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Nivolumab falls short in ccRCC patients with brain metastases
Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.
In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.
The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.
These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.
Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.
Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).
Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.
All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.
The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.
Response
The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.
Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.
The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.
All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
Survival
The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).
The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.
The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.
Safety
The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).
Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).
The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.
This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.
Trial results have raised more questions about the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma (ccRCC) and brain metastases, according to Jarred P. Reed, MD, and colleagues.
In a phase 2 trial, half of ccRCC patients with previously untreated brain metastases had intracranial progression while receiving treatment with nivolumab. The risk of intracranial progression was higher among patients with previously untreated brain metastases than among those who had received prior focal therapy. However, global progression-free survival rates were similarly short in patients with previously treated and untreated brain metastases.
It isn’t clear why nivolumab exhibited such “disappointing activity” in this trial, Dr. Reed and colleagues wrote in an editorial, but the authors presented several possibilities.
The study’s results may be explained by “unique biologic mechanisms” associated with brain metastasis in ccRCC. The brain microenvironment may weaken the response to nivolumab, or patients with brain metastases may have tumor cells better able to evade the immune system. These patients may also have specific alterations in signaling pathways that are important for cell survival.
To gain more insight, future immunotherapy trials should include patients with brain metastases, Dr. Reed and coauthors wrote.
Jarred P. Reed, MD, and coauthors Edwin M. Posadas, MD, and Robert A. Figlin, MD, are from Cedars-Sinai Medical Center in Los Angeles. The authors disclosed relationships with Bristol-Myers Squibb, which markets nivolumab, and many other companies. These comments are adapted from their editorial (J Clin Oncol. 2019 Aug 10;37[23]:1987-9).
Trial results have raised more questions about the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma (ccRCC) and brain metastases, according to Jarred P. Reed, MD, and colleagues.
In a phase 2 trial, half of ccRCC patients with previously untreated brain metastases had intracranial progression while receiving treatment with nivolumab. The risk of intracranial progression was higher among patients with previously untreated brain metastases than among those who had received prior focal therapy. However, global progression-free survival rates were similarly short in patients with previously treated and untreated brain metastases.
It isn’t clear why nivolumab exhibited such “disappointing activity” in this trial, Dr. Reed and colleagues wrote in an editorial, but the authors presented several possibilities.
The study’s results may be explained by “unique biologic mechanisms” associated with brain metastasis in ccRCC. The brain microenvironment may weaken the response to nivolumab, or patients with brain metastases may have tumor cells better able to evade the immune system. These patients may also have specific alterations in signaling pathways that are important for cell survival.
To gain more insight, future immunotherapy trials should include patients with brain metastases, Dr. Reed and coauthors wrote.
Jarred P. Reed, MD, and coauthors Edwin M. Posadas, MD, and Robert A. Figlin, MD, are from Cedars-Sinai Medical Center in Los Angeles. The authors disclosed relationships with Bristol-Myers Squibb, which markets nivolumab, and many other companies. These comments are adapted from their editorial (J Clin Oncol. 2019 Aug 10;37[23]:1987-9).
Trial results have raised more questions about the efficacy of immune checkpoint inhibitors in patients with clear cell renal cell carcinoma (ccRCC) and brain metastases, according to Jarred P. Reed, MD, and colleagues.
In a phase 2 trial, half of ccRCC patients with previously untreated brain metastases had intracranial progression while receiving treatment with nivolumab. The risk of intracranial progression was higher among patients with previously untreated brain metastases than among those who had received prior focal therapy. However, global progression-free survival rates were similarly short in patients with previously treated and untreated brain metastases.
It isn’t clear why nivolumab exhibited such “disappointing activity” in this trial, Dr. Reed and colleagues wrote in an editorial, but the authors presented several possibilities.
The study’s results may be explained by “unique biologic mechanisms” associated with brain metastasis in ccRCC. The brain microenvironment may weaken the response to nivolumab, or patients with brain metastases may have tumor cells better able to evade the immune system. These patients may also have specific alterations in signaling pathways that are important for cell survival.
