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Axitinib/pembrolizumab combo safe, effective against mRCC
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
This phase 1 trial highlights some issues that merit discussion. First, the eligibility criteria of the study population should be considered. Renal cell carcinoma is a very heterogeneous disease with a natural history that could range from an indolent clinical course to a slow progressive or an aggressive behavior. The prognostic models proposed by Memorial Sloan-Kettering Cancer Center and the International Metastatic Renal Cell Carcinoma Database Consortium are now validated for stratification of patients in clinical trials. By contrast, patients treated in clinical practice are often excluded from clinical trials and have a poor prognosis and derive less benefit from standard treatments. Atkins and colleagues treated a small number of patients from a highly selected study population, with no patients with poor clinical conditions or who had not undergone nephrectomy. Considering these aspects, how have the favorable prognostic features of the population affected the feasibility and efficacy of the treatment proposed? In this regard, only assessment of a larger number of patients in a less selected population can confirm these activity results.
Second, the absence of central radiological review in the trial could represent a major limitation in the interpretation of treatment response and the evaluation of progression-free survival. The Response Evaluation Criteria in Solid Tumors version 1.1 criteria used to assess response are often unable to distinguish between pseudoprogression, hyperprogression, and late response to immunotherapies. Therefore, the assessment of response during treatment with immune checkpoint inhibitors remains debated, and physicians often carefully consider the opportunity to continue treatment in cases with doubtful or mixed response and must decide whether to change the therapy on the basis of the clinical benefit being received by patients.
Third, another issue concerns the potential benefit of the combination therapy proposed. Axitinib is a multikinase inhibitor able to act on a broad spectrum of kinases related to angiogenesis. Axitinib monotherapy is considered a therapeutic option after an angiogenesis inhibitor for patients with metastatic renal cell carcinoma. Pembrolizumab is a PD-1 inhibitor under evaluation in combination strategies for the treatment of metastatic renal cell carcinoma. The combination of pembrolizumab and axitinib was safe and feasible, which is in contrast to results previously reported for other combinations, such as nivolumab plus pazopanib or sunitinib and pembrolizumab plus pazopanib. This evidence suggests that similar drugs might have different toxicity profiles when used in combination, and axitinib remains one the most tolerable tyrosine kinase inhibitors.
In summary, the combination of pembrolizumab and axitinib is very promising and the outcomes of Atkins and colleagues’ study could become the first evidence in favor of a combination of two drugs with different mechanisms of action for the treatment of metastatic renal cell carcinoma. Future research should attempt to select more patients who will respond to treatment on the basis of their clinical and molecular features.
Giuseppe Procopio, MD, Raffaele Ratta, MD, Filippo de Braud, MD, and Elena Verzoni, MD, are with the medical oncology department of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, and the medical oncology department of the University of Milan. The commentary was adapted and condensed from an editorial (Lancet Oncol. 2018 Feb 10. doi: 10.1016/S1470-2045[18]30092-5).
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
A combination of the tyrosine kinase inhibitor axitinib (Inlyta) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was associated with acceptable toxicities and showed promising activity against advanced renal cell carcinoma (RCC) in the first-line setting, results of a phase 1b trial indicate.
Of 11 patients enrolled in a dose-finding study and 41 enrolled in the expansion phase of that study, 38 had an objective response (complete or partial response), for an overall response rate of 73%, reported Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, and his colleagues.
“This phase 1b study showed that the combination of axitinib and pembrolizumab at nearly the full planned doses of each drug is tolerable in patients with treatment-naive advanced renal cell carcinoma,” they wrote. The report was published in The Lancet Oncology.
Previous studies of programmed death-1 (PD-1) checkpoint inhibitors such as pembrolizumab or nivolumab (Opdivo) combined with inhibitors of vascular endothelial growth factor (VEGF) have resulted in excessive toxicities attributed to off-target effects of the VEGF inhibitors used.
The investigators reasoned that because axitinib is more selective and specific for targets in the VEGF pathway, it might make a safer and more effective partner to a PD-1 inhibitor than the multikinase inhibitors sunitinib (Sutent) or pazopanib (Votrient).
“A formal systematic review was not done before doing this trial because most of the work combining VEGF pathway inhibitors with checkpoint inhibitors is new and not yet published,” Dr. Atkins and his associates explained.
As of the March 31, 2017, data cutoff, 52 patients from 10 U.S. centers had been treated with the same dose and schedule and were included in the analysis. All patients had tumors with clear cell renal carcinoma histologies; one also had sarcomatoid features.
There were three investigator-assessed dose-limiting toxicities (DLT, the primary endpoint) in the 11 patients treated in the dose-finding phase. One of the patients had a transient ischemic attack and two completed less than 75% of the planned axitinib dose because of treatment-related toxicities.
Of the 52 patients, 25 were still on treatment at the time of data cutoff: 22 who were still receiving both axitinib and pembrolizumab and 3 who were receiving only the PD-1 inhibitor. Eight of the patients continued on therapy despite disease progression.
Of the 27 patients who discontinued both drugs, 10 did so because of adverse events, 9 for disease progression, and others for various reasons such as mixed adverse events and disease progression, investigator discretion, global deterioration, or protocol violation.
Grade 3 or greater adverse events occurred in 34 patients (65%), and included hypertension, diarrhea, fatigue, and elevated alanine aminostransferase (ALT) levels.
The most common potentially immune-related adverse events were diarrhea, ALT elevations, hypothyroidism, and fatigue.
At a median follow-up of 20.4 months, 4 patients had a complete response, and 34 had a partial response. An additional eight patients had stable disease. Responses were seen in 18 of 24 patients with favorable-risk disease and in 18 of 26 patients with intermediate- or poor-risk disease. The median time to response was 2.8 months, and the median duration of response was 18.6 months.
“Future research should focus on investigating the mechanism of the potential synergistic effects of axitinib and pembrolizumab, and whether an immunotherapy-only approach (including combinations) enriched by the appropriate biomarkers, followed by VEGFR TKI salvage, might produce more durable off-treatment responses or whether administering VEGFR TKI monotherapy followed by PD-1 and PD-L1 pathway blockade might produce superior or equivalent results,” the investigators concluded.
Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
SOURCE: Atkins MB et al. Lancet Oncol 2018 Feb. 10. doi: 10.1016/S1470-2045(18)30081-0.
FROM THE LANCET ONCOLOGY
Key clinical point: A combination of axitinib and pembrolizumab was tolerable and showed activity against advanced/metastatic renal cell carcinoma.
Major finding: At a median of 20.4 months of follow-up, the overall response rate was 73%.
Study details: Open-label phase 1b dose-finding trial and expansion in 52 patients with advanced RCC.
Disclosures: Pfizer, in collaboration with Merck, sponsored the study. Dr. Atkins and several coauthors disclosed consulting fees from Pfizer, Merck, and other companies. Four of the coauthors are Pfizer employees and stockholders.
Source: Atkins MB et al. Lancet Oncol 2018 Feb 10. doi: 10.1016/S1470-2045(18)30081-0.
ERV expression may predict response to immune checkpoint blockade in ccRCC, other solid tumors
SAN FRANCISCO – The (ccRCC), according to findings from an analysis of nearly 5,000 tumor samples.
