure you get an adequate amount of sleep,” first author Dr. David Spiegel said in an interview.

“The nice thing about this is, all of our patients could spend almost a third of their lives in bed asleep, and it’s an easy thing to advise them to do and try and help them to do,” he added. “If we had a chemotherapy that had this kind of effect in this setting, we’d be very happy about that. So it’s something we can do that is low risk, no side effects, that can actually have an effect on outcome.”

The mechanisms at play are still unclear, according to Dr. Spiegel, who is the Jack, Samuel, and Lulu Willson Professor of Medicine, Stanford (Calif.) University.

One possibility is perturbation of cortisol levels. “Cortisol has anti-inflammatory effects. Pro-inflammatory cytokines can trigger [vascular endothelial growth factor], which can provide metastatic tumors with more vascular support,” he elaborated. “Cortisol also affects tumor suppressor gene expression… So it’s conceivable that you are having different levels of cortisol throughout the day and night that may have a subtle effect on inflammation or expression of tumor suppressor genes.”

Alternately, short sleep may be a marker for other lifestyle factors negatively affecting prognosis, he proposed. “People who don’t sleep well don’t exercise as well. They may not eat as well. There are a lot of other systems that kind of get triggered,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In previous research, the investigators found that subjectively reported sleep problems in chemotherapy-naïve patients with metastatic colorectal cancer were associated with increased risks of progression, death, and poor treatment response (Sleep Med. 2015 Mar;16:391-8). Additionally, patients with metastatic colorectal cancer with a longer objectively measured proportion of time in bed had better overall survival (Chronobiol Int. 2014 Oct;31:891-900).

In the new study, the median nightly sleep duration was 7.4 hours per night for the entire cohort. Compared with others, patients sleeping 7 hours nightly or less had poorer median overall survival (14.6 vs. 16.4 months, P = .04), and this association remained significant after adjusting for clinical, disease, and treatment factors (hazard ratio, 1.45; P = .012).

“What’s interesting is it’s not simply, as your disease is progressing, you are more anxious, you don’t sleep as well. You are dying anyway, so you are not sleeping well,” Dr. Spiegel commented. “This is a 5-year prediction of subsequent survival. And if you look at the curves, they stay separated pretty much throughout the ensuing 5 years. So it seems to be a strong and independent predictor of mortality.”

In contrast, short sleep duration was not significantly associated with progression-free survival, objective response rate, or grade 3 or 4 toxicity.

The findings are generally consistent with those of a study among women with metastatic breast cancer showing an impact of sleep on survival (Sleep. 2014 May 1;37:837-42). However, in that study, sleep efficiency, not duration, was associated with survival.

“My colleague Oxana Palesh has a brief behavioral intervention for sleep, and it is effective for improving sleep in the short term,” commented Dr. Spiegel. “The next thing would be to do a randomized trial to see if we can get them [short sleepers] to sleep longer and if that has an effect on outcome.”

SAN FRANCISCO – Sleep duration influences survival in the metastatic colorectal cancer population, according to a cohort study of 236 patients who wore wrist actigraphy devices for the 72 hours leading up to chemotherapy.

Those who slept 7 hours nightly or less had a 45% higher adjusted 5-year risk of death when compared with counterparts who logged more hours, investigators reported in a poster session at the Gastrointestinal Cancers Symposium.

Susan London/Frontline Medical News

“If you’ve got advanced cancer, losing sleep is something to lose sleep over. It would be a good idea to view part of your overall health program as making sure you get an adequate amount of sleep,” first author Dr. David Spiegel said in an interview.

“The nice thing about this is, all of our patients could spend almost a third of their lives in bed asleep, and it’s an easy thing to advise them to do and try and help them to do,” he added. “If we had a chemotherapy that had this kind of effect in this setting, we’d be very happy about that. So it’s something we can do that is low risk, no side effects, that can actually have an effect on outcome.”

The mechanisms at play are still unclear, according to Dr. Spiegel, who is the Jack, Samuel, and Lulu Willson Professor of Medicine, Stanford (Calif.) University.

One possibility is perturbation of cortisol levels. “Cortisol has anti-inflammatory effects. Pro-inflammatory cytokines can trigger [vascular endothelial growth factor], which can provide metastatic tumors with more vascular support,” he elaborated. “Cortisol also affects tumor suppressor gene expression… So it’s conceivable that you are having different levels of cortisol throughout the day and night that may have a subtle effect on inflammation or expression of tumor suppressor genes.”

Alternately, short sleep may be a marker for other lifestyle factors negatively affecting prognosis, he proposed. “People who don’t sleep well don’t exercise as well. They may not eat as well. There are a lot of other systems that kind of get triggered,” he said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

In previous research, the investigators found that subjectively reported sleep problems in chemotherapy-naïve patients with metastatic colorectal cancer were associated with increased risks of progression, death, and poor treatment response (Sleep Med. 2015 Mar;16:391-8). Additionally, patients with metastatic colorectal cancer with a longer objectively measured proportion of time in bed had better overall survival (Chronobiol Int. 2014 Oct;31:891-900).

In the new study, the median nightly sleep duration was 7.4 hours per night for the entire cohort. Compared with others, patients sleeping 7 hours nightly or less had poorer median overall survival (14.6 vs. 16.4 months, P = .04), and this association remained significant after adjusting for clinical, disease, and treatment factors (hazard ratio, 1.45; P = .012).

“What’s interesting is it’s not simply, as your disease is progressing, you are more anxious, you don’t sleep as well. You are dying anyway, so you are not sleeping well,” Dr. Spiegel commented. “This is a 5-year prediction of subsequent survival. And if you look at the curves, they stay separated pretty much throughout the ensuing 5 years. So it seems to be a strong and independent predictor of mortality.”

In contrast, short sleep duration was not significantly associated with progression-free survival, objective response rate, or grade 3 or 4 toxicity.

The findings are generally consistent with those of a study among women with metastatic breast cancer showing an impact of sleep on survival (Sleep. 2014 May 1;37:837-42). However, in that study, sleep efficiency, not duration, was associated with survival.

“My colleague Oxana Palesh has a brief behavioral intervention for sleep, and it is effective for improving sleep in the short term,” commented Dr. Spiegel. “The next thing would be to do a randomized trial to see if we can get them [short sleepers] to sleep longer and if that has an effect on outcome.”

SAN FRANCISCO – Tumor response assessments differ widely, in ways that may affect treatment decisions, depending on whether Response Evaluation Criteria in Solid Tumors (RECIST) are used, suggests a study reported at the ASCO Gastrointestinal Cancers Symposium.

Researchers at Jefferson Medical College, Philadelphia undertook a study using 292 scans performed in patients with solid tumors who were treated in clinical trials during 2013-2014.

Susan London/ Frontline Medical News

Results presented in a poster session showed that the RECIST report of tumor status agreed with the oncologist’s interpretation of the standard radiology report, generated without these criteria, only about half the time.

“This study basically came about when I saw all of these [standard] reports calling it progression, and I would get the RECIST report back saying it was stable. And we are actually making treatment decisions” based on that, senior author Dr. Ashwin R. Sama of Jefferson Medical College, Philadelphia, said in an interview. “This has never been studied, although everybody knew that there probably is a difference between regular reads and RECIST reads.”

“The correlation was about 50% – that’s like the flip of a coin. And that really has a big impact on treatment,” he added. “You don’t want to take patients off treatment too soon if they have stable disease; and vice versa, if they have progression, you don’t want to keep them on chemo that is not working.”

In the study, a single radiologist read the scans using RECIST criteria and generated a report. Multiple radiologists then read the same scans without using these criteria and generated a standard report. An oncologist and a resident separately interpreted the standard reports to classify patients as having a complete response, a partial response, stable disease, or progressive disease.

Overall agreement between the RECIST report and the oncologist-interpreted standard report was just 56%. In 29% of cases of RECIST-classified progressive disease, the oncologist interpreted the standard report as showing stable disease. On the other hand, in 19% of cases of RECIST-classified stable disease, the oncologist interpreted the standard report as showing progressive disease.

Findings were similar when the resident interpreted the standard report. Overall agreement with the RECIST report was just 54%. In 24% of cases of RECIST-classified progressive disease, the resident interpreted the standard report as showing stable disease. In 26% of cases of RECIST-classified stable disease, the resident interpreted the standard report as showing progressive disease.

