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DART trial hits the target in angiosarcoma
Rare cancers comprise about 20% of all cancers in the United States and Europe, according to recent estimates, but patients with rare cancers are vastly underrepresented in clinical trials.
Recently, there has been a focus on immune checkpoint blockade (ICB) in common cancer types. Since several rare tumor types share similar biologic features with the more common tumors, there is a need to test ICB in rare tumors, particularly because remissions with ICB can be durable.
Enter the DART trial, a phase 2, single-arm study of combinatorial ICB with ipilimumab plus nivolumab in patients with unresectable or metastatic rare cancers.
Results from DART were recently presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting. Michael J. Wagner, MD, of the University of Washington, Seattle, reported results in patients with advanced or unresectable angiosarcoma, one of the rare tumor types included in DART.
About angiosarcomas
Angiosarcomas account for less than 3% of all adult soft-tissue sarcomas, according to a review published in The Lancet Oncology. Angiosarcomas may arise in any part of the body, especially the head and neck (27%), breast (19.7%), and extremities (15.3%). These cancers can be primary or secondary (i.e., associated with prior radiation therapy or chronic lymphedema).
Angiosarcomas are aggressive, difficult to treat, and confer high mortality. The tumors are responsive to chemotherapy, but responses are brief. The estimated 5-year survival rate for all patients with angiosarcoma, including those who present with localized disease, is 30%-40%.
According to Dr. Wagner, a subset of angiosarcomas are characterized by high tumor mutational burden (TMB) and COSMIC signature 7, a DNA mutational signature that is consistent with other cancers caused by ultraviolet light exposure.
The high TMB subset of angiosarcomas is comparable with other cancer types that are responsive to ICB. Indeed, patients with angiosarcoma treated with ICB have shown responses, according to research published in the Journal for Immunotherapy of Cancer. However, no prospective studies of ICB in angiosarcoma have been published.
About DART
The DART trial includes more than 50 cohorts of rare cancer subtypes. Patients receive IV ipilimumab at 1 mg/kg every 6 weeks and IV nivolumab at 240 mg every 2 weeks.
The primary endpoint is objective response rate, as assessed by RECIST v1.1. Secondary endpoints include progression-free survival, overall survival, stable disease at 6 months, and toxicity.
The trial has a two-stage design. Six patients are enrolled in the first stage, and, if at least one patient responds to treatment, an additional 10 patients are enrolled in the second stage.
If at least two responses are seen among the 16 patients enrolled, further study of ICB is considered warranted.
Results in angiosarcoma
Dr. Wagner reported on the 16 angiosarcoma patients enrolled in DART. Nine patients had cutaneous primary tumors, seven had noncutaneous primary tumors, and three patients had radiation-associated angiosarcoma of the breast or chest wall.
Patients had received a median of two (range, zero to five) prior lines of therapy.
Adverse events (AEs) were consistent with prior safety results of the ipilimumab-nivolumab combination. Three-quarters of patients experienced an AE of any grade. The most common AEs were transaminase elevation, anemia, diarrhea, fatigue, hypothyroidism, pneumonitis, pruritus, and rash.
A quarter of patients had a grade 3-4 AE, and 12.5% of AEs led to premature treatment discontinuation. There were no fatal AEs.
The ORR was 25%. Responses occurred in 4 of the 16 patients, including 3 of 5 patients with primary cutaneous tumors of the scalp or face and 1 of 3 patients with radiation-associated breast angiosarcoma.
Two of the four responses and one case of stable disease have persisted for almost a year, and these patients remain on treatment. To put these results into perspective, Dr. Wagner noted that responses to cytotoxic chemotherapy rarely last 6 months.
The 6-month progression-free survival rate was 38%. The median overall survival has not yet been reached.
Dr. Wagner concluded that the combinatorial ICB regimen employed in DART was well tolerated and had an ORR of 25% in angiosarcoma regardless of primary site. Per the criteria of the DART trial, further investigation of ICB in angiosarcoma is warranted.
Molecular insights
Although correlative analyses of tumor tissue and peripheral blood are embedded in the DART trial, those analyses have not yet been performed. Eight of the 16 angiosarcoma patients had diagnostic molecular studies performed at their parent institutions, utilizing a variety of commercial platforms.
All eight patients for whom molecular data were available had at least two deleterious genomic alterations detected, but each had a distinct molecular profile.
Seven patients had TMB analyzed, including two partial responders to ICB. One of the seven patients had a high TMB, and this patient was one of the two responders. The other responder had an intermediate TMB.
Three patients had programmed death–ligand 1 staining on their tumors. Two of the three had high expression of PD-L1, including the responder with an intermediate TMB.
The real impact of DART
The DART trial is a “basket trial,” employing a similar treatment regimen for multiple tumor types. It provides a uniform framework for studying tumors that have been neglected in clinical trials heretofore.
Although the cohort of angiosarcoma patients is small, central pathology review was not required, and the treatment regimen was not compared directly with other potential therapies, the reported results of the ipilimumab-nivolumab regimen justify further study.
The biospecimens collected in DART will provide a rich source of data to identify common themes among responders and nonresponders, among patients who experience durable remissions and those who do not.
Angiosarcoma is not the only rare cancer for which combinatorial ICB has been valuable under the auspices of the DART trial. In Clinical Cancer Research, investigators reported an ORR of 44% among patients with high-grade neuroendocrine cancers, independent of primary site of origin. Progression-free survival at 6 months was 31%.
The DART trial is available at more than 800 sites, providing access to potentially promising treatment in a rigorous, scientifically valuable study for geographically underserved populations, including patients who live in rural areas.