To gain more insight, future immunotherapy trials should include patients with brain metastases, Dr. Reed and coauthors wrote.
Jarred P. Reed, MD, and coauthors Edwin M. Posadas, MD, and Robert A. Figlin, MD, are from Cedars-Sinai Medical Center in Los Angeles. The authors disclosed relationships with Bristol-Myers Squibb, which markets nivolumab, and many other companies. These comments are adapted from their editorial (J Clin Oncol. 2019 Aug 10;37[23]:1987-9).
Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.
In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.
The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.
These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.
Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.
Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).
Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.
All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.
The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.
Response
The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.
Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.
The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.
All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
Survival
The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).
The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.
The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.
Safety
The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).
Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).
The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.
This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.
Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.
In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.
The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.
These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.
Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.
Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).
Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.
All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.
The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.
Response
The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.
Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.
The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.
All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
Survival
The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).
The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.
The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.
Safety
The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).
Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).
The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.
This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.
SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.
FROM JOURNAL OF CLINICAL ONCOLOGY
Study outlines survival factors with nivolumab
Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.
A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.
In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.
“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.
In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.
Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).
One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).
“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.
The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.
SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.
Although the existence of a subset of patients experiencing long-term survival certainly substantiates the role of PD-1/ PD-L1 checkpoint blockade in cancer immunotherapy, it is noteworthy to consider that these agents as monotherapy have not yielded sufficient activity and efficacy to replace standard-of-care therapy in the first line of therapy in advanced solid tumors, with the exception of NSCLC expressing high levels of PD-L1 and melanoma; emerging results also restrict monotherapy to stringently defined subsets of patients with gastric, esophageal, head and neck, and bladder cancers. Baseline predictive biomarkers have demonstrated distinct shortcomings, the first being their poor discriminatory ability and low negative predictive value. The clinician keen on securing the best possible outcome for his patients is thus left with the necessity for indiscriminate administration of PD-1/PD-L1 checkpoint inhibitors.
Unsurprisingly, the field of combination therapies using PD-1/PD-L1 checkpoint blockade as a backbone has been growing exponentially; a recent review shows more than 2,250 immunotherapy trials, 1,716 of which are investigating PD-1/ PD-L1 checkpoint inhibitors with more than 240 combination partners. Analysis of the pipeline also reveals a 67% increase in the number of active agents, amounting to more than 3,300, between September 2017 and September 2018. A noteworthy development is a 113% increase in cell therapies, and an increase of agents targeting neoantigens identified through bioinformatics analysis of an individual patient’s tumor, suggesting a shift toward increased personalization of immunotherapy. The observation that clinical development of immunotherapy agents has outstripped our understanding of the cancer-immune interactions advocates for renewed collective efforts in standardizing immune monitoring methods in clinical trials to identify immune evasion pathways that are dominant and to build novel trial designs able to efficiently enhance matching of patients with therapy.
Stefan Zimmermann, MD, and Solange Peters, MD, PhD, are from the Centre Hospitalier Universitaire Vaudois in Lausanne,Switzerland. Their remarks are excerpted and adapted from an editorial accompanying the study (JAMA Oncol. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2186). Dr. Zimmerman disclosed fees for advisory roles, travel grants, and clinical research support from Bristol-Myers Squibb and others. Dr. Peters disclosed fees for advisory board participation and/or lectures from Bristol-Myers Squibb and others.
Although the existence of a subset of patients experiencing long-term survival certainly substantiates the role of PD-1/ PD-L1 checkpoint blockade in cancer immunotherapy, it is noteworthy to consider that these agents as monotherapy have not yielded sufficient activity and efficacy to replace standard-of-care therapy in the first line of therapy in advanced solid tumors, with the exception of NSCLC expressing high levels of PD-L1 and melanoma; emerging results also restrict monotherapy to stringently defined subsets of patients with gastric, esophageal, head and neck, and bladder cancers. Baseline predictive biomarkers have demonstrated distinct shortcomings, the first being their poor discriminatory ability and low negative predictive value. The clinician keen on securing the best possible outcome for his patients is thus left with the necessity for indiscriminate administration of PD-1/PD-L1 checkpoint inhibitors.
