Phase II Study of Nivolumab and Salvage Nivolumab/Ipilimumab in Treatment-Naive Patients With Advanced Clear Cell Renal Cell Carcinoma (HCRN GU16-260-Cohort A)

Abstract

PURPOSE To determine the value of tumor cell programmed death-ligand 1 (PD-L1) expression as a predictive biomarker of nivolumab monotherapy efficacy in treatment-naive patients with clear cell renal cell carcinoma (ccRCC) and the efficacy of salvage nivolumab/ipilimumab in patients with tumors unresponsive to nivolumab monotherapy. METHODS Eligible patients with treatment-naive ccRCC received nivolumab until progressive disease (PD), toxicity, or completing 96 treatment weeks (part A). Patients with PD before or stable disease at 48 weeks could receive salvage nivolumab/ipilimumab (part B). The primary end point was improvement in 1-year progression-free survival in patients with tumor PD-L1 expression > 20% versus 0%. RESULTS One hundred twenty-three patients were enrolled. The objective response rate (ORR) was 34.1% (95% CI, 25.8 to 43.2). ORR by International Metastatic RCC Database Consortium category was favorable-risk 57.1%, intermediate-risk/poor-risk 25.0%, and by sarcomatoid features 36.4%. The ORR was 26.9%, 50.0%, and 75.0% for patients with the tumor PD-L1 expression of 0, 1-20, or > 20%, respectively (trend test P value = .002). The median duration of response was 27.6 (19.3 to not reached) months, with 26 of 42 responders including 17 of 20 with favorable-risk disease remaining progression-free. The 1-year progression-free survival was 34.6% and 75.0% in the PD-L1 = 0% and > 20% categories, respectively ( P = .050). Ninety-seven patients with PD or prolonged stable disease were potentially eligible for part B, and 35 were enrolled. The ORR for part B was 11.4%. Grade ≥ 3 treatment-related adverse events occurred in 35% of patients on nivolumab and 43% of those on salvage nivolumab/ipilimumab. CONCLUSION Nivolumab monotherapy is active in treatment-naive ccRCC. Although efficacy appears to be less than that of nivolumab/ipilimumab in patients with intermediate-risk/poor-risk disease, favorable-risk patients had notable benefit. Efficacy correlated with tumor PD-L1 status. Salvage nivolumab/ipilimumab was frequently not feasible and of limited benefit.

Knowledge mapping and research hotspots of immunotherapy in renal cell carcinoma: A text-mining study from 2002 to 2021

“…Currently, a variety of ICIs have been approved by the FDA, and the combination of ICIs and tyrosine kinase inhibitors is the first-line treatment of clear cell RCC (ccRCC) ( 22 ). Moreover, ICI monotherapy is currently undergoing clinical trials and is expected to become a promising alternative therapeutic method for patients with combination therapy intolerance ( 23 – 25 ). The research focus in the field of RCC immunotherapy is constantly changing with the effect of drugs, indicating that the research topics related to cancer immunotherapy are being updated rapidly, and it is necessary to monitor the research progress.…”

Pre-treatment metastatic growth rate predicts clinical outcome of metastatic renal cell carcinoma treated with nivolumab

“…To date, several types of biomarkers such as the expression of programmed death-ligand 1 (PD-L1) in cancer tissues have been proposed to have a signi cant impact on the clinical response to nivolumab [5].…”

Up-front Nivolumab With or Without Salvage Ipilimumab Across International Metastatic Database Consortium Risk Groups in Metastatic Clear Cell Renal Cell Carcinoma

“…Retrospective reports gave support to the notion that patients could safely be treated with sequential CPI, possibly achieving added benefit. 8,9 In malignant melanoma where approval of CPI monotherapy preceded the successful development of the ipilimumab/nivolumab doublet, 10 CTLA-4-directed salvage strategies have been studied prospectively with a clear efficacy signal 11,12 All this motivated the design of the HCRN GU16-260 study presented by Atkins et al 13 This phase II response-adaptive trial offered up-front nivolumab to patients with treatment-naive metastatic ccRCC, irrespective of International Metastatic Database Consortium (IMDC) risk category (Part A). Patients who achieved an objective response were treated up to 96 weeks.…”

“…All this motivated the design of the HCRN GU16-260 study presented by Atkins et al 13 This phase II response-adaptive trial offered up-front nivolumab to patients with treatment-naive metastatic ccRCC, irrespective of International Metastatic Database Consortium (IMDC) risk category (Part A). Patients who achieved an objective response were treated up to 96 weeks.…”

“…In the article that accompanies this editorial, Atkins et al 13 report their findings from a phase II adaptive study sequencing nivolumab with or without ipilimumab in patients with treatment-naive metastatic renal cell cancer. Their report highlights not only the added insights but also the challenges investigators face when implementing response-adaptive study designs; it further provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies.…”