The key message for practicing oncologists and clinical investigators is that clinical trials in rare tumors are feasible and can yield hope for patients who might lack it otherwise.
DART is funded by the National Cancer Institute and Bristol-Myers Squibb. Dr. Wagner disclosed relationships with Deciphera, Adaptimmune, GlaxoSmithKline, Athenex, and Incyte.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Wagner M et al. SITC 2020, Abstract 795.
Rare cancers comprise about 20% of all cancers in the United States and Europe, according to recent estimates, but patients with rare cancers are vastly underrepresented in clinical trials.
Recently, there has been a focus on immune checkpoint blockade (ICB) in common cancer types. Since several rare tumor types share similar biologic features with the more common tumors, there is a need to test ICB in rare tumors, particularly because remissions with ICB can be durable.
Enter the DART trial, a phase 2, single-arm study of combinatorial ICB with ipilimumab plus nivolumab in patients with unresectable or metastatic rare cancers.
Results from DART were recently presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting. Michael J. Wagner, MD, of the University of Washington, Seattle, reported results in patients with advanced or unresectable angiosarcoma, one of the rare tumor types included in DART.
About angiosarcomas
Angiosarcomas account for less than 3% of all adult soft-tissue sarcomas, according to a review published in The Lancet Oncology. Angiosarcomas may arise in any part of the body, especially the head and neck (27%), breast (19.7%), and extremities (15.3%). These cancers can be primary or secondary (i.e., associated with prior radiation therapy or chronic lymphedema).
Angiosarcomas are aggressive, difficult to treat, and confer high mortality. The tumors are responsive to chemotherapy, but responses are brief. The estimated 5-year survival rate for all patients with angiosarcoma, including those who present with localized disease, is 30%-40%.
According to Dr. Wagner, a subset of angiosarcomas are characterized by high tumor mutational burden (TMB) and COSMIC signature 7, a DNA mutational signature that is consistent with other cancers caused by ultraviolet light exposure.
The high TMB subset of angiosarcomas is comparable with other cancer types that are responsive to ICB. Indeed, patients with angiosarcoma treated with ICB have shown responses, according to research published in the Journal for Immunotherapy of Cancer. However, no prospective studies of ICB in angiosarcoma have been published.
About DART
The DART trial includes more than 50 cohorts of rare cancer subtypes. Patients receive IV ipilimumab at 1 mg/kg every 6 weeks and IV nivolumab at 240 mg every 2 weeks.
The primary endpoint is objective response rate, as assessed by RECIST v1.1. Secondary endpoints include progression-free survival, overall survival, stable disease at 6 months, and toxicity.
The trial has a two-stage design. Six patients are enrolled in the first stage, and, if at least one patient responds to treatment, an additional 10 patients are enrolled in the second stage.
If at least two responses are seen among the 16 patients enrolled, further study of ICB is considered warranted.
Results in angiosarcoma
Dr. Wagner reported on the 16 angiosarcoma patients enrolled in DART. Nine patients had cutaneous primary tumors, seven had noncutaneous primary tumors, and three patients had radiation-associated angiosarcoma of the breast or chest wall.
Patients had received a median of two (range, zero to five) prior lines of therapy.
Adverse events (AEs) were consistent with prior safety results of the ipilimumab-nivolumab combination. Three-quarters of patients experienced an AE of any grade. The most common AEs were transaminase elevation, anemia, diarrhea, fatigue, hypothyroidism, pneumonitis, pruritus, and rash.
A quarter of patients had a grade 3-4 AE, and 12.5% of AEs led to premature treatment discontinuation. There were no fatal AEs.
The ORR was 25%. Responses occurred in 4 of the 16 patients, including 3 of 5 patients with primary cutaneous tumors of the scalp or face and 1 of 3 patients with radiation-associated breast angiosarcoma.
Two of the four responses and one case of stable disease have persisted for almost a year, and these patients remain on treatment. To put these results into perspective, Dr. Wagner noted that responses to cytotoxic chemotherapy rarely last 6 months.
The 6-month progression-free survival rate was 38%. The median overall survival has not yet been reached.
Dr. Wagner concluded that the combinatorial ICB regimen employed in DART was well tolerated and had an ORR of 25% in angiosarcoma regardless of primary site. Per the criteria of the DART trial, further investigation of ICB in angiosarcoma is warranted.
Molecular insights
Although correlative analyses of tumor tissue and peripheral blood are embedded in the DART trial, those analyses have not yet been performed. Eight of the 16 angiosarcoma patients had diagnostic molecular studies performed at their parent institutions, utilizing a variety of commercial platforms.
All eight patients for whom molecular data were available had at least two deleterious genomic alterations detected, but each had a distinct molecular profile.
Seven patients had TMB analyzed, including two partial responders to ICB. One of the seven patients had a high TMB, and this patient was one of the two responders. The other responder had an intermediate TMB.
Three patients had programmed death–ligand 1 staining on their tumors. Two of the three had high expression of PD-L1, including the responder with an intermediate TMB.
The real impact of DART
The DART trial is a “basket trial,” employing a similar treatment regimen for multiple tumor types. It provides a uniform framework for studying tumors that have been neglected in clinical trials heretofore.
Although the cohort of angiosarcoma patients is small, central pathology review was not required, and the treatment regimen was not compared directly with other potential therapies, the reported results of the ipilimumab-nivolumab regimen justify further study.
The biospecimens collected in DART will provide a rich source of data to identify common themes among responders and nonresponders, among patients who experience durable remissions and those who do not.
Angiosarcoma is not the only rare cancer for which combinatorial ICB has been valuable under the auspices of the DART trial. In Clinical Cancer Research, investigators reported an ORR of 44% among patients with high-grade neuroendocrine cancers, independent of primary site of origin. Progression-free survival at 6 months was 31%.