Similar associations may exist in other solid tumors, Shridar Ganesan, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
Merkel cell carcinoma, for example, has a high response rate despite its relatively low mutation burden. This is explained by the presence of infection with the Merkel cell polyomavirus in a low mutation burden subset, he said, noting that expression of the virus likely leads to expression of antigens that makes the disease both highly immunogenic and responsive to immune checkpoint therapy.
Expression of exogenous viruses is associated with response to immune checkpoint therapy in other cancers with low mutation burden, such as Epstein-Barr virus-positive gastric cancer, natural killer lymphoma, and Hodgkin disease.
“Intriguingly, renal cell carcinoma also has a relatively higher response rate to immune checkpoint therapy than would be anticipated by its relatively low mutation burden. However, this has no evidence of exogenous virus infection. Therefore, we turned our attention to endogenous retroviruses, which are an abundant potential stimulant of innate immunity in cancer,” he said.
Endogenous retroviruses (ERVs) now comprise about 5-8% of the human genome, and almost all of them have mutations that disable key coding genes of the retrovirus, meaning most cannot produce all the proteins necessary for viral replication.
“They’re essentially genomic fossils,” Dr. Ganesan said, adding that they all are silenced epigenetically in most normal adult tissues, both by DNA methylation and histone methylation. “However, inappropriate expression of endogenous retroviruses has been reported by multiple groups in some cancers and has been associated with evidence of immune activation. One can imagine that endogenous retroviral expression can be immunogenic both by expression of some [open reading frames] that are not disabled ... or just the viral RNA itself, which can be detected by cytoplasmic sensors ... and activate innate immunity,” he said.
To assess whether ERV expression corresponds with evidence of immune checkpoint activation in cancer, he and his colleagues conducted a pan-cancer analysis of more than 4,900 tumors across 21 cancer types using data from the Cancer Genome Atlas (TCGA).
“When we did this for about 66 annotated endogenous retroviruses in the TCGA database, we could see that different cancers had different amounts of retrovirus associated with immune activation ... in fact the strongest signal seen in this analysis was in clear cell renal cell carcinoma,” he said.
Signals were also seen in estrogen receptor–positive/human epidermal growth factor receptor 2-negative breast cancer, head and neck squamous cell carcinoma, and colon cancer.
A variety of ERVs were upregulated in RCC; different panels were associated with different cancer types. But two – ERVK.2 and ERV3.2 – were consistently upregulated across all the tumor types.
A closer look at ERV expression showed three clear clusters: extremely-high, intermediate, and low expression of ERV, and the very-high expression cluster had increased expression of numerous checkpoint genes, including CD8A, PD1, CTLA4, and LAG3 among others, compared with the low expression cluster.
This leads to the question of why a subset of RCCs have ERV expression.
In an attempt to answer that question, a transcript analysis was conducted to determine which transcripts are differentially regulated between the high and low ERV-expressing groups, and gene ontology analysis was performed.
“The results were quite striking. If you look at the modules that are differentially expressed between the high-ERV and the low-ERV groups, what pops up is really a lot of histone methyltransferase modules and chromatin regulation modules, ” he said, noting that this makes sense because of the silencing of ERV expression by histone methylation and DNA methylation, and suggests that “there is some deep abnormality in chromatin modulation in this subset of RCCs.
“This is intriguing, because RCCs are known to have mutations in chromatin modifying genes,” he said.
A look into whether the high-ERV–expressing group was enriched in any of these mutations showed some enrichment of BAP1 in the high- vs. low-expressing group, and that is currently being looked at further, he noted.
The next question was whether ERV expression correlated with response to immune checkpoint blockade in ccRCC, and this was looked at in a nonrandomized group of 15 patients with metastatic ccRCC who were treated with single-agent immune checkpoint therapy who had either clearly documented partial response or progressive disease. In 13 patient samples for which RNA expression of ERV3.2 was successfully measured by quantitative real-time polymerase chain reaction using two primer sets, ERV3.2 expression was significantly higher in responders vs. nonresponders in both primer sets (P less than .05 and .005).
“In summary, we have shown that expression of ERVs correlates with immune activation and increased expression of immune checkpoint genes in a subset of ccRCC, and perhaps several other solid tumor classes, and the expression of ERV3.2 is perhaps associated with response to PD1 blockade in this small preliminary cohort of ccRCC patients,” he said, noting that abnormal expression of ERV may be a biomarker of immune checkpoint therapy response in some cancers with a low mutation burden. “Mechanisms underlying ERV expression need to be investigated and may reflect underlying chromatin alterations or epigenetic abnormalities.”
Dr. Ganesan reported that his spouse is employed by Merck and that he is a consultant and/or advisory board member for Novartis, Roche, and Inspirata. He also holds patents with Inspirata.
SOURCE: Panda A et al., ASCO-SITC, Abstract #104.
SAN FRANCISCO – The (ccRCC), according to findings from an analysis of nearly 5,000 tumor samples.
Similar associations may exist in other solid tumors, Shridar Ganesan, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
Merkel cell carcinoma, for example, has a high response rate despite its relatively low mutation burden. This is explained by the presence of infection with the Merkel cell polyomavirus in a low mutation burden subset, he said, noting that expression of the virus likely leads to expression of antigens that makes the disease both highly immunogenic and responsive to immune checkpoint therapy.
Expression of exogenous viruses is associated with response to immune checkpoint therapy in other cancers with low mutation burden, such as Epstein-Barr virus-positive gastric cancer, natural killer lymphoma, and Hodgkin disease.
“Intriguingly, renal cell carcinoma also has a relatively higher response rate to immune checkpoint therapy than would be anticipated by its relatively low mutation burden. However, this has no evidence of exogenous virus infection. Therefore, we turned our attention to endogenous retroviruses, which are an abundant potential stimulant of innate immunity in cancer,” he said.
Endogenous retroviruses (ERVs) now comprise about 5-8% of the human genome, and almost all of them have mutations that disable key coding genes of the retrovirus, meaning most cannot produce all the proteins necessary for viral replication.
“They’re essentially genomic fossils,” Dr. Ganesan said, adding that they all are silenced epigenetically in most normal adult tissues, both by DNA methylation and histone methylation. “However, inappropriate expression of endogenous retroviruses has been reported by multiple groups in some cancers and has been associated with evidence of immune activation. One can imagine that endogenous retroviral expression can be immunogenic both by expression of some [open reading frames] that are not disabled ... or just the viral RNA itself, which can be detected by cytoplasmic sensors ... and activate innate immunity,” he said.
To assess whether ERV expression corresponds with evidence of immune checkpoint activation in cancer, he and his colleagues conducted a pan-cancer analysis of more than 4,900 tumors across 21 cancer types using data from the Cancer Genome Atlas (TCGA).
“When we did this for about 66 annotated endogenous retroviruses in the TCGA database, we could see that different cancers had different amounts of retrovirus associated with immune activation ... in fact the strongest signal seen in this analysis was in clear cell renal cell carcinoma,” he said.
Signals were also seen in estrogen receptor–positive/human epidermal growth factor receptor 2-negative breast cancer, head and neck squamous cell carcinoma, and colon cancer.
A variety of ERVs were upregulated in RCC; different panels were associated with different cancer types. But two – ERVK.2 and ERV3.2 – were consistently upregulated across all the tumor types.
A closer look at ERV expression showed three clear clusters: extremely-high, intermediate, and low expression of ERV, and the very-high expression cluster had increased expression of numerous checkpoint genes, including CD8A, PD1, CTLA4, and LAG3 among others, compared with the low expression cluster.