“Clinical trials commonly use RECIST as a way to interpret tumor response. However, outside of clinical trial settings, RECIST criteria are less commonly used, especially if you are in a nonacademic institution,” commented first author Dr. Aileen Deng of the Thomas Jefferson University Hospital, Philadelphia.

Variability in standard reports likely contributes to considerable variability in practice, she speculated. “There need to be better ways to standardize how we interpret serial images that are done for our patients with solid tumors,” she concluded.

Dr. Sama and Dr. Deng disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Tumor response assessments differ widely, in ways that may affect treatment decisions, depending on whether Response Evaluation Criteria in Solid Tumors (RECIST) are used, suggests a study reported at the ASCO Gastrointestinal Cancers Symposium.

Researchers at Jefferson Medical College, Philadelphia undertook a study using 292 scans performed in patients with solid tumors who were treated in clinical trials during 2013-2014.

Susan London/ Frontline Medical News

Results presented in a poster session showed that the RECIST report of tumor status agreed with the oncologist’s interpretation of the standard radiology report, generated without these criteria, only about half the time.

“This study basically came about when I saw all of these [standard] reports calling it progression, and I would get the RECIST report back saying it was stable. And we are actually making treatment decisions” based on that, senior author Dr. Ashwin R. Sama of Jefferson Medical College, Philadelphia, said in an interview. “This has never been studied, although everybody knew that there probably is a difference between regular reads and RECIST reads.”

“The correlation was about 50% – that’s like the flip of a coin. And that really has a big impact on treatment,” he added. “You don’t want to take patients off treatment too soon if they have stable disease; and vice versa, if they have progression, you don’t want to keep them on chemo that is not working.”

In the study, a single radiologist read the scans using RECIST criteria and generated a report. Multiple radiologists then read the same scans without using these criteria and generated a standard report. An oncologist and a resident separately interpreted the standard reports to classify patients as having a complete response, a partial response, stable disease, or progressive disease.

Overall agreement between the RECIST report and the oncologist-interpreted standard report was just 56%. In 29% of cases of RECIST-classified progressive disease, the oncologist interpreted the standard report as showing stable disease. On the other hand, in 19% of cases of RECIST-classified stable disease, the oncologist interpreted the standard report as showing progressive disease.

Findings were similar when the resident interpreted the standard report. Overall agreement with the RECIST report was just 54%. In 24% of cases of RECIST-classified progressive disease, the resident interpreted the standard report as showing stable disease. In 26% of cases of RECIST-classified stable disease, the resident interpreted the standard report as showing progressive disease.

“Clinical trials commonly use RECIST as a way to interpret tumor response. However, outside of clinical trial settings, RECIST criteria are less commonly used, especially if you are in a nonacademic institution,” commented first author Dr. Aileen Deng of the Thomas Jefferson University Hospital, Philadelphia.

Variability in standard reports likely contributes to considerable variability in practice, she speculated. “There need to be better ways to standardize how we interpret serial images that are done for our patients with solid tumors,” she concluded.

Dr. Sama and Dr. Deng disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – Tumor response assessments differ widely, in ways that may affect treatment decisions, depending on whether Response Evaluation Criteria in Solid Tumors (RECIST) are used, suggests a study reported at the ASCO Gastrointestinal Cancers Symposium.

Researchers at Jefferson Medical College, Philadelphia undertook a study using 292 scans performed in patients with solid tumors who were treated in clinical trials during 2013-2014.

Susan London/ Frontline Medical News

Results presented in a poster session showed that the RECIST report of tumor status agreed with the oncologist’s interpretation of the standard radiology report, generated without these criteria, only about half the time.

“This study basically came about when I saw all of these [standard] reports calling it progression, and I would get the RECIST report back saying it was stable. And we are actually making treatment decisions” based on that, senior author Dr. Ashwin R. Sama of Jefferson Medical College, Philadelphia, said in an interview. “This has never been studied, although everybody knew that there probably is a difference between regular reads and RECIST reads.”

“The correlation was about 50% – that’s like the flip of a coin. And that really has a big impact on treatment,” he added. “You don’t want to take patients off treatment too soon if they have stable disease; and vice versa, if they have progression, you don’t want to keep them on chemo that is not working.”

In the study, a single radiologist read the scans using RECIST criteria and generated a report. Multiple radiologists then read the same scans without using these criteria and generated a standard report. An oncologist and a resident separately interpreted the standard reports to classify patients as having a complete response, a partial response, stable disease, or progressive disease.

Overall agreement between the RECIST report and the oncologist-interpreted standard report was just 56%. In 29% of cases of RECIST-classified progressive disease, the oncologist interpreted the standard report as showing stable disease. On the other hand, in 19% of cases of RECIST-classified stable disease, the oncologist interpreted the standard report as showing progressive disease.

Findings were similar when the resident interpreted the standard report. Overall agreement with the RECIST report was just 54%. In 24% of cases of RECIST-classified progressive disease, the resident interpreted the standard report as showing stable disease. In 26% of cases of RECIST-classified stable disease, the resident interpreted the standard report as showing progressive disease.

“Clinical trials commonly use RECIST as a way to interpret tumor response. However, outside of clinical trial settings, RECIST criteria are less commonly used, especially if you are in a nonacademic institution,” commented first author Dr. Aileen Deng of the Thomas Jefferson University Hospital, Philadelphia.

Variability in standard reports likely contributes to considerable variability in practice, she speculated. “There need to be better ways to standardize how we interpret serial images that are done for our patients with solid tumors,” she concluded.

Dr. Sama and Dr. Deng disclosed that they had no relevant conflicts of interest.

SAN FRANCISCO – One biomarker appears down and out in the MAVERICC trial of first-line therapy for colorectal cancer, but another may yet deliver, according to findings reported at the Gastrointestinal Cancers Symposium.

A total of 376 patients with untreated metastatic colorectal cancer were enrolled in the phase II trial, which is comparing two combination regimens and exploring molecular strategies for predicting benefit from each.

The patients’ tumors were tested for expression of the excision repair cross-complementation group 1 (ERCC1) gene, a potential biomarker for chemoresistance to platinum compounds. And their plasma was tested for vascular endothelial growth factor A (VEGF-A), a potential biomarker for benefit from antiangiogenic and other therapy.

They were then randomized evenly to receive the oxaliplatin-containing modified FOLFOX6 regimen or the oxaliplatin-free FOLFIRI regimen, each combined with bevacizumab (Avastin), an antibody against VEGF that has antiangiogenic activity.

“FOLFIRI-bevacizumab and mFOLFOX-bevacizumab appear comparable in this exploratory study with respect to progression-free and overall survival,” reported first author Dr. Heinz-Josef Lenz, associate director for adult oncology and coleader of the gastrointestinal cancers program at the USC Norris Comprehensive Cancer Center in Los Angeles. “However, we saw a trend toward a benefit of FOLFIRI-bevacizumab over mFOLFOX-bevacizumab in this patient population and a particular difference in the left-sided tumors.”

At the same time, he cautioned that patients in the FOLFIRI arm got substantially more chemotherapy as counterparts in the mFOLFOX arm often stopped treatment because of oxaliplatin-related neurotoxicity.

Unexpectedly, patients having high tumor levels of ERCC1 did not fare significantly worse if given mFOLFOX6-bevacizumab than if given FOLFIRI-bevacizumab, with a difference of roughly a month in progression-free survival between them. But a caveat here was that only about a third of patients fell into the high ERCC1 category, whereas half have in previous trials, Dr. Lenz said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Results regarding the predictive value of VEGF-A, alone and in combination with ERCC1, are expected shortly, according to Dr. Lenz. Additionally, “we have extensive molecular analyses ongoing, and we will present these at ASCO this year, so stay tuned. There are some very exciting, interesting data developing.”

Invited discussant Dr. Wells A. Messersmith, professor and codivision head, division of medical oncology, at the University of Colorado at Denver, Aurora, commented that the trial’s data will have to mature to obtain a more definitive picture of overall survival, differences by tumor location, and the predictive value of ERCC1.