The DART trial is available at more than 800 sites, providing access to potentially promising treatment in a rigorous, scientifically valuable study for geographically underserved populations, including patients who live in rural areas.
The key message for practicing oncologists and clinical investigators is that clinical trials in rare tumors are feasible and can yield hope for patients who might lack it otherwise.
DART is funded by the National Cancer Institute and Bristol-Myers Squibb. Dr. Wagner disclosed relationships with Deciphera, Adaptimmune, GlaxoSmithKline, Athenex, and Incyte.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Wagner M et al. SITC 2020, Abstract 795.
Rare cancers comprise about 20% of all cancers in the United States and Europe, according to recent estimates, but patients with rare cancers are vastly underrepresented in clinical trials.
Recently, there has been a focus on immune checkpoint blockade (ICB) in common cancer types. Since several rare tumor types share similar biologic features with the more common tumors, there is a need to test ICB in rare tumors, particularly because remissions with ICB can be durable.
Enter the DART trial, a phase 2, single-arm study of combinatorial ICB with ipilimumab plus nivolumab in patients with unresectable or metastatic rare cancers.
Results from DART were recently presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting. Michael J. Wagner, MD, of the University of Washington, Seattle, reported results in patients with advanced or unresectable angiosarcoma, one of the rare tumor types included in DART.
About angiosarcomas
Angiosarcomas account for less than 3% of all adult soft-tissue sarcomas, according to a review published in The Lancet Oncology. Angiosarcomas may arise in any part of the body, especially the head and neck (27%), breast (19.7%), and extremities (15.3%). These cancers can be primary or secondary (i.e., associated with prior radiation therapy or chronic lymphedema).
Angiosarcomas are aggressive, difficult to treat, and confer high mortality. The tumors are responsive to chemotherapy, but responses are brief. The estimated 5-year survival rate for all patients with angiosarcoma, including those who present with localized disease, is 30%-40%.
According to Dr. Wagner, a subset of angiosarcomas are characterized by high tumor mutational burden (TMB) and COSMIC signature 7, a DNA mutational signature that is consistent with other cancers caused by ultraviolet light exposure.
The high TMB subset of angiosarcomas is comparable with other cancer types that are responsive to ICB. Indeed, patients with angiosarcoma treated with ICB have shown responses, according to research published in the Journal for Immunotherapy of Cancer. However, no prospective studies of ICB in angiosarcoma have been published.
About DART
The DART trial includes more than 50 cohorts of rare cancer subtypes. Patients receive IV ipilimumab at 1 mg/kg every 6 weeks and IV nivolumab at 240 mg every 2 weeks.
The primary endpoint is objective response rate, as assessed by RECIST v1.1. Secondary endpoints include progression-free survival, overall survival, stable disease at 6 months, and toxicity.
The trial has a two-stage design. Six patients are enrolled in the first stage, and, if at least one patient responds to treatment, an additional 10 patients are enrolled in the second stage.
If at least two responses are seen among the 16 patients enrolled, further study of ICB is considered warranted.
Results in angiosarcoma
Dr. Wagner reported on the 16 angiosarcoma patients enrolled in DART. Nine patients had cutaneous primary tumors, seven had noncutaneous primary tumors, and three patients had radiation-associated angiosarcoma of the breast or chest wall.
Patients had received a median of two (range, zero to five) prior lines of therapy.
Adverse events (AEs) were consistent with prior safety results of the ipilimumab-nivolumab combination. Three-quarters of patients experienced an AE of any grade. The most common AEs were transaminase elevation, anemia, diarrhea, fatigue, hypothyroidism, pneumonitis, pruritus, and rash.
A quarter of patients had a grade 3-4 AE, and 12.5% of AEs led to premature treatment discontinuation. There were no fatal AEs.
The ORR was 25%. Responses occurred in 4 of the 16 patients, including 3 of 5 patients with primary cutaneous tumors of the scalp or face and 1 of 3 patients with radiation-associated breast angiosarcoma.
Two of the four responses and one case of stable disease have persisted for almost a year, and these patients remain on treatment. To put these results into perspective, Dr. Wagner noted that responses to cytotoxic chemotherapy rarely last 6 months.
The 6-month progression-free survival rate was 38%. The median overall survival has not yet been reached.
Dr. Wagner concluded that the combinatorial ICB regimen employed in DART was well tolerated and had an ORR of 25% in angiosarcoma regardless of primary site. Per the criteria of the DART trial, further investigation of ICB in angiosarcoma is warranted.
Molecular insights
Although correlative analyses of tumor tissue and peripheral blood are embedded in the DART trial, those analyses have not yet been performed. Eight of the 16 angiosarcoma patients had diagnostic molecular studies performed at their parent institutions, utilizing a variety of commercial platforms.
All eight patients for whom molecular data were available had at least two deleterious genomic alterations detected, but each had a distinct molecular profile.
Seven patients had TMB analyzed, including two partial responders to ICB. One of the seven patients had a high TMB, and this patient was one of the two responders. The other responder had an intermediate TMB.
Three patients had programmed death–ligand 1 staining on their tumors. Two of the three had high expression of PD-L1, including the responder with an intermediate TMB.
The real impact of DART
The DART trial is a “basket trial,” employing a similar treatment regimen for multiple tumor types. It provides a uniform framework for studying tumors that have been neglected in clinical trials heretofore.
Although the cohort of angiosarcoma patients is small, central pathology review was not required, and the treatment regimen was not compared directly with other potential therapies, the reported results of the ipilimumab-nivolumab regimen justify further study.