This leads to the question of why a subset of RCCs have ERV expression.
In an attempt to answer that question, a transcript analysis was conducted to determine which transcripts are differentially regulated between the high and low ERV-expressing groups, and gene ontology analysis was performed.
“The results were quite striking. If you look at the modules that are differentially expressed between the high-ERV and the low-ERV groups, what pops up is really a lot of histone methyltransferase modules and chromatin regulation modules, ” he said, noting that this makes sense because of the silencing of ERV expression by histone methylation and DNA methylation, and suggests that “there is some deep abnormality in chromatin modulation in this subset of RCCs.
“This is intriguing, because RCCs are known to have mutations in chromatin modifying genes,” he said.
A look into whether the high-ERV–expressing group was enriched in any of these mutations showed some enrichment of BAP1 in the high- vs. low-expressing group, and that is currently being looked at further, he noted.
The next question was whether ERV expression correlated with response to immune checkpoint blockade in ccRCC, and this was looked at in a nonrandomized group of 15 patients with metastatic ccRCC who were treated with single-agent immune checkpoint therapy who had either clearly documented partial response or progressive disease. In 13 patient samples for which RNA expression of ERV3.2 was successfully measured by quantitative real-time polymerase chain reaction using two primer sets, ERV3.2 expression was significantly higher in responders vs. nonresponders in both primer sets (P less than .05 and .005).
“In summary, we have shown that expression of ERVs correlates with immune activation and increased expression of immune checkpoint genes in a subset of ccRCC, and perhaps several other solid tumor classes, and the expression of ERV3.2 is perhaps associated with response to PD1 blockade in this small preliminary cohort of ccRCC patients,” he said, noting that abnormal expression of ERV may be a biomarker of immune checkpoint therapy response in some cancers with a low mutation burden. “Mechanisms underlying ERV expression need to be investigated and may reflect underlying chromatin alterations or epigenetic abnormalities.”
Dr. Ganesan reported that his spouse is employed by Merck and that he is a consultant and/or advisory board member for Novartis, Roche, and Inspirata. He also holds patents with Inspirata.
SOURCE: Panda A et al., ASCO-SITC, Abstract #104.
SAN FRANCISCO – The (ccRCC), according to findings from an analysis of nearly 5,000 tumor samples.
Similar associations may exist in other solid tumors, Shridar Ganesan, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
Merkel cell carcinoma, for example, has a high response rate despite its relatively low mutation burden. This is explained by the presence of infection with the Merkel cell polyomavirus in a low mutation burden subset, he said, noting that expression of the virus likely leads to expression of antigens that makes the disease both highly immunogenic and responsive to immune checkpoint therapy.
Expression of exogenous viruses is associated with response to immune checkpoint therapy in other cancers with low mutation burden, such as Epstein-Barr virus-positive gastric cancer, natural killer lymphoma, and Hodgkin disease.
“Intriguingly, renal cell carcinoma also has a relatively higher response rate to immune checkpoint therapy than would be anticipated by its relatively low mutation burden. However, this has no evidence of exogenous virus infection. Therefore, we turned our attention to endogenous retroviruses, which are an abundant potential stimulant of innate immunity in cancer,” he said.
Endogenous retroviruses (ERVs) now comprise about 5-8% of the human genome, and almost all of them have mutations that disable key coding genes of the retrovirus, meaning most cannot produce all the proteins necessary for viral replication.
“They’re essentially genomic fossils,” Dr. Ganesan said, adding that they all are silenced epigenetically in most normal adult tissues, both by DNA methylation and histone methylation. “However, inappropriate expression of endogenous retroviruses has been reported by multiple groups in some cancers and has been associated with evidence of immune activation. One can imagine that endogenous retroviral expression can be immunogenic both by expression of some [open reading frames] that are not disabled ... or just the viral RNA itself, which can be detected by cytoplasmic sensors ... and activate innate immunity,” he said.
To assess whether ERV expression corresponds with evidence of immune checkpoint activation in cancer, he and his colleagues conducted a pan-cancer analysis of more than 4,900 tumors across 21 cancer types using data from the Cancer Genome Atlas (TCGA).
“When we did this for about 66 annotated endogenous retroviruses in the TCGA database, we could see that different cancers had different amounts of retrovirus associated with immune activation ... in fact the strongest signal seen in this analysis was in clear cell renal cell carcinoma,” he said.
Signals were also seen in estrogen receptor–positive/human epidermal growth factor receptor 2-negative breast cancer, head and neck squamous cell carcinoma, and colon cancer.
A variety of ERVs were upregulated in RCC; different panels were associated with different cancer types. But two – ERVK.2 and ERV3.2 – were consistently upregulated across all the tumor types.
A closer look at ERV expression showed three clear clusters: extremely-high, intermediate, and low expression of ERV, and the very-high expression cluster had increased expression of numerous checkpoint genes, including CD8A, PD1, CTLA4, and LAG3 among others, compared with the low expression cluster.
This leads to the question of why a subset of RCCs have ERV expression.
In an attempt to answer that question, a transcript analysis was conducted to determine which transcripts are differentially regulated between the high and low ERV-expressing groups, and gene ontology analysis was performed.
“The results were quite striking. If you look at the modules that are differentially expressed between the high-ERV and the low-ERV groups, what pops up is really a lot of histone methyltransferase modules and chromatin regulation modules, ” he said, noting that this makes sense because of the silencing of ERV expression by histone methylation and DNA methylation, and suggests that “there is some deep abnormality in chromatin modulation in this subset of RCCs.
“This is intriguing, because RCCs are known to have mutations in chromatin modifying genes,” he said.
A look into whether the high-ERV–expressing group was enriched in any of these mutations showed some enrichment of BAP1 in the high- vs. low-expressing group, and that is currently being looked at further, he noted.
The next question was whether ERV expression correlated with response to immune checkpoint blockade in ccRCC, and this was looked at in a nonrandomized group of 15 patients with metastatic ccRCC who were treated with single-agent immune checkpoint therapy who had either clearly documented partial response or progressive disease. In 13 patient samples for which RNA expression of ERV3.2 was successfully measured by quantitative real-time polymerase chain reaction using two primer sets, ERV3.2 expression was significantly higher in responders vs. nonresponders in both primer sets (P less than .05 and .005).
“In summary, we have shown that expression of ERVs correlates with immune activation and increased expression of immune checkpoint genes in a subset of ccRCC, and perhaps several other solid tumor classes, and the expression of ERV3.2 is perhaps associated with response to PD1 blockade in this small preliminary cohort of ccRCC patients,” he said, noting that abnormal expression of ERV may be a biomarker of immune checkpoint therapy response in some cancers with a low mutation burden. “Mechanisms underlying ERV expression need to be investigated and may reflect underlying chromatin alterations or epigenetic abnormalities.”
Dr. Ganesan reported that his spouse is employed by Merck and that he is a consultant and/or advisory board member for Novartis, Roche, and Inspirata. He also holds patents with Inspirata.
SOURCE: Panda A et al., ASCO-SITC, Abstract #104.
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Key clinical point: ERV3.2 expression is associated with immune checkpoint blockade response in ccRCC.
Major finding: ERV3.2 expression was significantly higher in responders vs. nonresponders in two primer sets (P less than .05 and.005).
Study details: A pan-cancer analysis of more 4,900 tumors.