“Should we be surprised to see that ERCC1 failed? From my standpoint, this joins a long list of failed predictive tests in cytotoxic chemotherapy,” he said. As opposed to RAS for predicting benefit from agents targeting the epidermal growth factor receptor pathway, and microsatellite instability for predicting benefit from immunotherapy, “the predictors for cytotoxics for the most part have failed. It’s really unclear why this is.”

“These agents work by damaging DNA. Perhaps that’s too primordial of a pathway, although certainly BRCA works,” Dr. Messersmith commented. “There’s a lot of redundancies and workarounds [in this pathway]. These pathways are also nonstatic and change in response to chemotherapy. Finally, there are hundreds if not thousands of variants in human populations.”

In the MAVERICC trial, patients in the FOLFIRI arm received three to six more cycles of their assigned chemotherapy and about three more cycles of bevacizumab than peers in the mFOLFOX6 arm, Dr. Lenz reported.

With a median follow-up of 18.5 months, the two regimens yielded similar median progression-free survival (10.1 vs. 12.6 months, P = .056) and overall survival (23.9 vs. 27.5 months, P = .086) in the entire trial population.

Among patients with high tumor ERCC1 expression, median progression-free survival was 9.9 months with mFOLFOX6-bevacizumab and 11.2 months with FOLFIRI-bevacizumab (P = .394). Among patients with low tumor ERCC1 expression, respective values were 11.0 and 12.7 months (P = .079).

Findings were essentially the same for overall survival. Among patients with high tumor ERCC1 expression, median overall survival was 22.6 months with mFOLFOX6-bevacizumab and 26.5 months with FOLFIRI-bevacizumab (P = .330). Among patients with low tumor ERCC1 expression, respective values were 25.5 and 27.9 months (P = .152).

“It seems that patients with low ERCC1 do better with both treatments overall, with FOLFIRI in progression-free survival and overall survival always on top, but not reaching statistical significance,” Dr. Lenz remarked.

In a prespecified analysis looking at the impact of tumor location, the group with left-sided tumors had better progression-free survival if they received FOLFIRI-bevacizumab instead of mFOLFOX-bevacizumab (13.8 vs. 10.2 months; hazard ratio, 0.71; P = .04). In contrast, there was no significant difference in the group with right-sided tumors.

“There are some trends for a difference in the expression of DNA repair between the right and the left. It seems on the right, it’s on the higher side than on the left,” Dr. Lenz commented, while cautioning that numbers of patients with right-sided tumors were fairly small.

The mFOLFOX and FOLFIRI arms had essentially the same rates of treatment-emergent adverse events of grade 3 or worse (80% and 81%). But the former had a higher rate of events leading to withdrawal from any study treatment (47% vs. 23%) and to outright study discontinuation (15% vs. 9%). “The majority of these events are related to neurotoxicity,” he reported.

Adverse events of interest because of bevacizumab’s mechanism of action, such as hypertension and bleeding, were similar across treatment arms and as expected, with no substantial impact from combining the agent with chemotherapy, according to Dr. Lenz.

SAN FRANCISCO – One biomarker appears down and out in the MAVERICC trial of first-line therapy for colorectal cancer, but another may yet deliver, according to findings reported at the Gastrointestinal Cancers Symposium.

A total of 376 patients with untreated metastatic colorectal cancer were enrolled in the phase II trial, which is comparing two combination regimens and exploring molecular strategies for predicting benefit from each.

The patients’ tumors were tested for expression of the excision repair cross-complementation group 1 (ERCC1) gene, a potential biomarker for chemoresistance to platinum compounds. And their plasma was tested for vascular endothelial growth factor A (VEGF-A), a potential biomarker for benefit from antiangiogenic and other therapy.

They were then randomized evenly to receive the oxaliplatin-containing modified FOLFOX6 regimen or the oxaliplatin-free FOLFIRI regimen, each combined with bevacizumab (Avastin), an antibody against VEGF that has antiangiogenic activity.

“FOLFIRI-bevacizumab and mFOLFOX-bevacizumab appear comparable in this exploratory study with respect to progression-free and overall survival,” reported first author Dr. Heinz-Josef Lenz, associate director for adult oncology and coleader of the gastrointestinal cancers program at the USC Norris Comprehensive Cancer Center in Los Angeles. “However, we saw a trend toward a benefit of FOLFIRI-bevacizumab over mFOLFOX-bevacizumab in this patient population and a particular difference in the left-sided tumors.”

At the same time, he cautioned that patients in the FOLFIRI arm got substantially more chemotherapy as counterparts in the mFOLFOX arm often stopped treatment because of oxaliplatin-related neurotoxicity.

Unexpectedly, patients having high tumor levels of ERCC1 did not fare significantly worse if given mFOLFOX6-bevacizumab than if given FOLFIRI-bevacizumab, with a difference of roughly a month in progression-free survival between them. But a caveat here was that only about a third of patients fell into the high ERCC1 category, whereas half have in previous trials, Dr. Lenz said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Results regarding the predictive value of VEGF-A, alone and in combination with ERCC1, are expected shortly, according to Dr. Lenz. Additionally, “we have extensive molecular analyses ongoing, and we will present these at ASCO this year, so stay tuned. There are some very exciting, interesting data developing.”

Invited discussant Dr. Wells A. Messersmith, professor and codivision head, division of medical oncology, at the University of Colorado at Denver, Aurora, commented that the trial’s data will have to mature to obtain a more definitive picture of overall survival, differences by tumor location, and the predictive value of ERCC1.

“Should we be surprised to see that ERCC1 failed? From my standpoint, this joins a long list of failed predictive tests in cytotoxic chemotherapy,” he said. As opposed to RAS for predicting benefit from agents targeting the epidermal growth factor receptor pathway, and microsatellite instability for predicting benefit from immunotherapy, “the predictors for cytotoxics for the most part have failed. It’s really unclear why this is.”

“These agents work by damaging DNA. Perhaps that’s too primordial of a pathway, although certainly BRCA works,” Dr. Messersmith commented. “There’s a lot of redundancies and workarounds [in this pathway]. These pathways are also nonstatic and change in response to chemotherapy. Finally, there are hundreds if not thousands of variants in human populations.”

In the MAVERICC trial, patients in the FOLFIRI arm received three to six more cycles of their assigned chemotherapy and about three more cycles of bevacizumab than peers in the mFOLFOX6 arm, Dr. Lenz reported.

With a median follow-up of 18.5 months, the two regimens yielded similar median progression-free survival (10.1 vs. 12.6 months, P = .056) and overall survival (23.9 vs. 27.5 months, P = .086) in the entire trial population.

Among patients with high tumor ERCC1 expression, median progression-free survival was 9.9 months with mFOLFOX6-bevacizumab and 11.2 months with FOLFIRI-bevacizumab (P = .394). Among patients with low tumor ERCC1 expression, respective values were 11.0 and 12.7 months (P = .079).

Findings were essentially the same for overall survival. Among patients with high tumor ERCC1 expression, median overall survival was 22.6 months with mFOLFOX6-bevacizumab and 26.5 months with FOLFIRI-bevacizumab (P = .330). Among patients with low tumor ERCC1 expression, respective values were 25.5 and 27.9 months (P = .152).

“It seems that patients with low ERCC1 do better with both treatments overall, with FOLFIRI in progression-free survival and overall survival always on top, but not reaching statistical significance,” Dr. Lenz remarked.

In a prespecified analysis looking at the impact of tumor location, the group with left-sided tumors had better progression-free survival if they received FOLFIRI-bevacizumab instead of mFOLFOX-bevacizumab (13.8 vs. 10.2 months; hazard ratio, 0.71; P = .04). In contrast, there was no significant difference in the group with right-sided tumors.

“There are some trends for a difference in the expression of DNA repair between the right and the left. It seems on the right, it’s on the higher side than on the left,” Dr. Lenz commented, while cautioning that numbers of patients with right-sided tumors were fairly small.

The mFOLFOX and FOLFIRI arms had essentially the same rates of treatment-emergent adverse events of grade 3 or worse (80% and 81%). But the former had a higher rate of events leading to withdrawal from any study treatment (47% vs. 23%) and to outright study discontinuation (15% vs. 9%). “The majority of these events are related to neurotoxicity,” he reported.

