Nivolumab Monotherapy Shows Efficacy in Favorable-Risk Metastatic ccRCC


The HCRN-GU16-260 trial reported results for patients with clear cell renal cell carcinoma who received frontline nivolumab followed by salvage nivolumab/ipilimumab on disease progression.

Nivolumab (Opdivo) monotherapy benefited patients with favorable-risk disease but not intermediate/poor risk versus nivolumab plus ipiliumuab (Yervoy) in patients with previously untreated clear cell renal cell carcinoma (ccRCC), according to a report published in the Journal of Clinical Oncology.1

In the single-arm phase 2 HCRN-GU16-260 trial (NCT03117309), nivolumab had an objective response rate (ORR) of 34.1% (95% CI, 25.8%-43.2%) in the overall trial population, which rose to 57.1% for patients with favorable risk. Higher ORR was also correlated with higher PD-L1 expression. Salvage therapy with nivolumab/ipilimumab had poor outcomes for the majority of patients who failed to respond to nivolumab monotherapy.

The combination of nivolumab and ipilimumab was approved as a frontline therapy for ccRCC based on the results of the CheckMate 214 trial (NCT02231749).2 Investigators in the HCRN-GU16-260 trial sought to assess the safety profile of nivolumab monotherapy, the efficacy of salvage nivolumab/ipilimumab, and whether PD-L1 could predict response or resistance to nivolumab.1

The trial enrolled 123 patients with ccRCC with at least 1 metastatic lesion who had no prior systemic therapy into cohort A. Cohort B included 36 patients with non–clear cell RCC histologies but this cohort was not discussed in the report. The primary end point was 1-year progression-free survival (PFS) rate, and secondary end points included ORR, duration of response (DOR), and toxicity.

Out of 123 patients, 35 were categorized as having International Metastatic RCC Database Consortium favorable risk, 76 had intermediate risk, and 12 had poor risk.

In part A of the trial, patients received 240 mg nivolumab once every 2 weeks for 6 cycles, then were assessed for response. Patients who had a complete response (CR) or partial response (PR) continued to receive nivolumab at a dose of 360 mg every 3 weeks for 4 cycles, then at a dose of 480 mg every 4 weeks for up to 72 weeks or discontinuation due to toxicity, progression, or death.

Patients in part A who had progressive disease (PD) at any point or a best response of stable disease (SD) at 48 weeks were enrolled in part B. They received the salvage regimen of nivolumab/ipilimumab at a dose of 3 mg/kg nivolumab and 1 mg/kg ipilimumab every 3 weeks for 4 cycles, then received nivolumab at a dose of 360 mg every 3 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks up to 48 weeks or discontinuation due to toxicity, progression, or death. Patients were not enrolled in part B if they had a grade 3 or higher immune-related adverse event (irAE) or if their physician determined they should receive other treatment for their symptomatic progressive disease.

The 1-year PFS rate was 65.1% (range, 46.8%-78.5%) for those with favorable-risk disease, 28.3% (range, 18.7%-38.8%) for those with intermediate-risk disease, and 33.3% (range, 10.3%-58.8%) for those with poor-risk disease. Thirty-two patients were progression free at 1 year. The median PFS was 8.3 months (range, 5.5-10.9) for all patients, 32.5 months for those with favorable-risk disease, and 5.4 and 5.2 months for patients with intermediate-risk and poor-risk disease, respectively.

In patients with PD-L1 expression of greater than 20%, the median PFS was 20.6 months (range, 4.2–NA), which was superior to the 7.7-month median PFS (range, 4.1-10.8) for patients with 0% PD-L1 expression. This met a primary goal of the study demonstrating that PD-L1 status could predict PFS outcomes.

At 1 year of follow-up, 26 patients had an ongoing response, 86 had PD, and 11 had SD maintained at 1 year. A total of 62 patients did not enroll in part B, 19 due to irAE, 25 due to receiving alternative therapy, 7 due to not having a biopsy done, and 11 for other reasons. Of the 35 patients who did enroll in part B, only 5 had a best response of CR or PR before progressing, while 3 maintained SD at 1 year and 27 had PD.

In part A, there were 34 patients (27.6%) with a PR and 8 (6.5%) with a CR. When assessed by risk category, the ORR was 57.1% (n = 20) in the favorable-risk group, 23.6% (n = 18) in the intermediate-risk group, and 33.3% (n = 4) in the poor-risk group.

For assessment by level of PD-L1 expression, 102 out of 123 patients in part A were evaluable. ORR was 75.0% (n = 6) for those with greater than 20% PD-L1 expression, 33.3% (n = 1) for those with between 5% and 20%, 53.8% (n = 7) in those with between 1% and 5%, and 26.9% (n = 21) for those with 0% PD-L1 expression, showing better responses for those with higher PD-L1 expression.

In part B, the ORR was 11.4%, with 4 out of 35 patients responding (95% CI, 3.2-26.7). Two of these patients had favorable risk and 2 had intermediate risk, and 2 each had 0% PD-L1 expression and 1% to 5% PD-L1 expression.

The median DOR in part A was 27.6 months (range, 19.3–not applicable [NA]). For the intermediate-risk group only, it was 11.3 (8.3-NA), while it was not reached in the favorable-risk group (21.5-NA) and not reached in the poor-risk group (2.2-NA). The median OS was not reached, with 77.7% of patients still alive at 24 months.

In terms of toxicity, treatment-emergent AEs of grade 3 or higher were observed in 43 out of 123 patients (35.0%) who received nivolumab in part A. However, 18 of these consisted of elevated lipase or amylase, which were asymptomatic. There was 1 death due to respiratory failure. In part B, 42.9% (n = 15) of patients who received salvage nivolumab/ipilimumab had grade 3 or higher treatment-emergent AEs, with 5 (14.3%) having asymptomatic elevated amylase or lipase. One patient died of treatment-related myositis. Grade 3 or higher toxicities were observed in 12 out of 30 patients (40.0%) in part B who had no grade 3 or higher AEs when receiving nivolumab alone in part A.

Investigators highlighted the correlation between higher PD-L1 expression and superior response and survival outcomes, though salvage therapy did not appear to be effective in most patients. The results show that for patients with favorable risk and high PD-L1 expression, nivolumab alone may be a good option as frontline therapy for ccRCC.


1. Atkins MB, Jegede OA, Haas NB, et al. 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). J Clin Oncol. 2022;40(25):2913-2923. doi:10.1200/JCO.21.02938

2. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. April 16, 2018. Accessed September 8, 2022.

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