Disclosures: Dr. Ganesan reported that his spouse is employed by Merck and that he is a consultant and/or advisory board member for Novartis, Roche, and Inspirata. He also holds patents with Inspirata
Source: Panda A et al. ASCO-SITC, Abstract #104.
Atezolizumab-bevacizumab combo tops sunitinib as first-line therapy for RCC
The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.
“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.
With a median follow-up of 15 months, compared with sunitinib, the combination of atezolizumab and bevacizumab prolonged investigator-assessed progression-free survival by 3.5 months among patients whose tumors were positive for PD-L1, defined as staining of at least 1% of tumor-infiltrating immune cells by immunohistochemistry. The difference translated to a 26% reduction in the risk of progression or death. However, the combination also had a significant edge in the trial population as a whole.
Overall survival and response rate likewise favored the combination of atezolizumab and bevacizumab. In addition, it was well tolerated, with a lower rate and severity of most adverse events. The exception was a higher rate of proteinuria, an established side effect of bevacizumab, with the combination.
“This trial met its primary endpoint,” Dr. Motzer concluded. “These study results support the consideration of atezolizumab plus bevacizumab as a first-line treatment option for PD-L1–positive patients with advanced renal cell carcinoma.”
Full results of IMmotion151 will be reported at the symposium, which runs Feb. 8-10 and is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”
It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.
“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
Study details
About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).
An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.
The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).
“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”
“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.
The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.
“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”
Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578
The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.
“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.
With a median follow-up of 15 months, compared with sunitinib, the combination of atezolizumab and bevacizumab prolonged investigator-assessed progression-free survival by 3.5 months among patients whose tumors were positive for PD-L1, defined as staining of at least 1% of tumor-infiltrating immune cells by immunohistochemistry. The difference translated to a 26% reduction in the risk of progression or death. However, the combination also had a significant edge in the trial population as a whole.
Overall survival and response rate likewise favored the combination of atezolizumab and bevacizumab. In addition, it was well tolerated, with a lower rate and severity of most adverse events. The exception was a higher rate of proteinuria, an established side effect of bevacizumab, with the combination.
“This trial met its primary endpoint,” Dr. Motzer concluded. “These study results support the consideration of atezolizumab plus bevacizumab as a first-line treatment option for PD-L1–positive patients with advanced renal cell carcinoma.”
Full results of IMmotion151 will be reported at the symposium, which runs Feb. 8-10 and is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”
It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.
“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
Study details
About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).
An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.
The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).
“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”
“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.
The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.
“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”
Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578
The combination of the immune checkpoint inhibitor atezolizumab and bevacizumab has efficacy and tolerability superior to that of sunitinib alone as first-line therapy for metastatic renal cell carcinoma, finds the IMmotion151 trial.
“Sunitinib has been the reference standard for this disease for the last 10 years,” lead study author Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium. But strategies using immunotherapy have generated considerable excitement as possible new treatment options.
With a median follow-up of 15 months, compared with sunitinib, the combination of atezolizumab and bevacizumab prolonged investigator-assessed progression-free survival by 3.5 months among patients whose tumors were positive for PD-L1, defined as staining of at least 1% of tumor-infiltrating immune cells by immunohistochemistry. The difference translated to a 26% reduction in the risk of progression or death. However, the combination also had a significant edge in the trial population as a whole.
Overall survival and response rate likewise favored the combination of atezolizumab and bevacizumab. In addition, it was well tolerated, with a lower rate and severity of most adverse events. The exception was a higher rate of proteinuria, an established side effect of bevacizumab, with the combination.
“This trial met its primary endpoint,” Dr. Motzer concluded. “These study results support the consideration of atezolizumab plus bevacizumab as a first-line treatment option for PD-L1–positive patients with advanced renal cell carcinoma.”
Full results of IMmotion151 will be reported at the symposium, which runs Feb. 8-10 and is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Findings in context
“This study represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, presscast moderator and ASCO expert. “For several years now, we’ve hosted debates on which treatment strategy is best for this disease, targeted therapy or immune therapy. Now this study, which is really the first of its kind, points to a combination of both as being highly effective in delaying cancer growth and showing an early trend toward improving survival as well.”
It is also noteworthy that the combination has good tolerability that appears better in several respects to that seen with sunitinib, he said. “In my opinion, the side effect profile also compares favorably to what we have seen to date with a dual immunotherapy regimen, namely, nivolumab (Opdivo) and ipilimumab.” Although that combination has also been shown to be more efficacious than sunitinib, nearly 60% of treated patients need steroids for immune-related side effects, compared with only 16% treated with the atezolizumab-bevacizumab combination in IMmotion151.
“I would agree with Dr. Motzer that this data supports consideration of atezolizumab and bevacizumab as a first-line option,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “I was intrigued to see that there seemed to be benefit with the combination of atezolizumab and bevacizumab irrespective of the presence or absence of PD-L1.”
Study details
About 40% of patients in IMmotion151 had PD-L1–positive tumors. Median investigator-assessed progression-free survival among these patients, a co-primary endpoint, was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02). More modest but still significant benefit was evident among the trial’s entire intention-to-treat population (11.2 vs. 8.4 months; hazard ratio, 0.83; P = .02).
An interim analysis showed that median overall survival among the PD-L1–positive cohort was not reached with atezolizumab-bevacizumab and was 23.3 months with sunitinib (hazard ratio, 0.68; P = .05). Overall survival among the entire trial population, another co-primary endpoint, was not reached in either treatment arm.
The PD-L1–positive cohort had an overall response rate of 43% with atezolizumab-bevacizumab and 35% with sunitinib (complete response rates of 9% and 4%). Corresponding values in the entire trial population were 37% and 33% (5% and 2%).
“Independent review of progression-free survival and response, where the scans are sent off to a committee and they read them blinded to the treatment arm, differed from investigator-assessed outcomes,” Dr. Motzer noted, with lesser benefit from the combination seen in the PD-L1–positive patients. “We are doing further analysis to see if we can identify why there was this difference.”
“One of the main benefits of atezolizumab plus bevacizumab is its safety profile. As an investigator on this study and other studies, I can attest to that: it’s very well tolerated,” he said.
The sunitinib group had higher rates of most treatment-related adverse events, both any grade and grade 3 or worse, especially palmar-plantar erythrodysesthesia, fatigue, and gastrointestinal events. The pattern was similar in the PD-L1–positive subset.
“We also have done an extensive quality of life analysis,” Dr. Motzer said, with some results to be reported at the symposium. “It appears that patients treated with atezolizumab plus bevacizumab have better quality of life compared to sunitinib by a particular scale that assesses trouble with symptoms.”
Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
SOURCE: Motzer RJ et al. GU Cancers Symposium Abstract 578
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Among patients with PD-L1-positive disease, median investigator-assessed progression-free survival was 11.2 months with atezolizumab-bevacizumab and 7.7 months with sunitinib (hazard ratio, 0.74; P = .02).
Data source: A randomized phase 3 trial among 915 patients with treatment-naive advanced or metastatic RCC (IMmotion151 trial).
Disclosures: Dr. Motzer disclosed that he has a consulting or advisory role with Pfizer, Novartis, Eisai, Exelixis, and Merck, and that his institution receives research funding from Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Eisai, Novartis, and Genentech/Roche. The study was sponsored by Genentech/Roche.
Source: Motzer RJ et al. GU Cancers Symposium Abstract 578
Retroperitoneal lymphadenectomy did not impact OS and DFS for high risk, nonmetastatic renal cell carcinoma
according to a secondary analysis of the ASSURE adjuvant trial.
