Author: Shreeya Nanda
This article provides a top-line overview of the CheckMate clinical trials of the PD-1 inhibitor nivolumab – either given alone or alongside the CTLA-4 inhibitor ipilimumab – in patients with renal cell carcinoma (RCC). There are nine trials at the time of writing, all of which are sponsored by the drug manufacturer Bristol-Myers Squibb.
CheckMate 010: Published
|Patient population: Previously treated advanced or metastatic RCC||Treatment: Nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks|
This study demonstrated the antitumor activity of nivolumab in patients who had received at least one prior antiangiogenic agent, but no more than three previous lines of therapy, for advanced or metastatic disease. These findings, which appeared in the Journal of Clinical Oncology in 2014, supported the investigation of the anti-PD-1 agent in phase 3 trials.
A subgroup analysis – described in JAMA Oncology in 2016 – indicated that continuing nivolumab after progression could be beneficial for some patients, while another analysis, reported in Clinical Cancer Research in 2019, identified a potential biomarker for nivolumab response, namely CD8+ tumor infiltrating cells (TICs) expressing PD-1 but not TIM-3 and LAG-3 (CD8+PD1+TIM3−LAG3−).
CheckMate 016: Published
|Patient population: Advanced or metastatic RCC||Treatments: Nivolumab plus ipilimumab, multiple dose combinations; nivolumab (2 mg/kg or 5 mg/kg every 3 weeks) plus either sunitinib 50 mg/day on a 4 weeks on, 2 weeks off schedule, or pazopanib 800 mg/day|
Initial results from the expansion phase of this study (median follow-up, 31.3–34.3 weeks), reported at the 2015 ASCO Annual Meeting, as well as data from the additional follow-up (median, 22.3 months), published in the Journal of Clinical Oncology in 2017, demonstrated the efficacy of both the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg and the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 3-weekly regimens in patients who had and had not received prior treatment.
As reported in the Journal for ImmunoTherapy of Cancer in 2018, supplementing nivolumab with the standard dose of the antiangiogenic agents sunitinib or pazopanib led to high rates of treatment-related AEs of grade 3 or 4 (80 and 72%, respectively), thereby “limiting future development of either combination regimen.”
CheckMate 025: Published
|Patient population: Previously treated advanced or metastatic clear cell RCC||Treatments: Nivolumab 3 mg/kg every 2 weeks; or everolimus 10 mg/day|
This pivotal trial showed a significant improvement in overall survival (OS) with nivolumab versus everolimus in patients who had received one or two prior antiangiogenic therapies, with a hazard ratio (HR) for death of 0.73 favoring the PD-1 inhibitor. These data were published in The New England Journal of Medicine in 2015.
Patient-reported outcomes (PROs) from the trial – which appeared in The Lancet Oncology in 2016 – showed that nivolumab-treated participants achieved significantly greater improvements in health-related quality of life than their counterparts given everolimus. And a Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) analysis published in Clinical Genitourinary Cancer in 2019 showed that nivolumab was associated with a significant and clinically meaningful improvement in quality-adjusted OS relative to everolimus.
A post-hoc subgroup analysis, reported in European Urology in 2017, demonstrated a trend for improved OS with nivolumab across multiple subgroups, including by IMDC and MSKCC risk criteria and age, while another, also published in European Urology in the same year, pointed to the potential of postprogression nivolumab treatment in some patients.
The superiority of nivolumab over everolimus was confirmed in the final efficacy analysis, conducted at a minimum follow-up of 5 years and published in Cancer in 2020.
And the previously identified biomarker of response to nivolumab – CD8+PD1+TIM3−LAG3− TICs – was validated using data from this study. These findings were presented at the virtual 2020 ASCO Annual Meeting.
Nivolumab also demonstrated improved efficacy and toxicity relative to everolimus among the Japanese participants of the trial, both at the 2-year and 3-year follow-up, which were reported in the Japanese Journal of Clinical Oncology in 2017 and 2019, respectively.
CheckMate 214: Published
|Patient population: Treatment-naïve advanced or metastatic RCC||Treatments: Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at the same dose every 2 weeks; or sunitinib 50 mg/day for 4 weeks of each 6-week cycle|
The primary analysis of the trial – conducted at a median follow-up of 25.2 months – showed a significant improvement with nivolumab plus ipilimumab versus sunitinib in the co-primary endpoints of OS (HR for death=0.63) and objective response rate (ORR; 42 vs 27%) in IMDC intermediate- and poor-risk patients. However, as described in The New England Journal of Medicine in 2018, the third primary endpoint of progression-free survival (PFS) favored the combination but was not statistically significant at this timepoint.