Unsurprisingly, the field of combination therapies using PD-1/PD-L1 checkpoint blockade as a backbone has been growing exponentially; a recent review shows more than 2,250 immunotherapy trials, 1,716 of which are investigating PD-1/ PD-L1 checkpoint inhibitors with more than 240 combination partners. Analysis of the pipeline also reveals a 67% increase in the number of active agents, amounting to more than 3,300, between September 2017 and September 2018. A noteworthy development is a 113% increase in cell therapies, and an increase of agents targeting neoantigens identified through bioinformatics analysis of an individual patient’s tumor, suggesting a shift toward increased personalization of immunotherapy. The observation that clinical development of immunotherapy agents has outstripped our understanding of the cancer-immune interactions advocates for renewed collective efforts in standardizing immune monitoring methods in clinical trials to identify immune evasion pathways that are dominant and to build novel trial designs able to efficiently enhance matching of patients with therapy.
Stefan Zimmermann, MD, and Solange Peters, MD, PhD, are from the Centre Hospitalier Universitaire Vaudois in Lausanne,Switzerland. Their remarks are excerpted and adapted from an editorial accompanying the study (JAMA Oncol. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2186). Dr. Zimmerman disclosed fees for advisory roles, travel grants, and clinical research support from Bristol-Myers Squibb and others. Dr. Peters disclosed fees for advisory board participation and/or lectures from Bristol-Myers Squibb and others.
Although the existence of a subset of patients experiencing long-term survival certainly substantiates the role of PD-1/ PD-L1 checkpoint blockade in cancer immunotherapy, it is noteworthy to consider that these agents as monotherapy have not yielded sufficient activity and efficacy to replace standard-of-care therapy in the first line of therapy in advanced solid tumors, with the exception of NSCLC expressing high levels of PD-L1 and melanoma; emerging results also restrict monotherapy to stringently defined subsets of patients with gastric, esophageal, head and neck, and bladder cancers. Baseline predictive biomarkers have demonstrated distinct shortcomings, the first being their poor discriminatory ability and low negative predictive value. The clinician keen on securing the best possible outcome for his patients is thus left with the necessity for indiscriminate administration of PD-1/PD-L1 checkpoint inhibitors.
Unsurprisingly, the field of combination therapies using PD-1/PD-L1 checkpoint blockade as a backbone has been growing exponentially; a recent review shows more than 2,250 immunotherapy trials, 1,716 of which are investigating PD-1/ PD-L1 checkpoint inhibitors with more than 240 combination partners. Analysis of the pipeline also reveals a 67% increase in the number of active agents, amounting to more than 3,300, between September 2017 and September 2018. A noteworthy development is a 113% increase in cell therapies, and an increase of agents targeting neoantigens identified through bioinformatics analysis of an individual patient’s tumor, suggesting a shift toward increased personalization of immunotherapy. The observation that clinical development of immunotherapy agents has outstripped our understanding of the cancer-immune interactions advocates for renewed collective efforts in standardizing immune monitoring methods in clinical trials to identify immune evasion pathways that are dominant and to build novel trial designs able to efficiently enhance matching of patients with therapy.
Stefan Zimmermann, MD, and Solange Peters, MD, PhD, are from the Centre Hospitalier Universitaire Vaudois in Lausanne,Switzerland. Their remarks are excerpted and adapted from an editorial accompanying the study (JAMA Oncol. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2186). Dr. Zimmerman disclosed fees for advisory roles, travel grants, and clinical research support from Bristol-Myers Squibb and others. Dr. Peters disclosed fees for advisory board participation and/or lectures from Bristol-Myers Squibb and others.
Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.
A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.
In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.
“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.
In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.
Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).
One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).
“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.
The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.
SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.
Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.
A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.
In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.
“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.
In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.
Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).
One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).
“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.
The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.
SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.
FROM JAMA ONCOLOGY
FDA approves bevacizumab-bvzr for several cancers
The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.
Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.
Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.
Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.
The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.
Specific indications for the biosimilar are as follows:
Metastatic colorectal cancer
Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.
Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.
Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.
First-line nonsquamous non–small cell lung cancer
Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.
Recurrent glioblastoma
Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.
Metastatic renal cell carcinoma
Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.
Persistent, recurrent, or metastatic cervical cancer
Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.
Complete prescribing information can be found on the FDA website.
The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.
Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.
Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.
Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.
The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.
Specific indications for the biosimilar are as follows:
Metastatic colorectal cancer
Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.
Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.
Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.
First-line nonsquamous non–small cell lung cancer
Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.
Recurrent glioblastoma
Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.
Metastatic renal cell carcinoma
Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.
Persistent, recurrent, or metastatic cervical cancer
Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.
Complete prescribing information can be found on the FDA website.
The Food and Drug Administration has approved bevacizumab-bvzr (Zirabev) – a biosimilar to bevacizumab (Avastin) – for the treatment of five cancers: metastatic colorectal cancer (mCRC); unresectable, locally advanced, recurrent or metastatic non-squamous non–small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer.
Approval was based on “review of a comprehensive data package which demonstrated biosimilarity of [bevacizumab-bvzr] to the reference product,” Pfizer said in a statement announcing the approval.
Bevacizumab-bvzr is the second bevacizumab biosimilar to be approved, following approval of Amgen’s bevacizumab-awwb (Mvasi) in 2017.
Warnings and precautions with the biosimilars, as with bevacizumab, include serious and sometimes fatal gastrointestinal perforation, surgery and wound healing complications, and sometimes serious and fatal hemorrhage.
The most common adverse events observed in bevacizumab patients are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.
Specific indications for the biosimilar are as follows:
Metastatic colorectal cancer
Bevacizumab-bvzr, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with mCRC.
Bevacizumab-bvzr, in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based chemotherapy, is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line bevacizumab product–containing regimen.
Bevacizumab-bvzr is not indicated for adjuvant treatment of colon cancer.
First-line nonsquamous non–small cell lung cancer
Bevacizumab-bvzr, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic NSCLC.
Recurrent glioblastoma
Bevacizumab-bvzr is indicated for the treatment of recurrent glioblastoma in adults.
Metastatic renal cell carcinoma
Bevacizumab-bvzr, in combination with interferon alfa, is indicated for the treatment of metastatic RCC.
Persistent, recurrent, or metastatic cervical cancer
Bevacizumab-bvzr, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.
Complete prescribing information can be found on the FDA website.
Nephrectomy may benefit select renal cancer patients based on risk factors
CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.
Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.
Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.
By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.
In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.
Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”
In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.
While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.
“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.
The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.
With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).
Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.
SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.
CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.
Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.
Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.
By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.
In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.
Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”
In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.
While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.
“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.
The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.
With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).
Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.
SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.
CHICAGO – While cytoreductive nephrectomy is generally still inadvisable in metastatic renal cell carcinoma patients who require medical therapy, an update of the CARMENA trial suggests the procedure may provide benefit for certain patients.
Patients with only one International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factor may benefit from cytoreductive nephrectomy, said CARMENA investigator Arnaud Méjean, MD, PhD, in a presentation at the annual meeting of the American Society of Clinical Oncology.
Among patients in CARMENA treated with nephrectomy plus sunitinib, median overall survival was 31.4 months for those with just one risk factor, and 17.6 months for those with two or more (hazard ratio, 1.68; 95% confidence interval, 1.10-2.57; P = .01), suggesting the procedure was “detrimental” to perform in the presence of multiple risk factors, the investigator said.
By contrast, among patients treated with sunitinib alone, there was no significant difference in median overall survival for patients with one risk factor versus those with two or more risk factors, said Dr. Méjean, who is with the Hôpital Européen Georges-Pompidou and Paris Descartes University.