Adverse events of interest because of bevacizumab’s mechanism of action, such as hypertension and bleeding, were similar across treatment arms and as expected, with no substantial impact from combining the agent with chemotherapy, according to Dr. Lenz.

SAN FRANCISCO – One biomarker appears down and out in the MAVERICC trial of first-line therapy for colorectal cancer, but another may yet deliver, according to findings reported at the Gastrointestinal Cancers Symposium.

A total of 376 patients with untreated metastatic colorectal cancer were enrolled in the phase II trial, which is comparing two combination regimens and exploring molecular strategies for predicting benefit from each.

The patients’ tumors were tested for expression of the excision repair cross-complementation group 1 (ERCC1) gene, a potential biomarker for chemoresistance to platinum compounds. And their plasma was tested for vascular endothelial growth factor A (VEGF-A), a potential biomarker for benefit from antiangiogenic and other therapy.

They were then randomized evenly to receive the oxaliplatin-containing modified FOLFOX6 regimen or the oxaliplatin-free FOLFIRI regimen, each combined with bevacizumab (Avastin), an antibody against VEGF that has antiangiogenic activity.

“FOLFIRI-bevacizumab and mFOLFOX-bevacizumab appear comparable in this exploratory study with respect to progression-free and overall survival,” reported first author Dr. Heinz-Josef Lenz, associate director for adult oncology and coleader of the gastrointestinal cancers program at the USC Norris Comprehensive Cancer Center in Los Angeles. “However, we saw a trend toward a benefit of FOLFIRI-bevacizumab over mFOLFOX-bevacizumab in this patient population and a particular difference in the left-sided tumors.”

At the same time, he cautioned that patients in the FOLFIRI arm got substantially more chemotherapy as counterparts in the mFOLFOX arm often stopped treatment because of oxaliplatin-related neurotoxicity.

Unexpectedly, patients having high tumor levels of ERCC1 did not fare significantly worse if given mFOLFOX6-bevacizumab than if given FOLFIRI-bevacizumab, with a difference of roughly a month in progression-free survival between them. But a caveat here was that only about a third of patients fell into the high ERCC1 category, whereas half have in previous trials, Dr. Lenz said at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Results regarding the predictive value of VEGF-A, alone and in combination with ERCC1, are expected shortly, according to Dr. Lenz. Additionally, “we have extensive molecular analyses ongoing, and we will present these at ASCO this year, so stay tuned. There are some very exciting, interesting data developing.”

Invited discussant Dr. Wells A. Messersmith, professor and codivision head, division of medical oncology, at the University of Colorado at Denver, Aurora, commented that the trial’s data will have to mature to obtain a more definitive picture of overall survival, differences by tumor location, and the predictive value of ERCC1.

“Should we be surprised to see that ERCC1 failed? From my standpoint, this joins a long list of failed predictive tests in cytotoxic chemotherapy,” he said. As opposed to RAS for predicting benefit from agents targeting the epidermal growth factor receptor pathway, and microsatellite instability for predicting benefit from immunotherapy, “the predictors for cytotoxics for the most part have failed. It’s really unclear why this is.”

“These agents work by damaging DNA. Perhaps that’s too primordial of a pathway, although certainly BRCA works,” Dr. Messersmith commented. “There’s a lot of redundancies and workarounds [in this pathway]. These pathways are also nonstatic and change in response to chemotherapy. Finally, there are hundreds if not thousands of variants in human populations.”

In the MAVERICC trial, patients in the FOLFIRI arm received three to six more cycles of their assigned chemotherapy and about three more cycles of bevacizumab than peers in the mFOLFOX6 arm, Dr. Lenz reported.

With a median follow-up of 18.5 months, the two regimens yielded similar median progression-free survival (10.1 vs. 12.6 months, P = .056) and overall survival (23.9 vs. 27.5 months, P = .086) in the entire trial population.

Among patients with high tumor ERCC1 expression, median progression-free survival was 9.9 months with mFOLFOX6-bevacizumab and 11.2 months with FOLFIRI-bevacizumab (P = .394). Among patients with low tumor ERCC1 expression, respective values were 11.0 and 12.7 months (P = .079).

Findings were essentially the same for overall survival. Among patients with high tumor ERCC1 expression, median overall survival was 22.6 months with mFOLFOX6-bevacizumab and 26.5 months with FOLFIRI-bevacizumab (P = .330). Among patients with low tumor ERCC1 expression, respective values were 25.5 and 27.9 months (P = .152).

“It seems that patients with low ERCC1 do better with both treatments overall, with FOLFIRI in progression-free survival and overall survival always on top, but not reaching statistical significance,” Dr. Lenz remarked.

In a prespecified analysis looking at the impact of tumor location, the group with left-sided tumors had better progression-free survival if they received FOLFIRI-bevacizumab instead of mFOLFOX-bevacizumab (13.8 vs. 10.2 months; hazard ratio, 0.71; P = .04). In contrast, there was no significant difference in the group with right-sided tumors.

“There are some trends for a difference in the expression of DNA repair between the right and the left. It seems on the right, it’s on the higher side than on the left,” Dr. Lenz commented, while cautioning that numbers of patients with right-sided tumors were fairly small.

The mFOLFOX and FOLFIRI arms had essentially the same rates of treatment-emergent adverse events of grade 3 or worse (80% and 81%). But the former had a higher rate of events leading to withdrawal from any study treatment (47% vs. 23%) and to outright study discontinuation (15% vs. 9%). “The majority of these events are related to neurotoxicity,” he reported.

Adverse events of interest because of bevacizumab’s mechanism of action, such as hypertension and bleeding, were similar across treatment arms and as expected, with no substantial impact from combining the agent with chemotherapy, according to Dr. Lenz.

SAN FRANCISCO – Radiation therapy for rectal cancer may actually reduce the risk of some other cancers that occur in the pelvis, according to a population-based cohort study conducted in the Netherlands.

The analysis of more than 29,000 patients treated for rectal cancer as their first primary tumor found that overall, they had a somewhat higher incidence of second pelvic tumors than did the general population, investigators reported at the Gastrointestinal Cancers Symposium.

But this did not appear to be caused by radiation effects, as the adjusted risk of these tumors was in fact 22% lower for the patients who received radiation than for those who did not.

“We did not find an increase in second tumors after previous radiotherapy for rectal cancer,” commented first author Anouk J.M. Rombouts, a medical student and doctoral candidate at Radboud University Medical Center in Nijmegen, the Netherlands. “Radiotherapy seemed to have a protective effect on the development of second cancers, predominantly for prostate cancer.”

The elevated incidence relative to the general population might instead be due to factors such as genetics and lifestyle behaviors that globally influence an individual’s cancer risk, she proposed at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Invited discussant Dr. Claus Rödel of the University of Frankfurt, Germany, noted that previous analyses of radiation therapy and risk of second cancers have had mixed findings. But mechanistically, several aspects of radiation therapy for rectal cancer could plausibly lower prostate cancer risk.

“A typical 3-D radiation treatment volume will at least cover the posterior part of the prostate, that will thus receive a dose of up to 50 Gy, which may indeed be able to sterilize prostate cancer cells, and thus prevent or at least postpone the clinical manifestation of prostate cancer,” he elaborated. “Also, it is known that pelvic radiotherapy will reduce hormone levels both in men and in women, and this also may account for the reduced risk of prostate cancer in men, and of breast cancer in women” as seen in another study.

“I think the data from the Netherlands group should not be interpreted in a way that they disavow the potential of radiotherapy to induce second cancers, but they suggest rather that there is a balance between radiation induction and radiation inhibition of second cancers,” Dr. Rödel concluded.

For the study, the investigators used national registry data to identify 29,214 patients in the Netherlands who were treated for nonmetastatic rectal cancer as their first primary cancer between 1989 and 2007. Overall, 53% received radiation therapy. The median duration of follow-up was 6.2 years.

Compared with the Dutch general population, the patients as a whole had a higher incidence of new pelvic tumors (standardized incidence ratio, 1.14), translating to an absolute excess risk of about 23 cases per 10,000 people per year, Ms. Rombouts reported.

The incidence of these tumors was 2.2% among the patients given radiation and 3.4% among those not given radiation (hazard ratio, 0.70).