The biospecimens collected in DART will provide a rich source of data to identify common themes among responders and nonresponders, among patients who experience durable remissions and those who do not.
Angiosarcoma is not the only rare cancer for which combinatorial ICB has been valuable under the auspices of the DART trial. In Clinical Cancer Research, investigators reported an ORR of 44% among patients with high-grade neuroendocrine cancers, independent of primary site of origin. Progression-free survival at 6 months was 31%.
The DART trial is available at more than 800 sites, providing access to potentially promising treatment in a rigorous, scientifically valuable study for geographically underserved populations, including patients who live in rural areas.
The key message for practicing oncologists and clinical investigators is that clinical trials in rare tumors are feasible and can yield hope for patients who might lack it otherwise.
DART is funded by the National Cancer Institute and Bristol-Myers Squibb. Dr. Wagner disclosed relationships with Deciphera, Adaptimmune, GlaxoSmithKline, Athenex, and Incyte.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Wagner M et al. SITC 2020, Abstract 795.
FROM SITC 2020
‘Impressive’ results with neoadjuvant T-VEC in advanced melanoma
T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.
“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.
The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.
“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.
The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
Survival results
The median follow-up for this interim analysis was 41.3 months.
The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.
These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).
“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.
The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).
Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.
Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).
In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.
“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.
No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.
“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.
“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.
“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.
“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
‘Impressive’ data support more research
“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.
“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.
“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”
Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.
However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.
“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.
An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.
“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”
The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.
SOURCE: Dummer R et al. SITC 2020, Abstract 432.
T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.
“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.
The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.
“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.
The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
Survival results
The median follow-up for this interim analysis was 41.3 months.
The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.
These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).
“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.
The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).
Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.
Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).
In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.
“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.
No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.
“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.
“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.
“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.
“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
‘Impressive’ data support more research
“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.
“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.
“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”
Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.
However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.
“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.
An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.
“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”
The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.
SOURCE: Dummer R et al. SITC 2020, Abstract 432.
T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.
“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.
The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.
“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.
The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
Survival results
The median follow-up for this interim analysis was 41.3 months.
The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.
These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).
“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.
The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).
Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.
Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).
In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.
“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.
No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.
“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.
“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.
“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.
“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
‘Impressive’ data support more research
“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.
“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.
“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”
Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.
However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.
“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.
An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.
“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”
The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.
SOURCE: Dummer R et al. SITC 2020, Abstract 432.
FROM SITC 2020
Immune checkpoint inhibitors don’t increase COVID-19 incidence or mortality, studies suggest
Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.
However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.
In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).
In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).
Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
COVID-19 incidence with ICIs
Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.
The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).
In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).
Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.
“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”
COVID-19 mortality with ICIs
For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.
Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.
In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.
Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).
At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.
The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.
“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.
“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
ICI therapy can continue, with precautions
“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.
“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.
However, the findings of the study by Tyan and colleagues are more “thought-provoking,” Dr. Doroshow said. She noted that a large study published in Nature Medicine showed previous ICI therapy in cancer patients with COVID-19 increased the risk for hospitalization or severe COVID-19 requiring high-flow oxygen or mechanical ventilation. The new study was much smaller and did not perform statistical comparisons for outcomes such as oxygen requirements.
“I would feel comfortable telling patients that the data suggests that ICI treatment does not increase their risk of COVID-19. However, if they were to be diagnosed with COVID-19, it is unclear whether their previous ICI treatment increases their risk for poor outcomes,” Dr. Doroshow said.
“I would feel comfortable continuing to treat patients with ICIs at this time, but because we know that patients with cancer are generally more likely to develop COVID-19 and have poor outcomes, it is critical that our patients be educated about social distancing and mask wearing to the extent that their living and working situations permit,” she added.
Mr. Pahalyants disclosed no relevant conflicts of interest, and his study did not receive any specific funding. Mr. Tyan disclosed that he is cofounder and chief science officer of Kinnos, and his study did not receive any specific funding. Dr. Doroshow disclosed no relevant conflicts of interest.
SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.
Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.
However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.
In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).
In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).
Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
COVID-19 incidence with ICIs
Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.
The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).
In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).
Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.
“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”
COVID-19 mortality with ICIs
For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.
Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.
In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.
Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).
At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.
The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.
“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.
“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
ICI therapy can continue, with precautions
“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.
“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.
However, the findings of the study by Tyan and colleagues are more “thought-provoking,” Dr. Doroshow said. She noted that a large study published in Nature Medicine showed previous ICI therapy in cancer patients with COVID-19 increased the risk for hospitalization or severe COVID-19 requiring high-flow oxygen or mechanical ventilation. The new study was much smaller and did not perform statistical comparisons for outcomes such as oxygen requirements.
“I would feel comfortable telling patients that the data suggests that ICI treatment does not increase their risk of COVID-19. However, if they were to be diagnosed with COVID-19, it is unclear whether their previous ICI treatment increases their risk for poor outcomes,” Dr. Doroshow said.
“I would feel comfortable continuing to treat patients with ICIs at this time, but because we know that patients with cancer are generally more likely to develop COVID-19 and have poor outcomes, it is critical that our patients be educated about social distancing and mask wearing to the extent that their living and working situations permit,” she added.
Mr. Pahalyants disclosed no relevant conflicts of interest, and his study did not receive any specific funding. Mr. Tyan disclosed that he is cofounder and chief science officer of Kinnos, and his study did not receive any specific funding. Dr. Doroshow disclosed no relevant conflicts of interest.
SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.
Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.
However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.
In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).
In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).
Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
COVID-19 incidence with ICIs
Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.
The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).
In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).
Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.
“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”
COVID-19 mortality with ICIs
For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.
Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.
In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.
Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).
At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.
The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.
“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.