In another analysis of the data, delayed nephrectomy after initial systemic therapy was associated with long overall survival in good responders, supporting that approach as a “good therapeutic strategy,” he said.
Based on these results, Dr. Méjean told ASCO attendees he would “go back to the operating theater to operate just very selected patients.”
In a podium discussion, Alexander Kutikov, MD, FACS, said CARMENA makes it “undeniable” that up-front cytoreductive therapy should be applied to a “very select group” of patients.
While that select group may be defined as the one IMDC risk factor group, Dr. Kutkov said it is also appropriate to offer cytoreductive nephrectomy to carefully selected patients who do not need immediate systemic therapy.
“If the plan is to observe without systemic therapy, proceed with cytoreductive nephrectomy, and for everybody else, I think we take great caution in offering cytoreductive nephrectomy, because it absolutely can harm,” said Dr. Kutikov, professor and chief of urologic oncology at Fox Chase Cancer Center, Philadelphia.
The CARMENA update confirmed that, in general, cytoreductive nephrectomy should not be the standard of care, according to Dr. Méjean.
With follow-up of 61.5 months, or longer than what was previously reported for the 450-patient trial, cytoreductive nephrectomy followed by sunitinib was again found to be not superior to sunitinib alone, he said. Median overall survival was 15.6 months for the nephrectomy plus sunitinib arm versus 19.8 months for the sunitinib arm, showing that sunitinib alone was noninferior based on the statistical design of the trial (hazard ratio, 0.97; 95% CI, 0.79-1.19, with a fixed upper limit for noninferiority of 1.20).
Dr. Méjean reported disclosures related to Ipsen, Novartis, Pfizer, Bristol-Myers Squibb, Janssen, Sanofi and Roche.
SOURCE: Méjean A et al. ASCO 2019, Abstract 4508.
REPORTING FROM ASCO 2019
Trial matches pediatric cancer patients to targeted therapies
Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.
Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.
The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.
Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.
Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.
He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?
The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.
After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:
- larotrectinib (targeting NTRK fusions).
- erdafitinib (targeting FGFR1/2/3/4).
- tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
- LY3023414 (targeting the PI3K/MTOR pathway).
- selumetinib (targeting the MAPK pathway).
- ensartinib (targeting ALK or ROS1).
- vemurafenib (targeting BRAF V600 mutations).
- olaparib (targeting defects in DNA damage repair).
- palbociclib (targeting alterations in cell cycle genes).
- ulixertinib (targeting MAPK pathway mutations).
Early results
From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.
The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).
A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.
“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.
Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.
Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.
“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”
The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.
SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.
Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.
Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.
The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.
Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.
Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.
He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?
The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.
After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:
- larotrectinib (targeting NTRK fusions).
- erdafitinib (targeting FGFR1/2/3/4).
- tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
- LY3023414 (targeting the PI3K/MTOR pathway).
- selumetinib (targeting the MAPK pathway).
- ensartinib (targeting ALK or ROS1).
- vemurafenib (targeting BRAF V600 mutations).
- olaparib (targeting defects in DNA damage repair).
- palbociclib (targeting alterations in cell cycle genes).
- ulixertinib (targeting MAPK pathway mutations).
Early results
From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.
The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).
A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.
“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.
Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.
Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.
“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”
The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.
SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.
Researchers have found they can screen pediatric cancer patients for genetic alterations and match those patients to appropriate targeted therapies.
Thus far, 24% of the patients screened have been matched and assigned to a treatment, and 10% have been enrolled on treatment protocols.
The patients were screened and matched as part of the National Cancer Institute–Children’s Oncology Group Pediatric MATCH (Molecular Analysis for Therapy Choice) trial.
Results from this trial are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.
Donald Williams Parsons, MD, PhD, of Baylor College of Medicine in Houston, Tex., presented some results at a press briefing in advance of the meeting. “[T]he last 10 years have been an incredible time in terms of learning more about the genetics and underlying molecular basis of both adult and pediatric cancers,” Dr. Parsons said.