Within the irradiated group, risk was higher for patients who received their radiation postoperatively compared with those who received it preoperatively (HR, 1.37).

“We think this might be due to the fact that patients who are treated preoperatively almost always finish their treatment, whereas patients who receive postoperative treatment due to various reasons do not complete treatment sometimes, because of bowel leakage or other reasons [that make them] unfit for adjuvant treatment,” she said. “We unfortunately did not have data on whether patients completed their treatment or not, so it might be a dose-related issue.”

By type of second tumor, patients who received radiation had lower risks specifically of prostate cancer (HR, 0.51) and rectosigmoid cancer (HR, 0.59). No significant differences were found for bladder, gynecologic, hematologic, or anal cancer, or for bony pelvic and pelvic lymph node malignancies.

Finally, in multivariate analysis, patients who received radiation therapy for their rectal cancer still had a reduced risk of second pelvic tumors relative to peers who did not receive this therapy (HR, 0.78). The difference was driven by a reduction in risk among men (HR, 0.59), consistent with the findings for prostate cancer; there was no significant increase or decrease in risk with radiation among women.

SAN FRANCISCO – Radiation therapy for rectal cancer may actually reduce the risk of some other cancers that occur in the pelvis, according to a population-based cohort study conducted in the Netherlands.

The analysis of more than 29,000 patients treated for rectal cancer as their first primary tumor found that overall, they had a somewhat higher incidence of second pelvic tumors than did the general population, investigators reported at the Gastrointestinal Cancers Symposium.

But this did not appear to be caused by radiation effects, as the adjusted risk of these tumors was in fact 22% lower for the patients who received radiation than for those who did not.

“We did not find an increase in second tumors after previous radiotherapy for rectal cancer,” commented first author Anouk J.M. Rombouts, a medical student and doctoral candidate at Radboud University Medical Center in Nijmegen, the Netherlands. “Radiotherapy seemed to have a protective effect on the development of second cancers, predominantly for prostate cancer.”

The elevated incidence relative to the general population might instead be due to factors such as genetics and lifestyle behaviors that globally influence an individual’s cancer risk, she proposed at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Invited discussant Dr. Claus Rödel of the University of Frankfurt, Germany, noted that previous analyses of radiation therapy and risk of second cancers have had mixed findings. But mechanistically, several aspects of radiation therapy for rectal cancer could plausibly lower prostate cancer risk.

“A typical 3-D radiation treatment volume will at least cover the posterior part of the prostate, that will thus receive a dose of up to 50 Gy, which may indeed be able to sterilize prostate cancer cells, and thus prevent or at least postpone the clinical manifestation of prostate cancer,” he elaborated. “Also, it is known that pelvic radiotherapy will reduce hormone levels both in men and in women, and this also may account for the reduced risk of prostate cancer in men, and of breast cancer in women” as seen in another study.

“I think the data from the Netherlands group should not be interpreted in a way that they disavow the potential of radiotherapy to induce second cancers, but they suggest rather that there is a balance between radiation induction and radiation inhibition of second cancers,” Dr. Rödel concluded.

For the study, the investigators used national registry data to identify 29,214 patients in the Netherlands who were treated for nonmetastatic rectal cancer as their first primary cancer between 1989 and 2007. Overall, 53% received radiation therapy. The median duration of follow-up was 6.2 years.

Compared with the Dutch general population, the patients as a whole had a higher incidence of new pelvic tumors (standardized incidence ratio, 1.14), translating to an absolute excess risk of about 23 cases per 10,000 people per year, Ms. Rombouts reported.

The incidence of these tumors was 2.2% among the patients given radiation and 3.4% among those not given radiation (hazard ratio, 0.70).

Within the irradiated group, risk was higher for patients who received their radiation postoperatively compared with those who received it preoperatively (HR, 1.37).

“We think this might be due to the fact that patients who are treated preoperatively almost always finish their treatment, whereas patients who receive postoperative treatment due to various reasons do not complete treatment sometimes, because of bowel leakage or other reasons [that make them] unfit for adjuvant treatment,” she said. “We unfortunately did not have data on whether patients completed their treatment or not, so it might be a dose-related issue.”

By type of second tumor, patients who received radiation had lower risks specifically of prostate cancer (HR, 0.51) and rectosigmoid cancer (HR, 0.59). No significant differences were found for bladder, gynecologic, hematologic, or anal cancer, or for bony pelvic and pelvic lymph node malignancies.

Finally, in multivariate analysis, patients who received radiation therapy for their rectal cancer still had a reduced risk of second pelvic tumors relative to peers who did not receive this therapy (HR, 0.78). The difference was driven by a reduction in risk among men (HR, 0.59), consistent with the findings for prostate cancer; there was no significant increase or decrease in risk with radiation among women.

SAN FRANCISCO – Radiation therapy for rectal cancer may actually reduce the risk of some other cancers that occur in the pelvis, according to a population-based cohort study conducted in the Netherlands.

The analysis of more than 29,000 patients treated for rectal cancer as their first primary tumor found that overall, they had a somewhat higher incidence of second pelvic tumors than did the general population, investigators reported at the Gastrointestinal Cancers Symposium.

But this did not appear to be caused by radiation effects, as the adjusted risk of these tumors was in fact 22% lower for the patients who received radiation than for those who did not.

“We did not find an increase in second tumors after previous radiotherapy for rectal cancer,” commented first author Anouk J.M. Rombouts, a medical student and doctoral candidate at Radboud University Medical Center in Nijmegen, the Netherlands. “Radiotherapy seemed to have a protective effect on the development of second cancers, predominantly for prostate cancer.”

The elevated incidence relative to the general population might instead be due to factors such as genetics and lifestyle behaviors that globally influence an individual’s cancer risk, she proposed at the symposium, sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Invited discussant Dr. Claus Rödel of the University of Frankfurt, Germany, noted that previous analyses of radiation therapy and risk of second cancers have had mixed findings. But mechanistically, several aspects of radiation therapy for rectal cancer could plausibly lower prostate cancer risk.

“A typical 3-D radiation treatment volume will at least cover the posterior part of the prostate, that will thus receive a dose of up to 50 Gy, which may indeed be able to sterilize prostate cancer cells, and thus prevent or at least postpone the clinical manifestation of prostate cancer,” he elaborated. “Also, it is known that pelvic radiotherapy will reduce hormone levels both in men and in women, and this also may account for the reduced risk of prostate cancer in men, and of breast cancer in women” as seen in another study.

“I think the data from the Netherlands group should not be interpreted in a way that they disavow the potential of radiotherapy to induce second cancers, but they suggest rather that there is a balance between radiation induction and radiation inhibition of second cancers,” Dr. Rödel concluded.

For the study, the investigators used national registry data to identify 29,214 patients in the Netherlands who were treated for nonmetastatic rectal cancer as their first primary cancer between 1989 and 2007. Overall, 53% received radiation therapy. The median duration of follow-up was 6.2 years.

Compared with the Dutch general population, the patients as a whole had a higher incidence of new pelvic tumors (standardized incidence ratio, 1.14), translating to an absolute excess risk of about 23 cases per 10,000 people per year, Ms. Rombouts reported.

The incidence of these tumors was 2.2% among the patients given radiation and 3.4% among those not given radiation (hazard ratio, 0.70).

Within the irradiated group, risk was higher for patients who received their radiation postoperatively compared with those who received it preoperatively (HR, 1.37).

“We think this might be due to the fact that patients who are treated preoperatively almost always finish their treatment, whereas patients who receive postoperative treatment due to various reasons do not complete treatment sometimes, because of bowel leakage or other reasons [that make them] unfit for adjuvant treatment,” she said. “We unfortunately did not have data on whether patients completed their treatment or not, so it might be a dose-related issue.”

By type of second tumor, patients who received radiation had lower risks specifically of prostate cancer (HR, 0.51) and rectosigmoid cancer (HR, 0.59). No significant differences were found for bladder, gynecologic, hematologic, or anal cancer, or for bony pelvic and pelvic lymph node malignancies.

Finally, in multivariate analysis, patients who received radiation therapy for their rectal cancer still had a reduced risk of second pelvic tumors relative to peers who did not receive this therapy (HR, 0.78). The difference was driven by a reduction in risk among men (HR, 0.59), consistent with the findings for prostate cancer; there was no significant increase or decrease in risk with radiation among women.

