First-Line Nivolumab and Ipilimumab vs Sunitinib in Advanced Renal Cell Carcinoma

AN: Welcome to The ASCO Post Podcast, brought to you by the editorial team at Harborside, publisher of The ASCO Post. I’m Andrew Nash, and I’m here today with my colleague Liz Janetschek.

This week, we’ll be talking about an extended follow-up of a phase III trial that investigated first-line nivolumab and ipilimumab vs sunitinib in advanced renal cell carcinoma. Then we’ll go over a research letter that identified strong predictors of response to immune checkpoint inhibitor treatment. Lastly, we’ll review a report on e-cigarette secondhand smoke exposure experienced by middle and high school students.

LJ: As reported in The Lancet Oncology by Motzer et al, extended follow-up of the phase III CheckMate 214 trial has shown a maintained survival benefit for first-line nivolumab plus ipilimumab vs sunitinib in patients with previously untreated intermediate- or poor-risk advanced renal cell carcinoma (RCC). Benefits were also observed in the entire study population, and no new safety signals were observed.

The open-label trial included 1,100 patients from 175 sites in 28 countries with advanced or metastatic RCC with a clear-cell component. Patients were randomly assigned 2:1 to receive nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for four doses followed by nivolumab at 3 mg/kg every 2 weeks or sunitinib at 50 mg once daily for 4 weeks in 6-week cycles. Among these patients, 425 vs 422 had intermediate- or poor-risk disease and 125 vs 124 had favorable-risk disease.

The primary endpoints were overall survival, progression-free survival, and objective response.

The current extended analysis occurred at a minimum follow-up of 30 months and median follow-up of 32.4 months, with a data cutoff in August 2018. Among patients with intermediate- or poor-risk disease, median overall survival was not reached in the arm treated with nivolumab/ipilimumab vs 26.6 months in the arm treated with sunitinib.

AN: Median progression-free survival was 8.2 vs 8.3 months; the progression-free survival curves for the two treatment groups began to separate after approximately 9 months, with the estimated 30-month progression-free survival being 28% vs 18%. Objective response rates were 42% vs 29%, and overall survival at 30 months was 60% vs 47%.

In the intent-to-treat population, median overall survival was not reached with nivolumab/ipilimumab vs 37.9 monthsin the arm treated with sunitinib. Investigator-assessed median progression-free survival was 9.7 vs 9.7 months, respectively; the progression-free survival curves for the two groups began to separate after 12 months, with the estimated 30-month progression-free survival being 28% vs 18%. Investigator-assessed objective response rates were 41% vs 34%. Overall survival at 30 months was 64% vs 56%.

Among favorable-risk patients, median overall survival was not reached in either group; overall survival at 30 months was 80% vs 85%. Investigator-assessed median progression-free survival was 13.9 vs 19.9 months, with 30-month rates of 29% vs 35%. Objective response rates were 39% vs 50%.

In the intent-to-treat population, 48% of patients in the nivolumab/ipilimumab group and 61% of patients in the sunitinib group received subsequent systemic therapies. In the nivolumab/ipilimumab group, the most common were sunitinib, pazopanib, axitinib, and cabozantinib. In the sunitinib group, the most common were nivolumab, axitinib, sunitinib, and everolimus.

LJ: No new safety signals for study treatments were identified during extended follow-up. Among all patients, treatment-related grade 3 or 4 adverse events occurred in 47% of patients treated with nivolumab/ipilimumab vs 64% of patients treated with sunitinib; the most common were increased levels of lipase, amylase, and alanine aminotransferase in the nivolumab/ipilimumab group and hypertension, fatigue, and palmar-plantar erythrodysesthesia in the sunitinib group.

Treatment-related adverse events led to study drug discontinuation in 22% vs 12% of patients. Potentially immune-related adverse events of any grade occurred in 81% vs 83% of patients within 30 days of the last dose of study drug. Among patients in the nivolumab/ipilimumab group, 29% received 40 mg or more of prednisone or its equivalent daily for potentially immune-related adverse events, with 19% receiving treatment for 2 weeks or more and 10% for 30 days or more.

No additional treatment-related deaths were observed since the primary analysis. Death was considered treatment-related in eight patients in the nivolumab/ipilimumab group and four patients in the sunitinib group.

The investigators concluded, “The results suggest that the superior efficacy of nivolumab/ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab/ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.”

For full disclosures of the study authors, visit thelancet.com.

AN: In a study reported in JAMA Oncology, Lee and Ruppin found that CD8-positive T-cell abundance, tumor mutational burden, and high PD1 gene expression were the strongest predictors of response to anti–programmed cell death 1 and ligand 1 (PD-1 and PD-L1) treatment across cancer types.

The analysis included the use of whole-exome and RNA sequencing data for about 7,200 patients from the Cancer Genome Atlas, as well as objective response rate data on 21 cancer types obtained from a collection of clinical trials of PD-1 or PD-L1 inhibitor therapy published by Yarchoan et al in The New England Journal of Medicine. A total of 36 variables representing tumor neoantigens, tumor microenvironment and inflammation, and checkpoint inhibitor targets were analyzed.

Among the 36 variables evaluated, the 3 most predictive of a response to PD-1/PD-L1 inhibitor therapy across cancer types represented each of the three categories of variables considered; they were, in order of predictive ability: estimated CD8-positive T-cell abundance, tumor mutational burden, and the interaction of tumor samples with high PD1 gene expression.

LJ: In an analysis combining the three variables, the combination was highly correlated with treatment response, accounting for more than 80% of objective response rate variability across tumor types.

The investigators concluded, stating that as far as they know, “this is the first systematic evaluation of the different variables associated with anti–PD-1 and PD-L1 therapy response across different tumor types. The findings suggest that the three key variables can explain most of the observed cross-cancer response variability, but their relative explanatory roles may vary in specific cancer types.”

For full disclosures of the study authors, visit jamanetwork.com.

AN: A growing number of students in middle school and high school are being exposed to secondhand aerosols from electronic cigarettes by living with or being around individuals who are vaping, according to data from a national survey. Such exposure increased rapidly in 2018 compared to the years 2015 to 2017, according to a research letter published by Tan et al in JAMA Network Open. 

The analysis was conducted using data collected by the National Youth Tobacco survey carried out under the auspices of the U.S. Centers for Disease Control and Prevention. Participants in the survey were asked how often they breathed smoke from someone who was smoking tobacco products and/or breathed vapor from someone using an e-cigarette in indoor or outdoor public places in the past 30 days.

The survey revealed that about one-third of the students said they were exposed to vaping aerosols in 2018—an increase by about 30% compared with the previous 3 years, according to the study authors. They called the increase in exposure to vaping aerosols “concerning,” given that an array of potentially hazardous chemicals are released by e-cigarettes. Fumes from e-cigarettes contain a variety of chemicals including nicotine, heavy metals, aldehydes, glycerin, and flavoring substances.

LJ: The prevalence of exposure to secondhand aerosols from e-cigarettes increased from about one in four students between 2015 and 2017 to one in three students in 2018. The increase is occurring, the report noted, despite laws introduced in a number of states to restrict e-cigarette use in 100% smoke-free or other venues, including schools.

The researchers added, “Education about potential secondhand aerosol harms for parents and youth and interventions to reduce youth vaping are needed to protect young people from being exposed to all forms of tobacco product emissions, including from e-cigarettes.”

The survey also found that secondhand tobacco smoke from conventional cigarettes remains a serious public health concern. About half the students surveyed reported exposure to secondhand tobacco smoke.

Disclosure: For full disclosures of the study authors, visit jamanetwork.com.

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