Patients were randomized to adjuvant sorafenib, sunitinib, or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial, and those at high risk – which was defined by cN+ disease or determined at their surgeon’s discretion – underwent LND. The primary objective was to assess the effect of LND on overall survival; secondary objectives included the effect of LND on disease-free survival and the benefit of adjuvant therapy vs. placebo in patients who underwent LND.
Overall, 1,943 patients were enrolled in the ASSURE trial, of which 36.1% (701 patients) underwent LND. A median of three lymph nodes (interquartile range, one to eight) was examined, and disease was pN+ in 23.4% patients. A majority of the patients were male (67.4%), with a median age of 56 years. Most (94.5%) patients underwent radical nephrectomy, and 57.2% patients had open surgery rather than laparoscopic. Tumors were clear cell in 81.7% of cases and Fuhrman grade 3-4 in 66.1%, investigators reported in the Journal Of Urology.
“There was no improvement in overall survival for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20). For patients who underwent lymphadenectomy with pN+ disease, no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy was overall safe, and did not increase the risk of surgical complications (14.2% vs. 13.4%; P = .63),” wrote Benjamin Ristau, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues. LND was independently associated with other markers of aggressive surgical resection, such as open surgery, radical nephrectomy, and adrenalectomy.
The role of lymphadenectomy in patients undergoing surgery for high-risk renal cell carcinoma remains elusive, the authors wrote. Future strategies include a prospective trial in which patients with high-risk renal cell carcinoma are randomized to specific lymphadenectomy templates.
This study was supported by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Christopher G. Wood reported conflicts of interest with Pfizer, Novartis and Argos. Other authors reported no conflicts of interest.
SOURCE: Ristau BT et al. J Urol. 2018 Jan. doi: 10.1016/j.juro.2017.07.042.
according to a secondary analysis of the ASSURE adjuvant trial.
Patients were randomized to adjuvant sorafenib, sunitinib, or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial, and those at high risk – which was defined by cN+ disease or determined at their surgeon’s discretion – underwent LND. The primary objective was to assess the effect of LND on overall survival; secondary objectives included the effect of LND on disease-free survival and the benefit of adjuvant therapy vs. placebo in patients who underwent LND.
Overall, 1,943 patients were enrolled in the ASSURE trial, of which 36.1% (701 patients) underwent LND. A median of three lymph nodes (interquartile range, one to eight) was examined, and disease was pN+ in 23.4% patients. A majority of the patients were male (67.4%), with a median age of 56 years. Most (94.5%) patients underwent radical nephrectomy, and 57.2% patients had open surgery rather than laparoscopic. Tumors were clear cell in 81.7% of cases and Fuhrman grade 3-4 in 66.1%, investigators reported in the Journal Of Urology.
“There was no improvement in overall survival for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20). For patients who underwent lymphadenectomy with pN+ disease, no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy was overall safe, and did not increase the risk of surgical complications (14.2% vs. 13.4%; P = .63),” wrote Benjamin Ristau, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues. LND was independently associated with other markers of aggressive surgical resection, such as open surgery, radical nephrectomy, and adrenalectomy.
The role of lymphadenectomy in patients undergoing surgery for high-risk renal cell carcinoma remains elusive, the authors wrote. Future strategies include a prospective trial in which patients with high-risk renal cell carcinoma are randomized to specific lymphadenectomy templates.
This study was supported by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Christopher G. Wood reported conflicts of interest with Pfizer, Novartis and Argos. Other authors reported no conflicts of interest.
SOURCE: Ristau BT et al. J Urol. 2018 Jan. doi: 10.1016/j.juro.2017.07.042.
according to a secondary analysis of the ASSURE adjuvant trial.
Patients were randomized to adjuvant sorafenib, sunitinib, or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial, and those at high risk – which was defined by cN+ disease or determined at their surgeon’s discretion – underwent LND. The primary objective was to assess the effect of LND on overall survival; secondary objectives included the effect of LND on disease-free survival and the benefit of adjuvant therapy vs. placebo in patients who underwent LND.
Overall, 1,943 patients were enrolled in the ASSURE trial, of which 36.1% (701 patients) underwent LND. A median of three lymph nodes (interquartile range, one to eight) was examined, and disease was pN+ in 23.4% patients. A majority of the patients were male (67.4%), with a median age of 56 years. Most (94.5%) patients underwent radical nephrectomy, and 57.2% patients had open surgery rather than laparoscopic. Tumors were clear cell in 81.7% of cases and Fuhrman grade 3-4 in 66.1%, investigators reported in the Journal Of Urology.
“There was no improvement in overall survival for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20). For patients who underwent lymphadenectomy with pN+ disease, no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy was overall safe, and did not increase the risk of surgical complications (14.2% vs. 13.4%; P = .63),” wrote Benjamin Ristau, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues. LND was independently associated with other markers of aggressive surgical resection, such as open surgery, radical nephrectomy, and adrenalectomy.
The role of lymphadenectomy in patients undergoing surgery for high-risk renal cell carcinoma remains elusive, the authors wrote. Future strategies include a prospective trial in which patients with high-risk renal cell carcinoma are randomized to specific lymphadenectomy templates.
This study was supported by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Christopher G. Wood reported conflicts of interest with Pfizer, Novartis and Argos. Other authors reported no conflicts of interest.
SOURCE: Ristau BT et al. J Urol. 2018 Jan. doi: 10.1016/j.juro.2017.07.042.
FROM THE JOURNAL OF UROLOGY
Key clinical point: Lymphadenectomy did not improve overall survival or disease-free survival in patients with high-risk, nonmetastatic renal cell carcinoma who received either adjuvant therapy or placebo.
Major finding: There was no overall survival benefit for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20).
Study details: Patients enrolled prospectively in the ASSURE trial.
Disclosures: The study was funded by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Although one author did report conflicts of interest with Pfizer, Novartis, and Argos, the rest reported no conflicts of interest.
Source: Ristau BT et al. J Urol. Jan 2018. doi: 10.1016/j.juro.2017.07.042.
OS similar among mRCC patients enrolled in clinical trials across different geographic regions
Overall survival was similar among patients enrolled in clinical trials for metastatic renal cell carcinoma (mRCC) across different geographic regions, according to a pooled retrospective analysis.
Demographic characteristics, clinicopathologic variables, survival, and toxicity data were collected across five geographic regions, including, United States/Canada (USC), Western Europe (WE), Eastern Europe (EE), Latin America (LA), and Asia/Africa/Oceania (AAO) for 4,736 patients who had mRCC treated between 2003 and 2013 and were enrolled in phase 2 and phase 3 clinical trials.
Patients in USC and WE were slightly older (mean ages, 60.6 and 60.5 years, respectively) and with higher numbers undergoing prior nephrectomy. Higher BMI was also observed in patients in the USC and LA regions. While ECOG performance status of 0 was more frequent in LA patients, treatment-related adverse events and use of statin and angiotensin inhibitor system was higher in USC.
“We highlight that, despite different baseline characteristics, OS was similar among patients enrolled in clinical trials across different geographic regions,” reported Andre P. Fay, MD, PhD, and colleagues from Dana Farber Cancer Institute, Boston, in Journal of Global Oncology. “Access to clinical trials may be an important alternative to eliminate health disparities and promote health equity in patients with mRCC.”
