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An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.
Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.
But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.
The report appeared in the March 3 issue of the Journal of Clinical Oncology.
"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.
The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).
PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.
The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.
The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.
Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.
About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.
Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.
Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.
An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.
Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.
Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.
"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.
Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.
Immunotherapy treatments for cancer might "raise survival curves to new heights," Dr. Geraldine O’Sullivan Coyne wrote in an editorial.
"The continued demonstration of promising clinical outcomes with the use of modern immunotherapy strategies such as nivolumab may allow medical oncologists to have raised expectations for patients with metastatic cancer," wrote Dr. Coyne and her colleagues.
Immune checkpoint inhibitors, including ipilimumab and nivolumab, hold much promise, as exemplified by their large number of complete and near-complete responses, the colleagues wrote. Both drugs showed a flattening of overall survival curves after 2 years, suggesting that at least some patients could derive considerable benefit from longer-term treatment.
"This tail in the curve raises questions about how to increase the number of patients who receive long-term clinical benefit, and how to predict who those patients might be."
Combining one of these drugs with another treatment might even compound its effect, they said. "One promising strategy, referred to as immunogenic intensification, combines one immune checkpoint inhibitor with a different [one] or a therapeutic vaccine ... Hypothetically, vaccine therapy could have a priming or steering effect on the immune system, potentially reducing the need for higher doses of immune checkpoint inhibition or multiple immune checkpoint inhibitors, and lessening the risk of inducing autoimmunity. Such approaches may have the potential to improve clinical outcomes while minimizing adverse effects."
There’s nowhere to go but up for the kinds of cancers being investigated with these drugs, they said.
"Current treatment for metastatic solid tumors ... remains palliative, but perhaps immune checkpoint inhibitors can be part of a strategy to enhance the number of patients who can enjoy sustained, durable responses. ... If future clinical trials validate the findings that have been seen in recent years, perhaps immunotherapy will not just raise expectations, but the all-important survival tail of Kaplan-Meier curves as well."
Dr. Geraldine O’Sullivan Coyne is a medical oncologist at the National Cancer Institute. Neither she nor her co-authors had any financial disclosures.
Immunotherapy treatments for cancer might "raise survival curves to new heights," Dr. Geraldine O’Sullivan Coyne wrote in an editorial.
"The continued demonstration of promising clinical outcomes with the use of modern immunotherapy strategies such as nivolumab may allow medical oncologists to have raised expectations for patients with metastatic cancer," wrote Dr. Coyne and her colleagues.
Immune checkpoint inhibitors, including ipilimumab and nivolumab, hold much promise, as exemplified by their large number of complete and near-complete responses, the colleagues wrote. Both drugs showed a flattening of overall survival curves after 2 years, suggesting that at least some patients could derive considerable benefit from longer-term treatment.
"This tail in the curve raises questions about how to increase the number of patients who receive long-term clinical benefit, and how to predict who those patients might be."
Combining one of these drugs with another treatment might even compound its effect, they said. "One promising strategy, referred to as immunogenic intensification, combines one immune checkpoint inhibitor with a different [one] or a therapeutic vaccine ... Hypothetically, vaccine therapy could have a priming or steering effect on the immune system, potentially reducing the need for higher doses of immune checkpoint inhibition or multiple immune checkpoint inhibitors, and lessening the risk of inducing autoimmunity. Such approaches may have the potential to improve clinical outcomes while minimizing adverse effects."
There’s nowhere to go but up for the kinds of cancers being investigated with these drugs, they said.
"Current treatment for metastatic solid tumors ... remains palliative, but perhaps immune checkpoint inhibitors can be part of a strategy to enhance the number of patients who can enjoy sustained, durable responses. ... If future clinical trials validate the findings that have been seen in recent years, perhaps immunotherapy will not just raise expectations, but the all-important survival tail of Kaplan-Meier curves as well."
Dr. Geraldine O’Sullivan Coyne is a medical oncologist at the National Cancer Institute. Neither she nor her co-authors had any financial disclosures.
Immunotherapy treatments for cancer might "raise survival curves to new heights," Dr. Geraldine O’Sullivan Coyne wrote in an editorial.
"The continued demonstration of promising clinical outcomes with the use of modern immunotherapy strategies such as nivolumab may allow medical oncologists to have raised expectations for patients with metastatic cancer," wrote Dr. Coyne and her colleagues.
Immune checkpoint inhibitors, including ipilimumab and nivolumab, hold much promise, as exemplified by their large number of complete and near-complete responses, the colleagues wrote. Both drugs showed a flattening of overall survival curves after 2 years, suggesting that at least some patients could derive considerable benefit from longer-term treatment.
"This tail in the curve raises questions about how to increase the number of patients who receive long-term clinical benefit, and how to predict who those patients might be."
Combining one of these drugs with another treatment might even compound its effect, they said. "One promising strategy, referred to as immunogenic intensification, combines one immune checkpoint inhibitor with a different [one] or a therapeutic vaccine ... Hypothetically, vaccine therapy could have a priming or steering effect on the immune system, potentially reducing the need for higher doses of immune checkpoint inhibition or multiple immune checkpoint inhibitors, and lessening the risk of inducing autoimmunity. Such approaches may have the potential to improve clinical outcomes while minimizing adverse effects."