“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
ICI therapy can continue, with precautions
“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.
“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.
However, the findings of the study by Tyan and colleagues are more “thought-provoking,” Dr. Doroshow said. She noted that a large study published in Nature Medicine showed previous ICI therapy in cancer patients with COVID-19 increased the risk for hospitalization or severe COVID-19 requiring high-flow oxygen or mechanical ventilation. The new study was much smaller and did not perform statistical comparisons for outcomes such as oxygen requirements.
“I would feel comfortable telling patients that the data suggests that ICI treatment does not increase their risk of COVID-19. However, if they were to be diagnosed with COVID-19, it is unclear whether their previous ICI treatment increases their risk for poor outcomes,” Dr. Doroshow said.
“I would feel comfortable continuing to treat patients with ICIs at this time, but because we know that patients with cancer are generally more likely to develop COVID-19 and have poor outcomes, it is critical that our patients be educated about social distancing and mask wearing to the extent that their living and working situations permit,” she added.
Mr. Pahalyants disclosed no relevant conflicts of interest, and his study did not receive any specific funding. Mr. Tyan disclosed that he is cofounder and chief science officer of Kinnos, and his study did not receive any specific funding. Dr. Doroshow disclosed no relevant conflicts of interest.
SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.
FROM SITC 2020
Neoadjuvant immunotherapy combo produces high response rate in melanoma
A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.
The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.
CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.
These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.
“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
Patients, treatment, and response
The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.
The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.
At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.
“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”
Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
Survival and safety
Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).
The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.
Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.
Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
Another treatment option?
“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.
“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.
However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.
Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.
The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.
SOURCE: Davar D et al. SITC 2020, Abstract 303.
A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.
The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.
CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.
These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.
“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
Patients, treatment, and response
The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.
The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.
At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.
“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”
Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
Survival and safety
Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).
The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.
Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.
Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
Another treatment option?
“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.
“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.
However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.
Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.
The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.
SOURCE: Davar D et al. SITC 2020, Abstract 303.
A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.
The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.
CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.
These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.
“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
Patients, treatment, and response
The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.
The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.
At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.
“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”
Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
Survival and safety
Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).
The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.
Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.
Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
Another treatment option?
“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.
“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.
However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.
Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.
The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.
SOURCE: Davar D et al. SITC 2020, Abstract 303.
FROM SITC 2020
Immunotherapy could fill unmet need in leptomeningeal metastases
Results from the trial were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks,” commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.
“While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types,” Dr. Naidoo added.
With this in mind, Dr. Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.
The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.
Response, safety, and biomarkers
Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Dr. Naidoo reported.
Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.
For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.
“This is consistent with published prospective studies of systemic agents for leptomeningeal disease,” Dr. Naidoo pointed out. “Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies.”
The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.
The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.
The trial’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).
A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.
Given the trial’s 38% CNS response rate, pembrolizumab “needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors,” Dr. Naidoo concluded. “Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity.”
An unmet need
“Leptomeningeal metastasis is a strong unmet need, although its occurrence is fortunately quite rare,” commented Kim Margolin, MD, a clinical professor and medical oncologist at City of Hope National Medical Center in Duarte, Calif., who was not involved in this study.
The trial is noteworthy for showing activity of programmed death–1 (PD-1) blockade given only systemically and not with additional intrathecal therapy (as has been done in a concurrent study at MD Anderson Cancer Center) and for providing insight into various biomarkers, Dr. Margolin said in an interview.
“I cannot take a stand on author conclusions other than to agree it warrants further evaluation in carefully selected patients, and it would be great to compare something like peripheral PD-1 blockade alone versus in combination with intrathecal therapy versus a combination such as CTLA4 blockade plus PD-1 blockade such as our group and others have shown to have increased activity in CNS metastases over PD-1 block alone,” Dr. Margolin said.
“The drugs in this class are already approved, so there is no reason not to try them,” she noted.
However, patients with leptomeningeal metastases of melanoma, for example, are likely to have already received anti-PD-1 immunotherapy.
“So the settings in which off-the-shelf PD-1 blockade would be useful are extremely limited,” she concluded.
The current trial was funded by Merck, the National Institutes of Health, the Lung Cancer Foundation of America, the International Association for the Study of Lung Cancer, and Johns Hopkins University Seed Grants. Dr. Naidoo disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, and Roche/Genentech. Dr. Margolin disclosed no relevant conflicts of interest.
SOURCE: Naidoo J et al. SITC 2020, Abstract 788.
Results from the trial were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks,” commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.
“While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types,” Dr. Naidoo added.
With this in mind, Dr. Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.
The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.
Response, safety, and biomarkers
Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Dr. Naidoo reported.
Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.
For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.
“This is consistent with published prospective studies of systemic agents for leptomeningeal disease,” Dr. Naidoo pointed out. “Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies.”
The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.
The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.
The trial’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).
A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.
Given the trial’s 38% CNS response rate, pembrolizumab “needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors,” Dr. Naidoo concluded. “Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity.”
An unmet need
“Leptomeningeal metastasis is a strong unmet need, although its occurrence is fortunately quite rare,” commented Kim Margolin, MD, a clinical professor and medical oncologist at City of Hope National Medical Center in Duarte, Calif., who was not involved in this study.
The trial is noteworthy for showing activity of programmed death–1 (PD-1) blockade given only systemically and not with additional intrathecal therapy (as has been done in a concurrent study at MD Anderson Cancer Center) and for providing insight into various biomarkers, Dr. Margolin said in an interview.
“I cannot take a stand on author conclusions other than to agree it warrants further evaluation in carefully selected patients, and it would be great to compare something like peripheral PD-1 blockade alone versus in combination with intrathecal therapy versus a combination such as CTLA4 blockade plus PD-1 blockade such as our group and others have shown to have increased activity in CNS metastases over PD-1 block alone,” Dr. Margolin said.