SAN FRANCISCO – Blockade of the cell surface receptor programmed death–1 (PD-1) is highly efficacious in patients with advanced noncolorectal cancers of the gastrointestinal tract that are deficient in mismatch repair, according to updated results of a phase II trial reported at the ASCO Gastrointestinal Cancers Symposium.

“Mutations have been shown to encode proteins that can be recognized and targeted by the immune system. The average tumor has dozens of somatic mutations; however, mismatch repair–deficient tumors harbor thousands of mutations,” noted first author Dr. Dung T. Le of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore. “This led to the hypothesis that immune augmentation with PD-1 blockade could be highly effective in mismatch repair–deficient tumors.”

Among 17 patients with noncolorectal cancers of the gastrointestinal tract treated with pembrolizumab in the trial and now having a median follow-up of 5.3 months, nearly half had a response according to radiographic criteria.

The findings expand on previously reported results for this cohort and also for a cohort in the trial having mismatch repair–deficient colorectal cancer, who benefited similarly (N Engl J Med. 2015;372:2509-20).

“Mismatch repair–deficient GI tumors are highly responsive to checkpoint blockade with anti–PD-1. Clinical benefit is noted across tumors with mismatch repair deficiency, including colon, stomach, duodenum, pancreas, ampullary, and bile duct cancers,” Dr. Le said at the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

Invited discussant Dr. Bertram Wiedenmann of Charité University Hospital in Berlin said that pembrolizumab, with PD-1 blockade, “has impressive efficacy to be validated in a larger cohort of patients with various gastroenteropancreatic primaries.”

“What I think is the million dollar question is why you have patients who are MSI [mismatch repair deficient] and still not responding to the treatment,” he added. “There might be some other alterations in addition to MSI explaining the nonresponders.”

“We have to look at the inflammatory signature of these patients, and the question of whether we can use them as companion markers, aside from PD-L1, also PD-L2,” Dr. Wiedenmann maintained, referring to the ligands that bind to PD-1.

Patients were eligible for the trial if they had progressive advanced tumors and had received at least one prior therapy. Their tumors were tested for mismatch repair status by way of a commercially available immunohistochemistry kit for mismatch repair deficiency, or a PCR-based assay for microsatellite instability. They were treated with pembrolizumab (Keytruda), an antibody that targets PD-1, every 2 weeks.

In the cohort with mismatch repair–deficient noncolorectal cancers, the updated overall response rate was 47%, and the disease control rate was 76%, Dr. Le reported. Responses and durable responses were seen across tumor types.

The duration of response has ranged from 4 to 20 months, with most patients whose tumors initially responded still doing so as of the data cutoff for analysis.

The rate of grade 3 or 4 treatment-related adverse events was 12%, accounted for entirely by cases of diarrhea and colitis. “However, these were short lived and didn’t require steroids,” Dr. Le noted.

None of the patients experienced grade 3 or 4 rash/pruritus or immune-related endocrine disorders.

“Biochemical response correlates with radiographic response,” she reported, as there was generally good (though not perfect) concordance between the radiographic response and the response according to reductions in levels of cancer antigen 19-9 (CA 19-9).

The median duration of progression-free survival was not estimable. The median duration of overall survival was 21 months, and the 18-month survival rate was approximately 86%.

Dr. Le disclosed that she receives research funding from Aduro Biotech, Bristol-Myers Squibb, and Merck. Merck Sharp & Dohme Corp. was a collaborator on the trial. Dr. Wiedenmann disclosed that he had no conflicts of interest.

SAN FRANCISCO – Blockade of the cell surface receptor programmed death–1 (PD-1) is highly efficacious in patients with advanced noncolorectal cancers of the gastrointestinal tract that are deficient in mismatch repair, according to updated results of a phase II trial reported at the ASCO Gastrointestinal Cancers Symposium.

“Mutations have been shown to encode proteins that can be recognized and targeted by the immune system. The average tumor has dozens of somatic mutations; however, mismatch repair–deficient tumors harbor thousands of mutations,” noted first author Dr. Dung T. Le of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore. “This led to the hypothesis that immune augmentation with PD-1 blockade could be highly effective in mismatch repair–deficient tumors.”

Among 17 patients with noncolorectal cancers of the gastrointestinal tract treated with pembrolizumab in the trial and now having a median follow-up of 5.3 months, nearly half had a response according to radiographic criteria.

The findings expand on previously reported results for this cohort and also for a cohort in the trial having mismatch repair–deficient colorectal cancer, who benefited similarly (N Engl J Med. 2015;372:2509-20).

“Mismatch repair–deficient GI tumors are highly responsive to checkpoint blockade with anti–PD-1. Clinical benefit is noted across tumors with mismatch repair deficiency, including colon, stomach, duodenum, pancreas, ampullary, and bile duct cancers,” Dr. Le said at the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

Invited discussant Dr. Bertram Wiedenmann of Charité University Hospital in Berlin said that pembrolizumab, with PD-1 blockade, “has impressive efficacy to be validated in a larger cohort of patients with various gastroenteropancreatic primaries.”

“What I think is the million dollar question is why you have patients who are MSI [mismatch repair deficient] and still not responding to the treatment,” he added. “There might be some other alterations in addition to MSI explaining the nonresponders.”

“We have to look at the inflammatory signature of these patients, and the question of whether we can use them as companion markers, aside from PD-L1, also PD-L2,” Dr. Wiedenmann maintained, referring to the ligands that bind to PD-1.

Patients were eligible for the trial if they had progressive advanced tumors and had received at least one prior therapy. Their tumors were tested for mismatch repair status by way of a commercially available immunohistochemistry kit for mismatch repair deficiency, or a PCR-based assay for microsatellite instability. They were treated with pembrolizumab (Keytruda), an antibody that targets PD-1, every 2 weeks.

In the cohort with mismatch repair–deficient noncolorectal cancers, the updated overall response rate was 47%, and the disease control rate was 76%, Dr. Le reported. Responses and durable responses were seen across tumor types.

The duration of response has ranged from 4 to 20 months, with most patients whose tumors initially responded still doing so as of the data cutoff for analysis.

The rate of grade 3 or 4 treatment-related adverse events was 12%, accounted for entirely by cases of diarrhea and colitis. “However, these were short lived and didn’t require steroids,” Dr. Le noted.

None of the patients experienced grade 3 or 4 rash/pruritus or immune-related endocrine disorders.

“Biochemical response correlates with radiographic response,” she reported, as there was generally good (though not perfect) concordance between the radiographic response and the response according to reductions in levels of cancer antigen 19-9 (CA 19-9).

The median duration of progression-free survival was not estimable. The median duration of overall survival was 21 months, and the 18-month survival rate was approximately 86%.

Dr. Le disclosed that she receives research funding from Aduro Biotech, Bristol-Myers Squibb, and Merck. Merck Sharp & Dohme Corp. was a collaborator on the trial. Dr. Wiedenmann disclosed that he had no conflicts of interest.

SAN FRANCISCO – Blockade of the cell surface receptor programmed death–1 (PD-1) is highly efficacious in patients with advanced noncolorectal cancers of the gastrointestinal tract that are deficient in mismatch repair, according to updated results of a phase II trial reported at the ASCO Gastrointestinal Cancers Symposium.

“Mutations have been shown to encode proteins that can be recognized and targeted by the immune system. The average tumor has dozens of somatic mutations; however, mismatch repair–deficient tumors harbor thousands of mutations,” noted first author Dr. Dung T. Le of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore. “This led to the hypothesis that immune augmentation with PD-1 blockade could be highly effective in mismatch repair–deficient tumors.”

Among 17 patients with noncolorectal cancers of the gastrointestinal tract treated with pembrolizumab in the trial and now having a median follow-up of 5.3 months, nearly half had a response according to radiographic criteria.

The findings expand on previously reported results for this cohort and also for a cohort in the trial having mismatch repair–deficient colorectal cancer, who benefited similarly (N Engl J Med. 2015;372:2509-20).