This study was supported by Pfizer and in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, DF/HCC Kidney Cancer Program, and the Trust Family, Loker Pinard, and Michael Brigham Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. All of the study authors reported disclosures with the sponsor, Pfizer, or other pharmaceutical companies.
SOURCE: Fay AP et al. J Global Oncol. 2018 Jan 17. doi: 10.1200/JGO.17.00119.
Overall survival was similar among patients enrolled in clinical trials for metastatic renal cell carcinoma (mRCC) across different geographic regions, according to a pooled retrospective analysis.
Demographic characteristics, clinicopathologic variables, survival, and toxicity data were collected across five geographic regions, including, United States/Canada (USC), Western Europe (WE), Eastern Europe (EE), Latin America (LA), and Asia/Africa/Oceania (AAO) for 4,736 patients who had mRCC treated between 2003 and 2013 and were enrolled in phase 2 and phase 3 clinical trials.
Patients in USC and WE were slightly older (mean ages, 60.6 and 60.5 years, respectively) and with higher numbers undergoing prior nephrectomy. Higher BMI was also observed in patients in the USC and LA regions. While ECOG performance status of 0 was more frequent in LA patients, treatment-related adverse events and use of statin and angiotensin inhibitor system was higher in USC.
“We highlight that, despite different baseline characteristics, OS was similar among patients enrolled in clinical trials across different geographic regions,” reported Andre P. Fay, MD, PhD, and colleagues from Dana Farber Cancer Institute, Boston, in Journal of Global Oncology. “Access to clinical trials may be an important alternative to eliminate health disparities and promote health equity in patients with mRCC.”
This study was supported by Pfizer and in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, DF/HCC Kidney Cancer Program, and the Trust Family, Loker Pinard, and Michael Brigham Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. All of the study authors reported disclosures with the sponsor, Pfizer, or other pharmaceutical companies.
SOURCE: Fay AP et al. J Global Oncol. 2018 Jan 17. doi: 10.1200/JGO.17.00119.
Overall survival was similar among patients enrolled in clinical trials for metastatic renal cell carcinoma (mRCC) across different geographic regions, according to a pooled retrospective analysis.
Demographic characteristics, clinicopathologic variables, survival, and toxicity data were collected across five geographic regions, including, United States/Canada (USC), Western Europe (WE), Eastern Europe (EE), Latin America (LA), and Asia/Africa/Oceania (AAO) for 4,736 patients who had mRCC treated between 2003 and 2013 and were enrolled in phase 2 and phase 3 clinical trials.
Patients in USC and WE were slightly older (mean ages, 60.6 and 60.5 years, respectively) and with higher numbers undergoing prior nephrectomy. Higher BMI was also observed in patients in the USC and LA regions. While ECOG performance status of 0 was more frequent in LA patients, treatment-related adverse events and use of statin and angiotensin inhibitor system was higher in USC.
“We highlight that, despite different baseline characteristics, OS was similar among patients enrolled in clinical trials across different geographic regions,” reported Andre P. Fay, MD, PhD, and colleagues from Dana Farber Cancer Institute, Boston, in Journal of Global Oncology. “Access to clinical trials may be an important alternative to eliminate health disparities and promote health equity in patients with mRCC.”
This study was supported by Pfizer and in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, DF/HCC Kidney Cancer Program, and the Trust Family, Loker Pinard, and Michael Brigham Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. All of the study authors reported disclosures with the sponsor, Pfizer, or other pharmaceutical companies.
SOURCE: Fay AP et al. J Global Oncol. 2018 Jan 17. doi: 10.1200/JGO.17.00119.
FROM journal of global oncology
Key clinical point: The potential differences in clinical outcomes may be contributed by differences in access to clinical trials, disease biology, reporting of adverse events, and quality of care.
Major finding: Patient characteristics differed according to geographic region. No statistically significant differences in OS were observed when the United States/Canada (USC) was compared with other regions: Latin America, Asia/Oceania/Africa, and Eastern Europe.
Study details: Pooled retrospective analysis of 4,736 patients who had mRCC treated between 2003 and 2013 and were enrolled in phase 2 and phase 3 clinical trials.
Disclosures: The study was funded by Pfizer and in part by the Dana Farber/Harvard Cancer Center. All of the study authors reported conflicts of interest involving the sponsor, Pfizer, or other pharmaceutical companies.
Source: Fay AP et al. J Global Oncol. 2018 Jan 17. doi: 10.1200/JGO.17.00119.
Phase 1 study: Human IL-10 plus checkpoint blockade looks promising in RCC, NSCLC
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
SOURCE: Naing A et al. SITC Abstract 012.
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
SOURCE: Naing A et al. SITC Abstract 012.
NATIONAL HARBOR, MD. – Pegylated human interleukin-10 in combination with anti–PD-1 therapy is well tolerated and shows promise for the treatment of both renal cell carcinoma and non–small cell lung cancer, according to findings from a phase 1 study.
The IL-10 product, AM0010 (pegilodecakin), was shown to be well tolerated as monotherapy, and was evaluated in combination with anti–PD-1 therapy in the two expansion cohorts included in the current analysis, Martin Oft, MD, said at the annual meeting of the Society for Immunotherapy of Cancer.
Of 34 evaluable renal cell carcinoma (RCC) patients included in one expansion cohort, 15 (44%) had an objective response at a median follow-up of 27 months, and two of those had a complete response (CR), Dr. Oft of ARMO BioSciences, Redwood City, Calif. reported.
In contrast, only 4 of 16 evaluable patients who received AM0010 monotherapy (25%) had an objective response, he said.
In eight patients who received AM0010 + pembrolizumab (Keytruda), the objective response rate was 50%, and both patients who had a complete response were in that group. The median progression-free survival (PFS) was 16.7 months. In 26 who received AM0010 + nivolumab (Opdivo), 11 had an objective response, but neither the complete response nor PFS rates had been reached in patients in that group, he noted.
The responses were durable.
“In fact, we had one patient who stopped treatment after a year in [complete remission] and is now 1 year in total remission without any further treatment,” he said.
Patients with non–small cell lung cancer (NSCLC) also experienced some benefit from the combination therapy. Objective responses were observed in 11 of 27 evaluable NSCLC patients (41%) who were treated with AM0010 and an anti–PD-1(9 of 22 [41%] who received AM0010 and nivolumab, and 2 of 5 [40%] who received AM0010 and pembrolizumab).
Progression-free survival was not reached in this cohort.
An analysis by PD-L1 status showed that 33% of NSCLC patients with PD-L1 levels less than 1% achieved a response, 67% of those with PD-L1 levels of 1%-49% achieved a response, and 80% of those with PD-L1 levels of 50% or greater achieved a response, he said, adding that the responses were very durable in all three groups.
Of note, NSCLC patients with liver metastasis have been shown in prior trials to have a lower overall response rate to immune checkpoint inhibition, but in this trial, 7 of 9 patients with NSCLC metastasis to the liver had a partial response (PR), Dr. Oft said.
The RCC and NSCLC patients had a median of 1 and 2 prior therapies, respectively.
AM0010 was given subcutaneously at a dose of 10 or 20 mcg/kg daily, pembrolizumab was given intravenously at 2mg/kg every 3 weeks, and nivolumab was given intravenously at a dose of 3 mg/kg every 2 weeks.