He pointed out, however, that it is not yet known if this information will be useful in guiding the treatment of pediatric cancers. Specifically, how many pediatric patients can be matched to targeted therapies, and how effective will those therapies be?
The Pediatric MATCH trial (NCT03155620) was developed to answer these questions. Researchers plan to enroll at least 1,000 patients in this trial. Patients are eligible if they are 1-21 years of age and have refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders.
After patients are enrolled in the trial, their tumor samples undergo DNA and RNA sequencing, and the results are used to match each patient to a targeted therapy. At present, the trial can match patients to one of 10 drugs:
- larotrectinib (targeting NTRK fusions).
- erdafitinib (targeting FGFR1/2/3/4).
- tazemetostat (targeting EZH2 or members of the SWI/SNF complex).
- LY3023414 (targeting the PI3K/MTOR pathway).
- selumetinib (targeting the MAPK pathway).
- ensartinib (targeting ALK or ROS1).
- vemurafenib (targeting BRAF V600 mutations).
- olaparib (targeting defects in DNA damage repair).
- palbociclib (targeting alterations in cell cycle genes).
- ulixertinib (targeting MAPK pathway mutations).
Early results
From July 2017 through December 2018, 422 patients were enrolled in the trial. The patients had more than 60 different diagnoses, including brain tumors, sarcomas, neuroblastoma, renal and liver cancers, and other malignancies.
The researchers received tumor samples from 390 patients, attempted sequencing of 370 samples (95%), and completed sequencing of 357 samples (92%).
A treatment target was found in 112 (29%) patients, 95 (24%) of those patients were assigned to a treatment, and 39 (10%) were enrolled in a protocol. The median turnaround time from sample receipt to treatment assignment was 15 days.
“In addition to the sequencing being successful, the patients are being matched to the different treatments,” Dr. Parsons said. He added that the study is ongoing, so more of the matched and assigned patients will be enrolled in protocols in the future.
Dr. Parsons also presented results by tumor type. A targetable alteration was identified in 26% (67/255) of all non–central nervous system solid tumors, 13% (10/75) of osteosarcomas, 50% (18/36) of rhabdomyosarcomas, 21% (7/33) of Ewing sarcomas, 25% (9/36) of other sarcomas, 19% (5/26) of renal cancers, 16% (3/19) of carcinomas, 44% (8/18) of neuroblastomas, 43% (3/7) of liver cancers, and 29% (4/14) of “other” tumors.
Drilling down further, Dr. Parsons presented details on specific alterations in one cancer type: astrocytomas. Targetable alterations were found in 74% (29/39) of astrocytomas. This includes NF1 mutations (18%), BRAF V600E (15%), FGFR1 fusions/mutations (10%), BRAF fusions (10%), PIK3CA mutations (8%), NRAS/KRAS mutations (5%), and other alterations.
“Pretty remarkably, in this one diagnosis, there are patients who have been matched to nine of the ten different treatment arms,” Dr. Parsons said. “This study is allowing us to evaluate targeted therapies – specific types of investigational drugs – in patients with many different cancer types, some common, some very rare. So, hopefully, we can study these agents and identify signals of activity where some of these drugs may work for our patients.”
The Pediatric MATCH trial is sponsored by the National Cancer Institute. Dr. Parsons has patents, royalties, and other intellectual property related to genes discovered through sequencing of several adult cancer types.
SOURCE: Parsons DW et al. ASCO 2019, Abstract 10011.
REPORTING FROM ASCO 2019
Model shows nivolumab plus ipilimumab cost effective in mRCC
First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.
“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.
The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.
“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.
Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.
After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.
With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.
“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.
The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.
The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.
SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.
First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.
“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.
The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.
“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.
Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.
After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.
With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.
“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.
The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.
The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.
SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.
First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.
“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.
The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.
“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.
Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.
After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.
With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.
“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.
The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.
The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.
SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.
REPORTING FROM JAMA ONCOLOGY
Tivozanib has PFS benefit over sorafenib in hard-to-treat RCC
SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.