“Mismatch repair–deficient GI tumors are highly responsive to checkpoint blockade with anti–PD-1. Clinical benefit is noted across tumors with mismatch repair deficiency, including colon, stomach, duodenum, pancreas, ampullary, and bile duct cancers,” Dr. Le said at the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

Invited discussant Dr. Bertram Wiedenmann of Charité University Hospital in Berlin said that pembrolizumab, with PD-1 blockade, “has impressive efficacy to be validated in a larger cohort of patients with various gastroenteropancreatic primaries.”

“What I think is the million dollar question is why you have patients who are MSI [mismatch repair deficient] and still not responding to the treatment,” he added. “There might be some other alterations in addition to MSI explaining the nonresponders.”

“We have to look at the inflammatory signature of these patients, and the question of whether we can use them as companion markers, aside from PD-L1, also PD-L2,” Dr. Wiedenmann maintained, referring to the ligands that bind to PD-1.

Patients were eligible for the trial if they had progressive advanced tumors and had received at least one prior therapy. Their tumors were tested for mismatch repair status by way of a commercially available immunohistochemistry kit for mismatch repair deficiency, or a PCR-based assay for microsatellite instability. They were treated with pembrolizumab (Keytruda), an antibody that targets PD-1, every 2 weeks.

In the cohort with mismatch repair–deficient noncolorectal cancers, the updated overall response rate was 47%, and the disease control rate was 76%, Dr. Le reported. Responses and durable responses were seen across tumor types.

The duration of response has ranged from 4 to 20 months, with most patients whose tumors initially responded still doing so as of the data cutoff for analysis.

The rate of grade 3 or 4 treatment-related adverse events was 12%, accounted for entirely by cases of diarrhea and colitis. “However, these were short lived and didn’t require steroids,” Dr. Le noted.

None of the patients experienced grade 3 or 4 rash/pruritus or immune-related endocrine disorders.

“Biochemical response correlates with radiographic response,” she reported, as there was generally good (though not perfect) concordance between the radiographic response and the response according to reductions in levels of cancer antigen 19-9 (CA 19-9).

The median duration of progression-free survival was not estimable. The median duration of overall survival was 21 months, and the 18-month survival rate was approximately 86%.

Dr. Le disclosed that she receives research funding from Aduro Biotech, Bristol-Myers Squibb, and Merck. Merck Sharp & Dohme Corp. was a collaborator on the trial. Dr. Wiedenmann disclosed that he had no conflicts of interest.

SAN FRANCISCO – Two immune checkpoint inhibitors that help restore the antitumor response are active and well tolerated in patients with advanced, generally heavily pretreated gastric and esophageal cancers, according to a pair of early-phase trials reported at the Gastrointestinal Cancers Symposium.

Results from CheckMate-032 showed that nivolumab, an antibody that targets the cell surface receptor programmed death-1 (PD-1), yielded a response rate of 14% in patients with advanced gastric and related cancers. And updated results from KEYNOTE-028 showed that pembrolizumab, another antibody targeting PD-1, led to a response rate of 30% in patients with advanced esophageal and related cancers that expressed the ligand programmed death ligand 1 (PD-L1).

“Checkpoint inhibitors are clearly promising new agents ... All compounds are still in development, but we already have at least phase 1 data that they are effective,” commented invited discussant Dr. Markus H. Möhler of the University Medical Center Mainz (Germany). “Combination treatment strategies are clearly under investigation, and it is our task as a scientific community to look into interesting modern combinations, like combinations with antiangiogenic agents or maybe even with stem cell inhibition.”

He commended the KEYNOTE-028 investigators, in particular, for their development of a tumor gene signature that appeared to predict benefit from pembrolizumab.

“Molecular and immunological characterization of the patients is key, and we have seen now in the pembrolizumab study with the six-gene signature the first step in the right direction,” Dr. Möhler said, recommending that it be correlated with data from The Cancer Genome Atlas project, which has identified four distinct molecular subtypes of esophagogastric cancer.

“It is now clear that some of these subtypes express higher PD-L1 compared to the others, particularly inflamed subtypes,” he elaborated. “Therefore, it is clear that all the studies in the future really should try to look into the correlation with these four gene subgroups characterized.”

CheckMate-032 trial

Patients with a variety of solid tumors were eligible for CheckMate-032, a phase I/II trial. First author Dr. Dung T. Le reported results for 59 patients with locoregionally advanced or metastatic gastric cancer, esophageal, or gastroesophageal junction cancer who had received at least one prior therapy.

The patients were treated with nivolumab (Opdivo) every 2 weeks. (Nivolumab is currently FDA approved for the treatment of melanoma, non–small cell lung cancer, and renal cancer.)

With a median follow-up of 4.6 months, the response rate was 14%, reported Dr. Le of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, at the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

However, “PD-L1 expression appears to be numerically associated with a higher objective response rate,” she noted. Specifically, the response rate was 27% among patients whose tumor cells showed 1% or greater PD-L1 staining, and an even higher 33% among those whose tumor cells showed 5% or greater PD-L1 staining.

Median overall survival was 5 months. The 6-month overall survival rate was 49%, and the 12-month rate was 36%.

“The adverse event profile was similar to that seen in patients with other tumor types,” Dr. Le commented.

In all, 17% of patients experienced grade 3 or 4 treatment-related adverse events, and 5% experienced grade 3 or 4 treatment-related serious adverse events. These events included elevation of liver enzymes, pneumonitis, fatigue, diarrhea, and vomiting. There were no treatment-related deaths.

KEYNOTE-028 trial

Patients with various types of advanced solid tumors were eligible for KEYNOTE-028, a phase Ib trial, if at least 1% of their tumor or inflammatory cells expressed PD-L1. First author Dr. Toshihiko Doi reported results for 23 patients with esophageal or gastroesophageal junction cancer who had experienced failure of standard therapy or were unable to tolerate it.

The patients were treated with pembrolizumab (Keytruda) every 2 weeks. (Pembrolizumab is currently FDA approved for the treatment of melanoma and non–small cell lung cancer.)

With a median follow-up of 7.1 months, the overall response rate was 30%, reported Dr. Doi of the National Cancer Center Hospital East in Chiba, Japan. By tumor histology, it was 29% for squamous cell carcinomas and 40% for adenocarcinomas.

He and his colleagues performed gene expression profiling of tumor tissue, identifying a six-gene interferon gamma signature that appeared predictive.

Specifically, patients with high signature scores, indicating more inflamed tumors, tended to have a better response rate than those with low scores (43% vs. 11%) as well as longer progression-free survival.

In all, 17% of patients experienced grade 3 treatment-related adverse events (reduced appetite, lymphopenia, liver disorder, and pruritic rash). There were no treatment-related deaths or discontinuations. With respect to adverse events of special interest because of their immune etiology, 9% of patients experienced hypothyroidism, 4% adrenal insufficiency, and 4% pruritic rash.

“Further evaluation of pembrolizumab in esophageal cancer is ongoing,” Dr. Doi concluded, pointing to the KEYNOTE-180 trial, which is testing the agent as third-line therapy, and the KEYNOTE-181 trial, which is pitting it against treatment of physician’s choice as second-line therapy.

SAN FRANCISCO – Two immune checkpoint inhibitors that help restore the antitumor response are active and well tolerated in patients with advanced, generally heavily pretreated gastric and esophageal cancers, according to a pair of early-phase trials reported at the Gastrointestinal Cancers Symposium.

Results from CheckMate-032 showed that nivolumab, an antibody that targets the cell surface receptor programmed death-1 (PD-1), yielded a response rate of 14% in patients with advanced gastric and related cancers. And updated results from KEYNOTE-028 showed that pembrolizumab, another antibody targeting PD-1, led to a response rate of 30% in patients with advanced esophageal and related cancers that expressed the ligand programmed death ligand 1 (PD-L1).

“Checkpoint inhibitors are clearly promising new agents ... All compounds are still in development, but we already have at least phase 1 data that they are effective,” commented invited discussant Dr. Markus H. Möhler of the University Medical Center Mainz (Germany). “Combination treatment strategies are clearly under investigation, and it is our task as a scientific community to look into interesting modern combinations, like combinations with antiangiogenic agents or maybe even with stem cell inhibition.”

He commended the KEYNOTE-028 investigators, in particular, for their development of a tumor gene signature that appeared to predict benefit from pembrolizumab.

