Salvage Nivolumab/Ipilimumab Appears Promising in Clear Cell Renal Cell Carcinoma

Michael B. Atkins, MD

Salvage nivolumab (Opdivo) plus ipilimumab (Yervoy) is a contender for an alternative frontline treatment approach for patients with clear cell renal cell carcinoma (ccRCC) and may be more beneficial than nivolumab monotherapy, according to results from the 2-part phase 2 HCRN GU16-260 study.

“Nivolumab monotherapy represents an alternative frontline approach, particularly for the ipilimumab or VEGFR tyrosine kinase inhibitor averse and possible for those with IMDC favorable risk. These results may also have relevance for the adjuvant setting,” Michael B. Atkins, MD, lead author and deputy director, Georgetown-Lombardi Comprehensive Cancer Center, said in his presentation. “However, the nivolumab/ipilimumab combination is likely preferred over nivolumab monotherapy when possible, particularly for intermediate and poor risk patients and those with sarcomatoid kidney cancer due to what appears to be a higher response rate, longer progression-free survival, longer duration of response, and more complete responses than what was observed in this study as well as the limited ability to salvage patients with later use of the combination.”

The overall response rate among all patients was 31.7% (95% CI, 23.6-40.7), with responses observed in 39 of the 123 patients. Seven patients had a complete response (CR; 5.7%), and 32 patients had a partial response (PR; 26.0%). Stable disease (SD) was observed in 46 patients (37.4%) and progressive disease (PD) in 38 patients (30.9%).

Among 22 patients with a sarcomatoid histology, 7 patients responded (31.8%), which were all PRs (95% CI, 13.9-54.9%). Patients were also stratified by their IMDC risk category, of either favorable-, intermediate-, or poor-risk.

Among patients with favorable-risk disease, the ORR was 50% (95% CI, 31.3-68.7), which included 4 CRs (13.3%) and 11 PRs (36.7%). Fifteen of these patients (50.0%) had SD, and none had PD. The ORR in the intermediate-risk group was 25% (95% CI, 16.6-35.1), with a CR achieved in 3 patients (3.8%) and a PR in 17 patients (21.2%). Twenty-six patients had SD (32.5%), and 34 patients had PD (42.5%). In the poor-risk group, the ORR was 25% (95% CI, 16.6-35.1), with 3 PRs (25%), 5 cases of SD (12%), and 4 cases of PD (33%).

The estimated median duration of response in part A for all patients was 19.3 months (95% CI, 10.9-not achieved [NA]). However, Atkins noted that with the number of patients still in response, this number may change.

The median progression-free survival was 8.3 months for all patients in part A (95% CI, 5.5-10.9), 19.3 months for those with favorable risk (95% CI, 8.1-NA), and 5.5 months for those with intermediate and poor risk (95% CI, 3.9-9.1).

Among all patients in part A, 31% experienced grade 3 or greater treatment-emergent adverse events (TEAEs). The most common TEAE of grade 3 or greater in severity was elevated lipase in 12 patients (10%), although this was almost exclusively asymptomatic. One patient died due to respiratory failure.

Overall, 65 patients were eligible for part B of the study, but 31 of these patients did not enroll. Of the 34 patients who enrolled in part B, 30 were deemed evaluable. Twenty-six of the 34 patients remain alive (76%).

In part B, no patients had a CR, but 4 of the 30 patients had a PR (13.3%), 7 had SD (23.3%0, and 19 had PD (63.3%). The ORR for nivolumab/ipilimumab salvage therapy was 13.3% (95% CI, 3.8-30.7%).

Two patients of the 4 with favorable disease had a PR (50%), 1 had SD (25%), and 1 had PD (25%). In the intermediate group, 2 out of 24 patients had a PR (8.3%), 6 had SD (25%), and 16 had PD (66.7%).

Overall survival has not yet been reached in this study, with 100 of 123 patients remaining alive (81%). Investigators anticipate that 73% of patients will be alive at 24 months.

“Due largely to study design, less than half the patients with PD or SD at 48 weeks were eligible for salvage nivolumab/ipilimumab,” Atkins said. “The salvage nivolumab/ipilimumab response rate was 13%. Toxicities for the combination were as expected.”

Twelve patients (40%) experienced a grade 3 or greater TEAE in part B, with elevated lipase observed in 7 of the 12 patients (23%).

A total of 159 patients enrolled in the study, of which 123 had ccRCC and 36 had non-ccRCC. Among those with ccRCC, 34 patients had moved to part B of the study after a median follow-up of 15.9 months, while 31 remained on treatment in part A, 16 went off treatment yet remained in response, 27 went off treatment with had PD, and 15 had died.

Eligible patients with ccRCC who were treatment-naïve in part A of the study received nivolumab at 240 mg every 2 weeks for 6 doses, then at 360 mg dose every 3 weeks for 4 doses, and at 480 mg every 4 weeks for up to 96 total weeks of treatment. Patients were eligible for part B of the study if they had disease progression at any time or had a best response of SD at 48 weeks of treatment. In part B, patients received the combination of nivolumab plus ipilimumab for 4 doses every 3 weeks followed by nivolumab maintenance for up to 48 weeks. Imaging was performed at baseline and every 12 weeks thereafter.

The median age of patients was 63 years (range, 32-86). Patients had an ECOG performance status of 0 (n = 79; 64%), 1 (n = 43; 35%), or 2 (n = 1; 1%). The majority of patients (n = 89) in this study were male (72%). Thirty patients had favorable-risk (24%), 80 had intermediate-risk (65%), and 12 had poor-risk (10%) disease. Twenty-two patients had sarcomatoid features (18%), and 28 patients had liver metastases (23%).

Nivolumab as a single agent is approved for the treatment of patients with ccRCC who are resistant to VEGFR TKI treatment, and this approval was based on findings from the CM 025 study. The combination of nivolumab and ipilimumab was approved for treatment-naïve patients with IMDC intermediate and poor- risk ccRCC based on the data from the CM 214 study. However, until recently, there has been limited data on the efficacy and toxicity of nivolumab monotherapy in treatment-naïve ccRCC, and the combination as salvage therapy in patients with no response or resistance to nivolumab monotherapy. There has been limited research on biomarkers that are predictive of response to nivolumab as well.

_Reference

_{Atkins MB, Jegede OA, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020.}