Tivozanib, an oral tyrosine kinase inhibitor of the VEGF family of receptors with a long half-life, is designed both to optimize receptor blockade and minimize off-target toxicities, lead investigator Brian I. Rini, MD, said at the the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Positive progression-free survival results of the TIVO-1 trial (J Clin Oncol. 2013;31:3791-9) led to approval of this agent as first-line therapy for RCC in Europe. However, the Food and Drug Administration rejected approval because of a trend toward poorer overall survival, which was likely related to imbalanced cross-over to active treatment.
The TIVO-3 trial enrolled 350 patients with advanced clear-cell RCC who had experienced failure of two or three prior regimens, including a VEGF receptor tyrosine kinase inhibitor. They were randomized evenly to open-label tivozanib (1.5 mg q.d., 3 weeks on and 1 week off) or sorafenib (Nexavar) (400 mg b.i.d. continuously).
Main results showed that progression-free survival was about 2 months longer with tivozanib, compared with sorafenib. The difference translated to a 27% reduction in risk of events, reported Dr. Rini, professor of medicine at Case Western Reserve University, Cleveland, and leader of the genitourinary oncology program at the Cleveland Clinic.
The benefit was similar for most subgroups. The tivozanib group had a higher incidence of hypertension, but lower incidences of diarrhea, hand-foot syndrome, and rash.
“Tivozanib significantly improved progression-free survival and objective response rate compared to sorafenib in patients with treatment-refractory advanced RCC. It was superior in the subset of patients previously treated with checkpoint inhibitors, as well as the subset who had had two prior TKIs,” Dr. Rini said. “Responses to tivozanib, perhaps most impressively, were more durable than those with sorafenib. Tivozanib was very well tolerated, with on-target hypertension as the most common adverse event, but lower rates of off-target toxicities.”
Overall survival data at present show a trend toward shorter survival with tivozanib, but are not yet mature. Definitive results are expected later this year.
Study details
About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.
Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.
Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.
In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.
An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.
The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).
Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.
SOURCE: Rini BI et al. GUCS 2019, Abstract 541.
SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.
Tivozanib, an oral tyrosine kinase inhibitor of the VEGF family of receptors with a long half-life, is designed both to optimize receptor blockade and minimize off-target toxicities, lead investigator Brian I. Rini, MD, said at the the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Positive progression-free survival results of the TIVO-1 trial (J Clin Oncol. 2013;31:3791-9) led to approval of this agent as first-line therapy for RCC in Europe. However, the Food and Drug Administration rejected approval because of a trend toward poorer overall survival, which was likely related to imbalanced cross-over to active treatment.
The TIVO-3 trial enrolled 350 patients with advanced clear-cell RCC who had experienced failure of two or three prior regimens, including a VEGF receptor tyrosine kinase inhibitor. They were randomized evenly to open-label tivozanib (1.5 mg q.d., 3 weeks on and 1 week off) or sorafenib (Nexavar) (400 mg b.i.d. continuously).
Main results showed that progression-free survival was about 2 months longer with tivozanib, compared with sorafenib. The difference translated to a 27% reduction in risk of events, reported Dr. Rini, professor of medicine at Case Western Reserve University, Cleveland, and leader of the genitourinary oncology program at the Cleveland Clinic.
The benefit was similar for most subgroups. The tivozanib group had a higher incidence of hypertension, but lower incidences of diarrhea, hand-foot syndrome, and rash.
“Tivozanib significantly improved progression-free survival and objective response rate compared to sorafenib in patients with treatment-refractory advanced RCC. It was superior in the subset of patients previously treated with checkpoint inhibitors, as well as the subset who had had two prior TKIs,” Dr. Rini said. “Responses to tivozanib, perhaps most impressively, were more durable than those with sorafenib. Tivozanib was very well tolerated, with on-target hypertension as the most common adverse event, but lower rates of off-target toxicities.”
Overall survival data at present show a trend toward shorter survival with tivozanib, but are not yet mature. Definitive results are expected later this year.