“The drugs in this class are already approved, so there is no reason not to try them,” she noted.
However, patients with leptomeningeal metastases of melanoma, for example, are likely to have already received anti-PD-1 immunotherapy.
“So the settings in which off-the-shelf PD-1 blockade would be useful are extremely limited,” she concluded.
The current trial was funded by Merck, the National Institutes of Health, the Lung Cancer Foundation of America, the International Association for the Study of Lung Cancer, and Johns Hopkins University Seed Grants. Dr. Naidoo disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, and Roche/Genentech. Dr. Margolin disclosed no relevant conflicts of interest.
SOURCE: Naidoo J et al. SITC 2020, Abstract 788.
Results from the trial were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Unfortunately, when patients present with leptomeningeal disease, they usually have a poor prognosis. Their median survival is measured at 6-24 weeks,” commented lead study author Jarushka Naidoo, MBBCh, an adjunct assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, and a consultant medical oncologist at Beaumont Hospital in Dublin.
“While there may be some standard approaches for how we treat leptomeningeal disease, there are no universal standard therapies that are efficacious across solid tumor types,” Dr. Naidoo added.
With this in mind, Dr. Naidoo and colleagues tested systemic pembrolizumab in a trial of patients with leptomeningeal metastases from solid tumors.
The trial closed early because of poor accrual, after enrolling 13 patients: 5 with breast carcinoma, 3 with high-grade glioma, 3 with non–small cell lung cancer, 1 with squamous cell carcinoma of the skin, and 1 with head and neck squamous carcinoma. Nine patients (69%) had received at least two prior lines of systemic therapy.
Response, safety, and biomarkers
Overall, five patients (38%) had a central nervous system response, as ascertained from radiologic response on MRI, cytologic response in cerebrospinal fluid (CSF), and/or clinical response in neurologic symptoms, Dr. Naidoo reported.
Two patients had a complete CNS response: a patient with squamous cell carcinoma of the skin, who was still alive at 3 years, and a patient with non–small cell lung cancer, who survived 9 months but succumbed to metastases elsewhere.
For the entire cohort, median CNS progression-free survival was 2.9 months, and median overall survival was 4.9 months.
“This is consistent with published prospective studies of systemic agents for leptomeningeal disease,” Dr. Naidoo pointed out. “Notably, even though numbers are small, we do see the tail-on-the-curve phenomenon in both of these survival curves, which is consistent with immune checkpoint blockade prospective studies.”
The rate of grade 3 or higher treatment-related adverse events was 15.4%, and there were no grade 3 or higher immune-related adverse events.
The number of patients was too small for formal correlational testing, but both patients who achieved a complete response developed immune-related adverse events.
The trial’s biomarker analyses showed that an aneuploidy assay using CSF tumor-derived DNA performed well at detecting leptomeningeal metastases, with sensitivity of 84.6%, compared with just 53.8% for CSF cytopathology (the current preferred method).
A multiplex assay of CSF cytokines identified similar baseline profiles for patients who went on to have responses and showed similar changes in profile (notably a reduction in proinflammatory cytokines) for the two patients who had complete responses.
Given the trial’s 38% CNS response rate, pembrolizumab “needs to be studied in larger populations of patients to confirm this result, but it could be used as a potential treatment option for patients with leptomeningeal disease from solid tumors,” Dr. Naidoo concluded. “Reassuringly, pembrolizumab was well tolerated, and this is extremely important in a patient population that is traditionally quite frail and in which other standard therapies that are used, such as high-dose methotrexate or intrathecal chemotherapy, are associated with far higher rates of toxicity.”
An unmet need
“Leptomeningeal metastasis is a strong unmet need, although its occurrence is fortunately quite rare,” commented Kim Margolin, MD, a clinical professor and medical oncologist at City of Hope National Medical Center in Duarte, Calif., who was not involved in this study.
The trial is noteworthy for showing activity of programmed death–1 (PD-1) blockade given only systemically and not with additional intrathecal therapy (as has been done in a concurrent study at MD Anderson Cancer Center) and for providing insight into various biomarkers, Dr. Margolin said in an interview.
“I cannot take a stand on author conclusions other than to agree it warrants further evaluation in carefully selected patients, and it would be great to compare something like peripheral PD-1 blockade alone versus in combination with intrathecal therapy versus a combination such as CTLA4 blockade plus PD-1 blockade such as our group and others have shown to have increased activity in CNS metastases over PD-1 block alone,” Dr. Margolin said.
“The drugs in this class are already approved, so there is no reason not to try them,” she noted.
However, patients with leptomeningeal metastases of melanoma, for example, are likely to have already received anti-PD-1 immunotherapy.
“So the settings in which off-the-shelf PD-1 blockade would be useful are extremely limited,” she concluded.
The current trial was funded by Merck, the National Institutes of Health, the Lung Cancer Foundation of America, the International Association for the Study of Lung Cancer, and Johns Hopkins University Seed Grants. Dr. Naidoo disclosed relationships with AstraZeneca, Merck, Bristol Myers Squibb, and Roche/Genentech. Dr. Margolin disclosed no relevant conflicts of interest.
SOURCE: Naidoo J et al. SITC 2020, Abstract 788.
FROM SITC 2020
Risk factors for severe immune-related AEs identified
The first nationwide study of severe immune-related adverse events among cancer patients treated with immune checkpoint inhibitors helps identify those at elevated risk. The findings were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Immune-related adverse events are a very serious side effect of immune checkpoint inhibitor therapy, and as this therapy has become more common for treating advanced cancers, the incidence of immune-related adverse events has increased as well,” said presenting author William Murphy, a dual MD and MBA student at Harvard Medical School and Harvard Business School, both in Boston.
