Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and brain metastases: results from the CheckMate 920 trial.
Authors: Emamekhoo Hamid , Olsen Mark R , Carthon Bradley Curtis , Drakaki Alexandra , Percent Ivor John , Molina Ana M. , Cho Daniel C. , Bendell Johanna C. , Gordan Lucio N. , Rezazadeh Kalebasty Arash , George Daniel J. , Hutson Thomas E. , Arrowsmith Edward , Zhang Joshua , Zoco Jesus , Johansen Jennifer L. , Leung David , Tykodi Scott S. 
Published: June 2021

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Background: Combination therapy with nivolumab plus ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability in patients with previously untreated advanced renal cell carcinoma (aRCC). Previous phase 3 clinical trials of patients with advanced or metastatic cancers have mostly excluded patients with brain metastases. CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NIVO+IPI treatment in patients with aRCC with a high unmet medical need. We present updated safety and efficacy results for the cohort of patients with aRCC of any histology and brain metastases from CheckMate 920 (NCT02982954). Methods: Patients with previously untreated advanced/metastatic aRCC of any histology, with asymptomatic brain metastases (not currently receiving corticosteroids or radiation), and Karnofsky performance status ≥ 70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks × 4 doses followed by NIVO 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 (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 28 treated patients with brain metastases, 85.7% were men; median (range) age was 60 (38–87) years, and 14.3% had sarcomatoid features. With 24.5 months minimum follow-up of the 28 patients enrolled, median duration of therapy (range) was 3.4 (0.0–23.3) months for NIVO and 2.1 (0.0–3.3) months for IPI. No grade 5 imAEs occurred. Grade 3–4 imAEs by category were diarrhea/colitis (7.1%), hypophysitis (3.6%), rash (3.6%), hepatitis (3.6%), and diabetes mellitus (3.6%). Of the 25 patients who were evaluable for ORR, the ORR was 32.0% (95% CI, 14.9–53.5). No patients achieved complete response, 8 achieved partial response, and 10 patients had stable disease. Median time to response (range) was 2.8 (2.4–3.0) months. Median duration (range) of response was 24.0 (3.9–not estimable [NE]) months; 4 of 8 responders remain without reported progression. Of 28 patients, 7 (25%) had intracranial progression. Median PFS (n = 28) was 9.0 (95% CI, 2.9–12.0) months. Median OS (n = 28) was still not reached (95% CI, 14.1 months–NE). Conclusions: In patients with previously untreated aRCC and brain metastases, a population with high unmet medical need that is often underrepresented in clinical trials, the approved treatment regimen of NIVO+IPI followed by NIVO for aRCC showed no new safety signals and continues to show encouraging antitumor activity with longer follow-up. Clinical trial information: NCT02982954.