With extended follow-up, the combination continued to demonstrate superiority over sunitinib in terms of OS and ORR for the intermediate- and poor-risk group, and the PFS improvement also reached statistical significance. The data from a median 32.4 months of follow-up were published in in The Lancet Oncology in 2019, while those from a minimum 42.0 months of follow-up appeared in the Journal for ImmunoTherapy of Cancer in 2020.
The PRO results, published in The Lancet Oncology in 2019, also favored nivolumab plus ipilimumab, and the findings for the intention-to-treat population, which additionally included favorable-risk patients, were similar to those of the primary analysis population in these four reports. But exploratory efficacy analyses restricted to the favorable-risk group appeared to favor sunitinib.
A post-hoc analysis found that the benefit afforded by first-line nivolumab–ipilimumab is irrespective of the number of IMDC risk factors for intermediate- (one or two risk factors) and poor-risk (3–6 factors) participants. These results were reported in European Urology in 2019.
A report on the Japanese intermediate- and poor-risk participants of the trial – published in the Japanese Journal of Clinical Oncology in 2019 – demonstrated a trend towards better OS and a numerically higher ORR with the combination than sunitinib, but the researchers believe that longer follow-up is needed to confirm the OS benefit.
CheckMate 374: Published
|Patient population: Advanced or metastatic clear cell RCC||Treatment: Nivolumab 240 mg every 2 weeks for up to 2 years|
CheckMate 374 consists of three cohorts: patients with clear cell RCC who had previously received 1–2 anti-VEGF therapies, but no more than three lines of systemic therapy in total; patients with non-clear cell disease who had received 0–3 prior treatments; and those with brain metastases.
As reported at the 2017 NCRI Cancer Conference, the 240 mg flat dose of nivolumab had acceptable tolerability in clear cell and non-clear cell RCC patients, with low rates of immune-related adverse events (irAEs) in both groups over a median follow-up of 8 months.
Additional data from the clear cell and non-clear cell cohorts, both published in Clinical Genitourinary Cancer in 2020, showed the continued tolerability of flat-dose nivolumab at a median follow-up of 17.0 and 11.0 months, respectively. Nivolumab also showed promising efficacy, with corresponding median OS times of 21.8 and 16.3 months.
CheckMate 920: Ongoing
|Patient population: Treatment-naïve advanced or metastatic RCC||Treatment: Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks|
This multicohort trial includes patients with a Karnofsky performance status (KPS) of at least 70% who have clear cell RCC, non-clear cell RCC, or any histology with asymptomatic brain metastases. A fourth cohort comprises patients with a KPS of 50–60% regardless of histology and brain metastases status.
An interim analysis of the brain metastases cohort, presented at the 2019 ASCO Annual Meeting, indicated the combination is active in these patients, with a median PFS of 9.0 months and median OS unreached at a minimum follow-up of 6.5 months. And the safety profile was consistent with that reported in previous studies.
CheckMate 9ER: Ongoing
|Patient population: Previously treated advanced or metastatic RCC||Treatments: Nivolumab plus cabozantinib; sunitinib (doses not specified)|
The investigators are evaluating the efficacy and safety of combining nivolumab with the multikinase inhibitor cabozantinib for the first-line treatment of advanced RCC. The comparator treatment is sunitinib and the primary endpoint is PFS.
CheckMate 800: Ongoing
|Patient population: Advanced RCC||Treatment: Nivolumab plus ipilimumab (doses not specified)|
This study is investigating the safety and efficacy of simultaneous and sequential administration of nivolumab and ipilimumab in the advanced RCC setting.
CheckMate 914: Recruiting
|Patient population: Localized RCC at high risk for relapse after nephrectomy||Treatment: Nivolumab; nivolumab plus ipilimumab; placebo (doses not specified)|
This placebo-controlled trial is assessing adjuvant nivolumab, either given alone or alongside ipilimumab, in patients with a high recurrence risk following radical or partial nephrectomy. The primary endpoint of the study is disease-free survival.
CheckMate 76U: Recruiting
|Patient population: Advanced tumors||Treatment: Subcutaneous nivolumab plus ipilimumab (doses not specified)|