“Molecular and immunological characterization of the patients is key, and we have seen now in the pembrolizumab study with the six-gene signature the first step in the right direction,” Dr. Möhler said, recommending that it be correlated with data from The Cancer Genome Atlas project, which has identified four distinct molecular subtypes of esophagogastric cancer.

“It is now clear that some of these subtypes express higher PD-L1 compared to the others, particularly inflamed subtypes,” he elaborated. “Therefore, it is clear that all the studies in the future really should try to look into the correlation with these four gene subgroups characterized.”

CheckMate-032 trial

Patients with a variety of solid tumors were eligible for CheckMate-032, a phase I/II trial. First author Dr. Dung T. Le reported results for 59 patients with locoregionally advanced or metastatic gastric cancer, esophageal, or gastroesophageal junction cancer who had received at least one prior therapy.

The patients were treated with nivolumab (Opdivo) every 2 weeks. (Nivolumab is currently FDA approved for the treatment of melanoma, non–small cell lung cancer, and renal cancer.)

With a median follow-up of 4.6 months, the response rate was 14%, reported Dr. Le of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, at the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

However, “PD-L1 expression appears to be numerically associated with a higher objective response rate,” she noted. Specifically, the response rate was 27% among patients whose tumor cells showed 1% or greater PD-L1 staining, and an even higher 33% among those whose tumor cells showed 5% or greater PD-L1 staining.

Median overall survival was 5 months. The 6-month overall survival rate was 49%, and the 12-month rate was 36%.

“The adverse event profile was similar to that seen in patients with other tumor types,” Dr. Le commented.

In all, 17% of patients experienced grade 3 or 4 treatment-related adverse events, and 5% experienced grade 3 or 4 treatment-related serious adverse events. These events included elevation of liver enzymes, pneumonitis, fatigue, diarrhea, and vomiting. There were no treatment-related deaths.

KEYNOTE-028 trial

Patients with various types of advanced solid tumors were eligible for KEYNOTE-028, a phase Ib trial, if at least 1% of their tumor or inflammatory cells expressed PD-L1. First author Dr. Toshihiko Doi reported results for 23 patients with esophageal or gastroesophageal junction cancer who had experienced failure of standard therapy or were unable to tolerate it.

The patients were treated with pembrolizumab (Keytruda) every 2 weeks. (Pembrolizumab is currently FDA approved for the treatment of melanoma and non–small cell lung cancer.)

With a median follow-up of 7.1 months, the overall response rate was 30%, reported Dr. Doi of the National Cancer Center Hospital East in Chiba, Japan. By tumor histology, it was 29% for squamous cell carcinomas and 40% for adenocarcinomas.

He and his colleagues performed gene expression profiling of tumor tissue, identifying a six-gene interferon gamma signature that appeared predictive.

Specifically, patients with high signature scores, indicating more inflamed tumors, tended to have a better response rate than those with low scores (43% vs. 11%) as well as longer progression-free survival.

In all, 17% of patients experienced grade 3 treatment-related adverse events (reduced appetite, lymphopenia, liver disorder, and pruritic rash). There were no treatment-related deaths or discontinuations. With respect to adverse events of special interest because of their immune etiology, 9% of patients experienced hypothyroidism, 4% adrenal insufficiency, and 4% pruritic rash.

“Further evaluation of pembrolizumab in esophageal cancer is ongoing,” Dr. Doi concluded, pointing to the KEYNOTE-180 trial, which is testing the agent as third-line therapy, and the KEYNOTE-181 trial, which is pitting it against treatment of physician’s choice as second-line therapy.

SAN FRANCISCO – Two immune checkpoint inhibitors that help restore the antitumor response are active and well tolerated in patients with advanced, generally heavily pretreated gastric and esophageal cancers, according to a pair of early-phase trials reported at the Gastrointestinal Cancers Symposium.

Results from CheckMate-032 showed that nivolumab, an antibody that targets the cell surface receptor programmed death-1 (PD-1), yielded a response rate of 14% in patients with advanced gastric and related cancers. And updated results from KEYNOTE-028 showed that pembrolizumab, another antibody targeting PD-1, led to a response rate of 30% in patients with advanced esophageal and related cancers that expressed the ligand programmed death ligand 1 (PD-L1).

“Checkpoint inhibitors are clearly promising new agents ... All compounds are still in development, but we already have at least phase 1 data that they are effective,” commented invited discussant Dr. Markus H. Möhler of the University Medical Center Mainz (Germany). “Combination treatment strategies are clearly under investigation, and it is our task as a scientific community to look into interesting modern combinations, like combinations with antiangiogenic agents or maybe even with stem cell inhibition.”

He commended the KEYNOTE-028 investigators, in particular, for their development of a tumor gene signature that appeared to predict benefit from pembrolizumab.

“Molecular and immunological characterization of the patients is key, and we have seen now in the pembrolizumab study with the six-gene signature the first step in the right direction,” Dr. Möhler said, recommending that it be correlated with data from The Cancer Genome Atlas project, which has identified four distinct molecular subtypes of esophagogastric cancer.

“It is now clear that some of these subtypes express higher PD-L1 compared to the others, particularly inflamed subtypes,” he elaborated. “Therefore, it is clear that all the studies in the future really should try to look into the correlation with these four gene subgroups characterized.”

CheckMate-032 trial

Patients with a variety of solid tumors were eligible for CheckMate-032, a phase I/II trial. First author Dr. Dung T. Le reported results for 59 patients with locoregionally advanced or metastatic gastric cancer, esophageal, or gastroesophageal junction cancer who had received at least one prior therapy.

The patients were treated with nivolumab (Opdivo) every 2 weeks. (Nivolumab is currently FDA approved for the treatment of melanoma, non–small cell lung cancer, and renal cancer.)

With a median follow-up of 4.6 months, the response rate was 14%, reported Dr. Le of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, at the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

However, “PD-L1 expression appears to be numerically associated with a higher objective response rate,” she noted. Specifically, the response rate was 27% among patients whose tumor cells showed 1% or greater PD-L1 staining, and an even higher 33% among those whose tumor cells showed 5% or greater PD-L1 staining.

Median overall survival was 5 months. The 6-month overall survival rate was 49%, and the 12-month rate was 36%.

“The adverse event profile was similar to that seen in patients with other tumor types,” Dr. Le commented.

In all, 17% of patients experienced grade 3 or 4 treatment-related adverse events, and 5% experienced grade 3 or 4 treatment-related serious adverse events. These events included elevation of liver enzymes, pneumonitis, fatigue, diarrhea, and vomiting. There were no treatment-related deaths.

KEYNOTE-028 trial

Patients with various types of advanced solid tumors were eligible for KEYNOTE-028, a phase Ib trial, if at least 1% of their tumor or inflammatory cells expressed PD-L1. First author Dr. Toshihiko Doi reported results for 23 patients with esophageal or gastroesophageal junction cancer who had experienced failure of standard therapy or were unable to tolerate it.

The patients were treated with pembrolizumab (Keytruda) every 2 weeks. (Pembrolizumab is currently FDA approved for the treatment of melanoma and non–small cell lung cancer.)

With a median follow-up of 7.1 months, the overall response rate was 30%, reported Dr. Doi of the National Cancer Center Hospital East in Chiba, Japan. By tumor histology, it was 29% for squamous cell carcinomas and 40% for adenocarcinomas.

He and his colleagues performed gene expression profiling of tumor tissue, identifying a six-gene interferon gamma signature that appeared predictive.

Specifically, patients with high signature scores, indicating more inflamed tumors, tended to have a better response rate than those with low scores (43% vs. 11%) as well as longer progression-free survival.

In all, 17% of patients experienced grade 3 treatment-related adverse events (reduced appetite, lymphopenia, liver disorder, and pruritic rash). There were no treatment-related deaths or discontinuations. With respect to adverse events of special interest because of their immune etiology, 9% of patients experienced hypothyroidism, 4% adrenal insufficiency, and 4% pruritic rash.

“Further evaluation of pembrolizumab in esophageal cancer is ongoing,” Dr. Doi concluded, pointing to the KEYNOTE-180 trial, which is testing the agent as third-line therapy, and the KEYNOTE-181 trial, which is pitting it against treatment of physician’s choice as second-line therapy.