“However, because there is no ICD code for immune-related adverse events, it’s very difficult to study them at a population level. Most of the current literature around the incidence of immune-related adverse events and factors that are predictive of incidence are based on clinical trials and small studies,” Mr. Murphy noted.
He and his colleagues analyzed claims data from a U.S. nationwide health insurance plan for 14,378 patients who had a primary cancer and received at least one administration of an immune checkpoint inhibitor – an inhibitor of PD-1, PD-L1, or CTLA4 – during 2011-2019.
Over 19,117 patient-years of follow-up, 504 patients (3.5%) developed a severe immune-related adverse event (irAE), defined as one occurring within 2 years of their treatment and requiring inpatient hospitalization and new immunosuppression.
The incidence of severe irAEs per patient treatment year was 2.6% overall, rising from 0% in 2011 to 3.7% in 2016.
In multivariate analysis, patients had an elevated risk of severe irAEs if they received combination immunotherapy as compared with monotherapy (odds ratio, 2.44; P < .001).
On the other hand, risk fell with advancing age (OR, 0.98 per additional year; P < .001). And risk was lower for patients with melanoma (OR, 0.70; P = .01), renal cell carcinoma (OR, 0.71; P = .03), and other cancers (OR, 0.50; P < .001), compared with lung cancer.
Sex, geographic region, income, employment status, and comorbidity were not significantly associated with the risk of severe irAEs.
“We hope that patients and providers can use this evidence from a nationwide study of severe irAEs to guide treatment and management decisions,” Mr. Murphy concluded.
Real-world evidence
“As the use of immune checkpoint inhibitors increases for patients with a variety of different tumor types, there is increasing need for population-level evidence for patients treated outside of clinical trials,” said Allison Betof Warner, MD, PhD, an assistant attending physician with the melanoma service at Memorial Sloan Kettering Cancer Center in New York.
“This is a well-conducted study with an innovative approach to using real-world evidence to examine immune-related adverse events,” she added.
To her knowledge, it is the first study to look at multiple cancers for which immunotherapy is approved, Dr. Betof Warner said. This approach resulted in a large patient sample, giving power to detect differences between groups.
“The authors’ finding that combination immunotherapy is associated with more severe irAEs is in line with our clinical experience and other data sets, and the data regarding increased odds of severe irAEs in younger patients and those with lung cancer raise interesting biological questions about the etiology of irAEs,” Dr. Betof Warner noted.
However, certain factors complicate interpretation of the study’s findings, she cautioned. One such factor is requiring hospitalization to define an irAE.
“Practice patterns regarding hospitalization vary quite widely from center to center. For example, in some centers, all patients with immune-mediated colitis are hospitalized, whereas in others, these patients are managed predominantly in the outpatient setting, even in cases of high-grade toxicity,” she explained. “Practice patterns have also changed drastically over time as oncologists have grown more comfortable managing immune-related adverse events.”
Another factor is potential confounding. For example, patients with melanoma are more likely to receive combination immunotherapy given its longstanding approval for this cancer, whereas it is comparatively new for other cancers. Also, age may differ across cancers.
“The data the authors have provided are a great starting point, but I think further analysis is needed before these observations can be validated and integrated into practice,” Dr. Betof Warner concluded.
This study did not receive any specific funding. Mr. Murphy and Dr. Betof Warner disclosed no relevant conflicts of interest.
SOURCE: Murphy W et al. SITC 2020, Abstract 854.
The first nationwide study of severe immune-related adverse events among cancer patients treated with immune checkpoint inhibitors helps identify those at elevated risk. The findings were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Immune-related adverse events are a very serious side effect of immune checkpoint inhibitor therapy, and as this therapy has become more common for treating advanced cancers, the incidence of immune-related adverse events has increased as well,” said presenting author William Murphy, a dual MD and MBA student at Harvard Medical School and Harvard Business School, both in Boston.
“However, because there is no ICD code for immune-related adverse events, it’s very difficult to study them at a population level. Most of the current literature around the incidence of immune-related adverse events and factors that are predictive of incidence are based on clinical trials and small studies,” Mr. Murphy noted.
He and his colleagues analyzed claims data from a U.S. nationwide health insurance plan for 14,378 patients who had a primary cancer and received at least one administration of an immune checkpoint inhibitor – an inhibitor of PD-1, PD-L1, or CTLA4 – during 2011-2019.
Over 19,117 patient-years of follow-up, 504 patients (3.5%) developed a severe immune-related adverse event (irAE), defined as one occurring within 2 years of their treatment and requiring inpatient hospitalization and new immunosuppression.
The incidence of severe irAEs per patient treatment year was 2.6% overall, rising from 0% in 2011 to 3.7% in 2016.
In multivariate analysis, patients had an elevated risk of severe irAEs if they received combination immunotherapy as compared with monotherapy (odds ratio, 2.44; P < .001).
On the other hand, risk fell with advancing age (OR, 0.98 per additional year; P < .001). And risk was lower for patients with melanoma (OR, 0.70; P = .01), renal cell carcinoma (OR, 0.71; P = .03), and other cancers (OR, 0.50; P < .001), compared with lung cancer.
Sex, geographic region, income, employment status, and comorbidity were not significantly associated with the risk of severe irAEs.
“We hope that patients and providers can use this evidence from a nationwide study of severe irAEs to guide treatment and management decisions,” Mr. Murphy concluded.