Study details
About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.
Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.
Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.
In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.
An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.
The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).
Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.
SOURCE: Rini BI et al. GUCS 2019, Abstract 541.
SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.
Tivozanib, an oral tyrosine kinase inhibitor of the VEGF family of receptors with a long half-life, is designed both to optimize receptor blockade and minimize off-target toxicities, lead investigator Brian I. Rini, MD, said at the the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Positive progression-free survival results of the TIVO-1 trial (J Clin Oncol. 2013;31:3791-9) led to approval of this agent as first-line therapy for RCC in Europe. However, the Food and Drug Administration rejected approval because of a trend toward poorer overall survival, which was likely related to imbalanced cross-over to active treatment.
The TIVO-3 trial enrolled 350 patients with advanced clear-cell RCC who had experienced failure of two or three prior regimens, including a VEGF receptor tyrosine kinase inhibitor. They were randomized evenly to open-label tivozanib (1.5 mg q.d., 3 weeks on and 1 week off) or sorafenib (Nexavar) (400 mg b.i.d. continuously).
Main results showed that progression-free survival was about 2 months longer with tivozanib, compared with sorafenib. The difference translated to a 27% reduction in risk of events, reported Dr. Rini, professor of medicine at Case Western Reserve University, Cleveland, and leader of the genitourinary oncology program at the Cleveland Clinic.
The benefit was similar for most subgroups. The tivozanib group had a higher incidence of hypertension, but lower incidences of diarrhea, hand-foot syndrome, and rash.
“Tivozanib significantly improved progression-free survival and objective response rate compared to sorafenib in patients with treatment-refractory advanced RCC. It was superior in the subset of patients previously treated with checkpoint inhibitors, as well as the subset who had had two prior TKIs,” Dr. Rini said. “Responses to tivozanib, perhaps most impressively, were more durable than those with sorafenib. Tivozanib was very well tolerated, with on-target hypertension as the most common adverse event, but lower rates of off-target toxicities.”
Overall survival data at present show a trend toward shorter survival with tivozanib, but are not yet mature. Definitive results are expected later this year.
Study details
About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.
Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.
Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.
In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.
An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.
The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).
Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.
SOURCE: Rini BI et al. GUCS 2019, Abstract 541.
REPORTING FROM GUCS 2019
First-line avelumab/axitinib for RCC benefits wide range of patients
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
REPORTING FROM GUCS 2019
Pembrolizumab-axitinib nearly halves risk of death in RCC
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
REPORTING FROM GUCS 2019
Key clinical point: The combination of pembrolizumab and axitinib may become a new first-line standard of care in advanced renal cell carcinoma.
Major finding: Compared with sunitinib monotherapy, pembrolizumab and axitinib combination therapy prolonged progression-free survival (hazard ratio, 0.69; P = .0001) and overall survival (HR, 0.53; P less than .0001).
Study details: A phase 3, randomized, controlled trial among 861 patients with untreated locally advanced or metastatic renal cell carcinoma (KEYNOTE-426).
Disclosures: Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from AstraZeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
Source: Powles T et al. GUCS 2019, Abstract 543.
Severe adverse events seen in placebo arm of cancer clinical trials
A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.
Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.
Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.
Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).
Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.
The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.
The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.
They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.
“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.
They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.
No conflicts of interest were declared.
SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.
A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.
Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.
Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.
Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).
Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.
The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.
The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.
They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.
“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.
They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.
No conflicts of interest were declared.
SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.
A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.
Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.
Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.
Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).
Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.
The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.
The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.
They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.
“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.
They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.
No conflicts of interest were declared.
SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.
FROM JAMA NETWORK OPEN
Key clinical point: Serious adverse events can occur in patients treated only with placebo in cancer clinical trials.
Major finding: The incidence of grade 3-4 placebo adverse events was 18% in cancer clinical trials.
Study details: Systematic review and meta-analysis of 10 randomized, placebo-controlled, double-blind trials.
Disclosures: No conflicts of interest were declared.
Source: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.