There’s nowhere to go but up for the kinds of cancers being investigated with these drugs, they said.
"Current treatment for metastatic solid tumors ... remains palliative, but perhaps immune checkpoint inhibitors can be part of a strategy to enhance the number of patients who can enjoy sustained, durable responses. ... If future clinical trials validate the findings that have been seen in recent years, perhaps immunotherapy will not just raise expectations, but the all-important survival tail of Kaplan-Meier curves as well."
Dr. Geraldine O’Sullivan Coyne is a medical oncologist at the National Cancer Institute. Neither she nor her co-authors had any financial disclosures.
An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.
Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.
But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.
The report appeared in the March 3 issue of the Journal of Clinical Oncology.
"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.
The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).
PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.
The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.
The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.
Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.
About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.
Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.
Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.
An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.
Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.
Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.
"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.
Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.
An immunomodulator that targets the PD-1 pathway effected sustained remission in 31% of patients who took it for advanced melanoma.
Remission lasted a median of 2 years, with 1- and 2-year overall survival of 62% and 43% respectively, wrote Dr. Suzanne Topalian and colleagues.
But perhaps even more exciting, they said, is that the benefit of nivolumab persisted for at least 16 weeks in all patients who had to discontinue therapy.
The report appeared in the March 3 issue of the Journal of Clinical Oncology.
"The persistence of partial tumor regression and stable disease ... suggests that PD-1 blockade may reset the immune equilibrium between tumor and host," wrote Dr. Topalian, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, and her coauthors.
The findings "are consistent with a mechanism by which an effective tumor-selective immune memory response may have been established in some patients, similar to immune memory against specific infectious organisms after antigen exposure," the investigators wrote (J. Clin. Oncol. 2014 March [doi:10.1200/JCO.2013.53.0105]).
PD-1 is an immune checkpoint that helps regulate the autoimmune action of activated T cells. Tumor cells can co-opt this pathway, using it to hide from T cell attack. Blocking PD-1 unmasks tumor cells, allowing the immune system to target them more effectively.
The 2-year follow-up study tracked response rates in 107 patients with advanced melanoma, who were part of a larger study of 306 patients with various solid-tumor cancers. The initial results of the phase I trial were reported at the 2013 meeting of the American Society of Clinical Oncology.
The new report focuses only on the patients with melanoma, who have completed treatment for at least 14 months, and up to 4 years. All of the patients had undergone two to five prior systemic treatments. They received up to 96 weeks of biweekly nivolumab infusions in varying doses.
Median progression-free survival was 3.7 months; 1- and 2-year progression-free survival rates were 36% and 27%, respectively.
About a third of the patients (33; 31%) experienced an objective response to the drug, with a median duration of 2 years. Fifteen of these (45%) occurred within the first 8 weeks of treatment, the investigators wrote. Of these responding patients, 19 (58%) were still responding when the data were analyzed, the authors noted.
Tumors regressed at various sites, including, in one patient, an unresectable lesion that had eroded through the zygomatic arch into the orbit. Response occurred within 4 months of treatment initiation. This lesion remains in remission. A biopsy showed fibrosis and infiltrating lymphocytes, but no tumor cells. This finding hints that residual tumor seen in some patients’ imaging may in fact be scarring. If that is true, the researchers said, they could have underestimated the real response rate.
Seventeen of the 33 patients who responded discontinued treatment for reasons other than progression. Among these, 12 (71%) maintained their response for 16-56 weeks; in eight of these, response was ongoing at the time of data analysis. Among these is a patient who had metastatic lesions in the adrenal gland, small bowel, and mesenteric lymph nodes.
An additional 7% (7 patients) experienced stable disease for at least 24 weeks at doses of 0.1 to 10 mg/kg. "Unconventional" response patterns not meeting RECIST criteria occurred in four patients, but there was no associated dose pattern; three had received 1 mg/kg and the fourth, 10 mg/kg. Disease progressed in 11 patients treated at doses of 0.1 to 03 mg/kg; none of these responded to a dose escalation, the investigators said.
Nivolumab’s safety data were excellent when compared with other cancer treatments, they noted. Most adverse events occurred within the first 6 months – a hint that close observation and early intervention could minimize their impact. The most common were fatigue (32%), rash (23%), and diarrhea (18%). Grades 3 and 4 adverse events occurred in 24 patients. Treatment-related select adverse events of any grade occurred in 58 (54%). The most common were skin disorders (36%), gastrointestinal events (18%), and endocrinopathies (13%) – not unexpected in an immunomodulating drug. There were no drug-related deaths in the study.
Although this study examined nivolumab as monotherapy, others are looking at a possibly synergistic effect when it’s given with other immunomodulators, and with chemotherapy, kinase inhibitors, or cancer vaccines.
"Innovative, rational treatment combinations based on preclinical evidence may be needed to realize the full therapeutic potential of PD-1 blockade," the investigators said.
Dr. Topalian and several of her coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.
Major finding: The PD-1 receptor inhibitor nivolumab effected sustained response in 31% of those who took it for advanced melanoma.
Data source: A retrospective study of 107 patients with advanced melanoma.
Disclosures: Dr. Topalian and several coauthors received research funding or had other financial relationships with Bristol-Myers Squibb, sponsor of the study.