Real-world evidence
“As the use of immune checkpoint inhibitors increases for patients with a variety of different tumor types, there is increasing need for population-level evidence for patients treated outside of clinical trials,” said Allison Betof Warner, MD, PhD, an assistant attending physician with the melanoma service at Memorial Sloan Kettering Cancer Center in New York.
“This is a well-conducted study with an innovative approach to using real-world evidence to examine immune-related adverse events,” she added.
To her knowledge, it is the first study to look at multiple cancers for which immunotherapy is approved, Dr. Betof Warner said. This approach resulted in a large patient sample, giving power to detect differences between groups.
“The authors’ finding that combination immunotherapy is associated with more severe irAEs is in line with our clinical experience and other data sets, and the data regarding increased odds of severe irAEs in younger patients and those with lung cancer raise interesting biological questions about the etiology of irAEs,” Dr. Betof Warner noted.
However, certain factors complicate interpretation of the study’s findings, she cautioned. One such factor is requiring hospitalization to define an irAE.
“Practice patterns regarding hospitalization vary quite widely from center to center. For example, in some centers, all patients with immune-mediated colitis are hospitalized, whereas in others, these patients are managed predominantly in the outpatient setting, even in cases of high-grade toxicity,” she explained. “Practice patterns have also changed drastically over time as oncologists have grown more comfortable managing immune-related adverse events.”
Another factor is potential confounding. For example, patients with melanoma are more likely to receive combination immunotherapy given its longstanding approval for this cancer, whereas it is comparatively new for other cancers. Also, age may differ across cancers.
“The data the authors have provided are a great starting point, but I think further analysis is needed before these observations can be validated and integrated into practice,” Dr. Betof Warner concluded.
This study did not receive any specific funding. Mr. Murphy and Dr. Betof Warner disclosed no relevant conflicts of interest.
SOURCE: Murphy W et al. SITC 2020, Abstract 854.
The first nationwide study of severe immune-related adverse events among cancer patients treated with immune checkpoint inhibitors helps identify those at elevated risk. The findings were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.
“Immune-related adverse events are a very serious side effect of immune checkpoint inhibitor therapy, and as this therapy has become more common for treating advanced cancers, the incidence of immune-related adverse events has increased as well,” said presenting author William Murphy, a dual MD and MBA student at Harvard Medical School and Harvard Business School, both in Boston.
“However, because there is no ICD code for immune-related adverse events, it’s very difficult to study them at a population level. Most of the current literature around the incidence of immune-related adverse events and factors that are predictive of incidence are based on clinical trials and small studies,” Mr. Murphy noted.
He and his colleagues analyzed claims data from a U.S. nationwide health insurance plan for 14,378 patients who had a primary cancer and received at least one administration of an immune checkpoint inhibitor – an inhibitor of PD-1, PD-L1, or CTLA4 – during 2011-2019.
Over 19,117 patient-years of follow-up, 504 patients (3.5%) developed a severe immune-related adverse event (irAE), defined as one occurring within 2 years of their treatment and requiring inpatient hospitalization and new immunosuppression.
The incidence of severe irAEs per patient treatment year was 2.6% overall, rising from 0% in 2011 to 3.7% in 2016.
In multivariate analysis, patients had an elevated risk of severe irAEs if they received combination immunotherapy as compared with monotherapy (odds ratio, 2.44; P < .001).
On the other hand, risk fell with advancing age (OR, 0.98 per additional year; P < .001). And risk was lower for patients with melanoma (OR, 0.70; P = .01), renal cell carcinoma (OR, 0.71; P = .03), and other cancers (OR, 0.50; P < .001), compared with lung cancer.
Sex, geographic region, income, employment status, and comorbidity were not significantly associated with the risk of severe irAEs.
“We hope that patients and providers can use this evidence from a nationwide study of severe irAEs to guide treatment and management decisions,” Mr. Murphy concluded.
Real-world evidence
“As the use of immune checkpoint inhibitors increases for patients with a variety of different tumor types, there is increasing need for population-level evidence for patients treated outside of clinical trials,” said Allison Betof Warner, MD, PhD, an assistant attending physician with the melanoma service at Memorial Sloan Kettering Cancer Center in New York.
“This is a well-conducted study with an innovative approach to using real-world evidence to examine immune-related adverse events,” she added.
To her knowledge, it is the first study to look at multiple cancers for which immunotherapy is approved, Dr. Betof Warner said. This approach resulted in a large patient sample, giving power to detect differences between groups.
“The authors’ finding that combination immunotherapy is associated with more severe irAEs is in line with our clinical experience and other data sets, and the data regarding increased odds of severe irAEs in younger patients and those with lung cancer raise interesting biological questions about the etiology of irAEs,” Dr. Betof Warner noted.
However, certain factors complicate interpretation of the study’s findings, she cautioned. One such factor is requiring hospitalization to define an irAE.
“Practice patterns regarding hospitalization vary quite widely from center to center. For example, in some centers, all patients with immune-mediated colitis are hospitalized, whereas in others, these patients are managed predominantly in the outpatient setting, even in cases of high-grade toxicity,” she explained. “Practice patterns have also changed drastically over time as oncologists have grown more comfortable managing immune-related adverse events.”
Another factor is potential confounding. For example, patients with melanoma are more likely to receive combination immunotherapy given its longstanding approval for this cancer, whereas it is comparatively new for other cancers. Also, age may differ across cancers.
“The data the authors have provided are a great starting point, but I think further analysis is needed before these observations can be validated and integrated into practice,” Dr. Betof Warner concluded.
This study did not receive any specific funding. Mr. Murphy and Dr. Betof Warner disclosed no relevant conflicts of interest.
SOURCE: Murphy W et al. SITC 2020, Abstract 854.
FROM SITC 2020