Safety and efficacy of nivolumab plus ipilimumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase 3b/4 CheckMate 920 trial

Abstract

BackgroundCheckMate 920 (NCT02982954) is a multicohort, phase 3b/4 clinical trial of nivolumab plus ipilimumab treatment in predominantly US community-based patients with previously untreated advanced renal cell carcinoma (RCC) and clinical features mostly excluded from phase 3 trials. We report safety and efficacy results from the advanced non-clear cell RCC (nccRCC) cohort of CheckMate 920.MethodsPatients with previously untreated advanced/metastatic nccRCC, Karnofsky performance status ≥70%, and any International Metastatic Renal Cell Carcinoma Database Consortium risk received up to four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks followed by nivolumab 480 mg every 4 weeks for ≤2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥3 immune-mediated adverse events (AEs) within 100 days of last dose of study drug. Key secondary endpoints included objective response rate (ORR), progression-free survival (PFS; both investigator-assessed), time to response (TTR), and duration of response (DOR), all using RECIST V.1.1. Overall survival (OS) was exploratory.ResultsFifty-two patients with nccRCC (unclassified histology, 42.3%; papillary, 34.6%; chromophobe, 13.5%; translocation-associated, 3.8%; collecting duct, 3.8%; renal medullary, 1.9%) received treatment. With 24.1 months minimum study follow-up, median duration of therapy (range) was 3.5 (0.0–25.8) months for nivolumab and 2.1 (0.0–3.9) months for ipilimumab. Median (range) number of doses received was 4.5 (1–28) for nivolumab and 4.0 (1–4) for ipilimumab. Grade 3–4 immune-mediated AEs were diarrhea/colitis (7.7%), rash (5.8%), nephritis and renal dysfunction (3.8%), hepatitis (1.9%), adrenal insufficiency (1.9%), and hypophysitis (1.9%). No grade 5 immune-mediated AEs occurred. ORR (n=46) was 19.6% (95% CI 9.4 to 33.9). Two patients achieved complete response (papillary, n=1; unclassified, n=1), seven achieved partial response (papillary, n=4; unclassified, n=3), and 17 had stable disease. Median TTR was 2.8 (range 2.1–14.8) months. Median DOR was not reached (range 0.0+−27.8+); eight of nine responders remain without reported progression. Median PFS (n=52) was 3.7 (95% CI 2.7 to 4.6) months. Median OS (n=52) was 21.2 (95% CI 16.6 to not estimable) months.ConclusionsNivolumab plus ipilimumab for previously untreated advanced nccRCC showed no new safety signals and encouraging antitumor activity.Trial registration numberNCT02982954.

Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course

“…Many studies have further extended the interval of ipilimumab to 6 weeks (49, 50, 94-97) or even longer. In the CheckMate 920 study of renal cancer, Cohort 1 patients received 6 mg/kg Q8W nivolumab plus 1 mg/kg Q8W ipilimumab, alternating with nivolumab 480 mg Q8W, with an ORR of 34.4%, median PFS 4.8 months, which was not significantly different from the results of several other cohorts using N3I1 regimen followed by nivolumab 480 mg Q4W (51,52). The MAYA study evaluated the efficacy of temozolomide followed by nivolumab 480 mg Q4W plus ipilimumab 1 mg/kg Q8W in microsatellite-stable, O6methylguanine-DNA methyltransferase-silenced metastatic colorectal cancer, with an ORR of 45% to the whole treatment strategy, median PFS of 7.1 months and median OS of 18.4 months (53).…”

Case Report: A Case of Renal Cell Carcinoma Unclassified With Medullary Phenotype Exhibiting a Favorable Response to Combined Immune Checkpoint Blockade

“…The patients with 1% or greater PD-L1 expression have been demonstrated to receive significant clinical benefits from ipilimumab plus nivolumab compared with nivolumab alone. In contrast, those with less than 1% PD-L1 expression showed comparable outcomes to both treatment ( 15 , 16 ). Thus, selection of ipilimumab plus nivolumab in the present case was reasonable.…”

Metastatic Type II Papillary Renal Cell Carcinoma With Recurrent Complete Responses to Sunitinib: A Case Report With a Literature Review

“…The effectiveness of first-line immunotherapy-based treatments in non-clear cell RCC has been demonstrated in multiple phase II and observational retrospective studies [ 16 - 18 ]. A phase III randomized trial is currently ongoing, looking at first-line nivolumab and ipilimumab versus sunitinib in non-clear cell RCC.…”