Treatment-related adverse events included anemia, thrombocytopenia, and fatigue, and all were reversible and transient, Dr. Oft said, noting that grade 3 or 4 adverse events were mostly absent in patients receiving the lower dose; thus the recommended phase 2 dose is 10 mcg/kg.
“It’s important to note that three of those six patients [receiving the lower dose] in fact had a PR or CR so this lower dose did not come at the expense of efficacy,” he added.
The mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer patients lies in the fact that IL‐10 has anti‐inflammatory functions and stimulates the cytotoxicity and proliferation of antigen-activated CD8+ T cells. T cell receptor–mediated activation of CD8+ T cells elevates IL‐10 receptors and PD‐1, Dr. Oft explained.
The robust efficacy data and the observed CD8+ T cell activation seen in these expansion cohorts is promising and encourages the continued study of AM0010 in combination with PD-1 inhibition, he concluded, noting that larger studies are planned for the coming year.
Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
SOURCE: Naing A et al. SITC Abstract 012.
REPORTING FROM SITC 2017
Key clinical point:
Major finding: 15 of 34 RCC patients had an objective response and two of those had a complete response.
Study details: Expansion cohorts including 64 patients from a phase 1 study.
Disclosures: Dr. Oft is a founder and employee of ARMO BioSciences, which sponsored this study.
Source: A. Naing et al. SITC 2017 Abstract 012.
In Brazil, few patients get second- and third-line treatment for metastatic RCC
, a retrospective study showed.
Of 3,990 patients with metastatic renal cell carcinoma (mRCC), 79% received an appropriate first-line treatment – mainly a vascular endothelial growth factor agent. But only 20% went on to get a second-line agent, and just 5% received a third-line agent, Paulo G. Bergerot, MD, and his colleagues reported in the Journal of Global Oncology.
Patients in private institutions were significantly more likely to receive appropriate first- and second-line treatment than those in public institutions, although the numbers receiving third-line agents were similarly low, reported Dr. Bergerot of the Federal University of São Paulo and his coauthors.
The study highlights sharp discrepancies between treatment in Brazil and more developed countries, the team noted.
“Previous reports from the International Metastatic Renal Cell Carcinoma Database Consortium suggest that approximately 48% of patients who receive first-line therapy proceed to second-line therapy. In addition, among patients who received first-line therapy in this experience, approximately 21% received third-line therapy,” the investigators wrote.
The reasons behind the differences aren’t entirely clear, but cost and clinicians’ knowledge of emerging study data could be major factors, they suggested.
“In particular, we suspect limited availability and cost of second-line treatments to be a barrier, although our data set did not have the capability of confirming this. Another barrier to receipt of second-line therapy might be educational gaps among practitioners. Emerging data from phase 3 studies supporting the use of agents in the refractory setting may not be widely broadcast. The discordance in receipt of therapies in private and public settings is perhaps the greatest indication that financial and social barriers likely affect treatment paradigms in Brazil,” the authors wrote.
Slow dissemination of clinical knowledge may also be reflected in another of the team’s findings: 240 patients received “nontraditional” first-line cytotoxic treatments, which lacked regulatory approval and had little supporting evidence for treating mRCC, the investigators reported.
Dr. Bergerot had no relevant financial disclosures, although several of his coauthors reported financial relationships with various pharmaceutical companies.
SOURCE: Bergerot et al. J Glob Oncol. 2017 Dec 27. doi: 10.1200/JGO.17.00113.
, a retrospective study showed.
Of 3,990 patients with metastatic renal cell carcinoma (mRCC), 79% received an appropriate first-line treatment – mainly a vascular endothelial growth factor agent. But only 20% went on to get a second-line agent, and just 5% received a third-line agent, Paulo G. Bergerot, MD, and his colleagues reported in the Journal of Global Oncology.
Patients in private institutions were significantly more likely to receive appropriate first- and second-line treatment than those in public institutions, although the numbers receiving third-line agents were similarly low, reported Dr. Bergerot of the Federal University of São Paulo and his coauthors.
The study highlights sharp discrepancies between treatment in Brazil and more developed countries, the team noted.
“Previous reports from the International Metastatic Renal Cell Carcinoma Database Consortium suggest that approximately 48% of patients who receive first-line therapy proceed to second-line therapy. In addition, among patients who received first-line therapy in this experience, approximately 21% received third-line therapy,” the investigators wrote.
The reasons behind the differences aren’t entirely clear, but cost and clinicians’ knowledge of emerging study data could be major factors, they suggested.
“In particular, we suspect limited availability and cost of second-line treatments to be a barrier, although our data set did not have the capability of confirming this. Another barrier to receipt of second-line therapy might be educational gaps among practitioners. Emerging data from phase 3 studies supporting the use of agents in the refractory setting may not be widely broadcast. The discordance in receipt of therapies in private and public settings is perhaps the greatest indication that financial and social barriers likely affect treatment paradigms in Brazil,” the authors wrote.
Slow dissemination of clinical knowledge may also be reflected in another of the team’s findings: 240 patients received “nontraditional” first-line cytotoxic treatments, which lacked regulatory approval and had little supporting evidence for treating mRCC, the investigators reported.
Dr. Bergerot had no relevant financial disclosures, although several of his coauthors reported financial relationships with various pharmaceutical companies.
SOURCE: Bergerot et al. J Glob Oncol. 2017 Dec 27. doi: 10.1200/JGO.17.00113.
, a retrospective study showed.
Of 3,990 patients with metastatic renal cell carcinoma (mRCC), 79% received an appropriate first-line treatment – mainly a vascular endothelial growth factor agent. But only 20% went on to get a second-line agent, and just 5% received a third-line agent, Paulo G. Bergerot, MD, and his colleagues reported in the Journal of Global Oncology.
Patients in private institutions were significantly more likely to receive appropriate first- and second-line treatment than those in public institutions, although the numbers receiving third-line agents were similarly low, reported Dr. Bergerot of the Federal University of São Paulo and his coauthors.
The study highlights sharp discrepancies between treatment in Brazil and more developed countries, the team noted.
“Previous reports from the International Metastatic Renal Cell Carcinoma Database Consortium suggest that approximately 48% of patients who receive first-line therapy proceed to second-line therapy. In addition, among patients who received first-line therapy in this experience, approximately 21% received third-line therapy,” the investigators wrote.
The reasons behind the differences aren’t entirely clear, but cost and clinicians’ knowledge of emerging study data could be major factors, they suggested.
“In particular, we suspect limited availability and cost of second-line treatments to be a barrier, although our data set did not have the capability of confirming this. Another barrier to receipt of second-line therapy might be educational gaps among practitioners. Emerging data from phase 3 studies supporting the use of agents in the refractory setting may not be widely broadcast. The discordance in receipt of therapies in private and public settings is perhaps the greatest indication that financial and social barriers likely affect treatment paradigms in Brazil,” the authors wrote.
Slow dissemination of clinical knowledge may also be reflected in another of the team’s findings: 240 patients received “nontraditional” first-line cytotoxic treatments, which lacked regulatory approval and had little supporting evidence for treating mRCC, the investigators reported.
Dr. Bergerot had no relevant financial disclosures, although several of his coauthors reported financial relationships with various pharmaceutical companies.
SOURCE: Bergerot et al. J Glob Oncol. 2017 Dec 27. doi: 10.1200/JGO.17.00113.
FROM THE JOURNAL OF GLOBAL ONCOLOGY
Key clinical point: Few Brazilians with mRCC receive anything after their first-line treatment.
Major finding: First-line agents were used in 79% of the cohort, but only 20% got second-line treatments and just 5%, third-line treatment.
Study details: A retrospective database study involving 3,990 patients with mRCC.
Disclosures: Dr. Bergerot had no relevant financial disclosures, although several of his coauthors disclosed financial relationships with pharmaceutical companies.
Source: Bergerot et al. J Glob Oncol. 2017 Dec 27. doi: 10.1200/JGO.17.00113.
Mutations linked to checkpoint inhibitor response in RCC
in a derivation and validation study involving a total of 98 patients.
This finding “has important implications as a molecular tool for considering immunotherapy responsiveness” in patients with ccRCC and possibly patients with other cancer types, wrote Eliezer M. Van Allen, MD, of Dana Farber Cancer Institute in Boston and coauthors.
The derivation cohort included 35 patients with metastatic ccRCC treated with nivolumab in a prospective clinical trial. Genome sequencing of pretreatment tumor specimens showed that improved survival after treatment was significantly linked with truncating mutations in a gene, PBRM1, that codes for a protein in the SWI/SNF chromatin-remodeling complex. Patients in the derivation cohort who had these mutations were nearly 13-fold more likely to have clinical benefit from treatment, compared with those without these mutations.
The validation study included specimens and treatment-outcome results from 63 patients with metastatic ccRCC treated with either nivolumab or a different checkpoint inhibitor, such as atezolizumab (Tecentriq). In the validation study, PBRM1 mutations linked with a sixfold higher rate of clinical benefit from treatment.
The researchers noted that the types of mutations they identified as likely involved occur in more than 20% of all cancer types. Results from mouse studies have suggested that tumor cells with these types of mutations are more sensitive to T cell–mediated cytotoxicity, an observation that “lends a mechanistic basis” to the observed findings.
The study received funding in part from Bristol-Myers Squibb, the company that markets nivolumab (Obdivo). Several researchers involved in this study have received honoraria and research support from Bristol-Myers Squibb and from several other drug companies.
[email protected]
On Twitter @mitchelzoler
SOURCE: Miao D et al. Science. 2018 Jan 4. doi: 10.1126/science.aan5951
in a derivation and validation study involving a total of 98 patients.
This finding “has important implications as a molecular tool for considering immunotherapy responsiveness” in patients with ccRCC and possibly patients with other cancer types, wrote Eliezer M. Van Allen, MD, of Dana Farber Cancer Institute in Boston and coauthors.
The derivation cohort included 35 patients with metastatic ccRCC treated with nivolumab in a prospective clinical trial. Genome sequencing of pretreatment tumor specimens showed that improved survival after treatment was significantly linked with truncating mutations in a gene, PBRM1, that codes for a protein in the SWI/SNF chromatin-remodeling complex. Patients in the derivation cohort who had these mutations were nearly 13-fold more likely to have clinical benefit from treatment, compared with those without these mutations.
The validation study included specimens and treatment-outcome results from 63 patients with metastatic ccRCC treated with either nivolumab or a different checkpoint inhibitor, such as atezolizumab (Tecentriq). In the validation study, PBRM1 mutations linked with a sixfold higher rate of clinical benefit from treatment.
The researchers noted that the types of mutations they identified as likely involved occur in more than 20% of all cancer types. Results from mouse studies have suggested that tumor cells with these types of mutations are more sensitive to T cell–mediated cytotoxicity, an observation that “lends a mechanistic basis” to the observed findings.
The study received funding in part from Bristol-Myers Squibb, the company that markets nivolumab (Obdivo). Several researchers involved in this study have received honoraria and research support from Bristol-Myers Squibb and from several other drug companies.
[email protected]
On Twitter @mitchelzoler
SOURCE: Miao D et al. Science. 2018 Jan 4. doi: 10.1126/science.aan5951
in a derivation and validation study involving a total of 98 patients.
This finding “has important implications as a molecular tool for considering immunotherapy responsiveness” in patients with ccRCC and possibly patients with other cancer types, wrote Eliezer M. Van Allen, MD, of Dana Farber Cancer Institute in Boston and coauthors.
The derivation cohort included 35 patients with metastatic ccRCC treated with nivolumab in a prospective clinical trial. Genome sequencing of pretreatment tumor specimens showed that improved survival after treatment was significantly linked with truncating mutations in a gene, PBRM1, that codes for a protein in the SWI/SNF chromatin-remodeling complex. Patients in the derivation cohort who had these mutations were nearly 13-fold more likely to have clinical benefit from treatment, compared with those without these mutations.
The validation study included specimens and treatment-outcome results from 63 patients with metastatic ccRCC treated with either nivolumab or a different checkpoint inhibitor, such as atezolizumab (Tecentriq). In the validation study, PBRM1 mutations linked with a sixfold higher rate of clinical benefit from treatment.
The researchers noted that the types of mutations they identified as likely involved occur in more than 20% of all cancer types. Results from mouse studies have suggested that tumor cells with these types of mutations are more sensitive to T cell–mediated cytotoxicity, an observation that “lends a mechanistic basis” to the observed findings.
The study received funding in part from Bristol-Myers Squibb, the company that markets nivolumab (Obdivo). Several researchers involved in this study have received honoraria and research support from Bristol-Myers Squibb and from several other drug companies.
[email protected]
On Twitter @mitchelzoler
SOURCE: Miao D et al. Science. 2018 Jan 4. doi: 10.1126/science.aan5951
FROM SCIENCE
Key clinical point: Mutations in PBRM1 linked with better survival after immune checkpoint inhibitor therapy.
Major finding: Patients with a PBRM1 mutation were 6- to 13-fold more likely to have clinical benefit from checkpoint inhibitor treatment.
Study details: Derivation and validation studies that included 98 total patients with metastatic clear cell renal cell carcinoma.
Disclosures: The study received funding in part from Bristol-Myers Squibb, the company that markets nivolumab (Obdivo). Several researchers involved in this study have received honoraria and research support from Bristol-Myers Squibb and from several other drug companies.
Source: Miao D et al. Science. 2018 Jan 4. doi: 10.1126/science.aan5951.
FDA approves cabozantinib for the frontline treatment of advanced RCC
The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).
The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.
The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.
Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.
Cabozantinib is marketed as Cabometyx by Exelixis.
The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).
The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.
The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.
Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.
Cabozantinib is marketed as Cabometyx by Exelixis.
The Food and Drug Administration has approved cabozantinib for the frontline treatment of patients with advanced renal cell carcinoma (RCC).
The drug was approved in 2016 for patients who had received prior antiangiogenic therapy.
The expanded approval was based on improvement in progression-free survival when compared with sunitinib in the phase 2 CABOSUN trial of 157 patients with previously untreated RCC, according to a statement from the company.
Grade 3 or 4 adverse reactions were reported in 68% of patients receiving cabozantinib, compared with 65% of patients receiving sunitinib. The most frequent adverse reactions in patients treated with cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope. Approximately one-fifth of patients discontinued treatment in both arms.
Cabozantinib is marketed as Cabometyx by Exelixis.
First-in-class glutaminase inhibitor combats anti-PD-1/PD-L1 resistance
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
AT SITC 2017
Key clinical point:
Major finding: The objective response rate in advanced melanoma patients refractory to anti-PD-1/PD-L1 therapy was 19%.
Data source: A phase 1/2 study of 82 patients.
Disclosures: Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel or as a board member for multiple companies.