Salvage Nivolumab/Ipilimumab Following Nivolumab Affords Treatment-Free Survival in RCC

Michael B. Atkins, MD

Salvage treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) following progression on frontline nivolumab monotherapy led to sustained activity and significant treatment-free survival (TFS) and toxicity-free TFS in patients with advanced clear cell renal cell carcinoma (ccRCC), according to updated findings from cohort A of the phase 2 HCRN GU16-260 trial (NCT03117309) published in the Journal for Immunotherapy of Cancer.¹

At median follow-up of 37.7 months (range, 32.5-46.1), the results showed that the 36-month mean TFS for the overall population was 9.4 months (95% CI, 7.6-11.3). Favorable-risk patients had a mean TFS of 12.9 months (95% CI, 9.7-16.1), which included 1.5 months with grade 3 or greater treatment-related adverse effects (TRAEs). Intermediate- and poor-risk patients had a mean TFS of 8.0 months (95% CI, 5.8-10.2), which included 1.0 month with grade 3 or greater TRAEs.

Moreover, at 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate and poor-risk patients were alive and free from subsequent systemic therapy.

“Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naive patients with advanced RCC and, similar to nivolumab/ipilimumab in [the phase 3] CheckMate-214 [trial (NCT02231749)], results in substantial TFS and toxicity-free TFS,” Michael B. Atkins, MD, lead study author and deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, and coauthors, wrote in the publication. “TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.”

TFS with immunotherapy can provide understanding of the overall survival (OS) time patients spend between treatment cessation and the start of subsequent therapy, with and without toxicity as previously demonstrated in the phase 3 CheckMate-067 (NCT01844505) and CheckMate-214 trials in patients with advanced melanoma and RCC, respectively. In both trials patients who were randomly assigned to the nivolumab/ipilimumab arms experienced significant TFS benefits.

As such, investigators sought to quantify TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and limit exposure to immunotherapy.

In cohort A, patients with untreated, metastatic ccRCC received nivolumab monotherapy at 240 mg every 2 weeks for 6 cycles. At initial disease assessment, patients with a partial or complete response proceeded to part A, where they received nivolumab at 360 mg every 3 weeks for 4 cycles, followed by nivolumab at 480 mg every 4 weeks until progressive disease (PD), toxicity, or completion of 72 weeks of study treatment. Patients with SD or a best response of stable disease at 48 weeks proceeded to part B, where they received nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 cycles followed by nivolumab at 360 mg once every 3 weeks for 4 doses followed by nivolumab at 480 mg once every 4 weeks until PD, toxicity, or completion of 48 weeks of study treatment.²

Previously reported data from cohort A of the trial demonstrated that the objective response rate (ORR) was 34.1% (95% CI, 25.8%-43.2%), 57.1% in favorable-risk patients and 25.0% in intermediate- and poor-risk patients. The median duration of response was 27.6 months (range, 19.3-not reached). Of the 97 patients with disease progression or prolonged stable disease eligible for part B, 35 were enrolled. The ORR for part B was 11.4%.²

For the present analysis, investigators evaluated data from 128 patients with advanced ccRCC who received up to 2 years of nivolumab monotherapy in the first line. Eligible patients (n = 37; 29%) with disease progression at any point or stable disease at 48 weeks received salvage therapy with the combination of nivolumab and ipilimumab for up to 1 year.¹

TFS was defined as the area between Kaplan-Meier curves for the time from registration to treatment cessation and the time from registration to the start of subsequent systemic therapy or death, estimated from 36-month mean times. The time on or off study therapy with grade 3 or greater TRAEs was also documented.

At the time of analysis, 68.3% of patients were alive, including 96.8% of those with favorable-risk disease according to the International Metastatic RCC Database Consortium and 56.6% of those with intermediate- or poor-risk disease. The 36-month mean time on study therapy was 11.5 months, which included 0.6 months (95% CI, 0.2-0.9), or 2% of the total period, with grade 3 or greater TRAEs, 16.0 months for favorable-risk patients and 9.6 months for intermediate and poor-risk patients.

Notably, the TFS time with grade 3 or greater toxicity spanned only 1.2 months (95% CI, 0.5-1.9), or 3% of the total period.

“Providing such information together with TFS results adds value to traditionally reported trial results, such as median PFS, median OS, ORRs, and toxicity percentages. This information could prove valuable in helping patients balance risks and benefits when making treatment decisions,” the authors wrote.

Additional results indicated that the overall population had a 36-month mean OS of 29.9 months (95% CI, 27.9-31.8 months), which consisted of the study treatment (11.5 months; 95% CI, 10.2-12.9), TFS (9.4 months; 95% CI, 7.6-11.3), and survival after the start of subsequent therapy (8.9 months; 95% CI, 6.8-11.0). In the favorable-risk patients, the mean TFS comprised 36% of the 36-month period, and the mean OS was 35.7 months (95% CI, 35.3-36.2), or 99% of the 36-month period. In the intermediate- and poor-risk patients, the mean TFS comprised 22% of the 36-month period, and the mean OS was 27.4 months (95% CI, 24.9-29.9 months), or 76% of the 36-month period.

Updated efficacy results demonstrated that the ORR was 35.9% (95% CI, 27.7%-44.9%). The 3-year OS rate was 68.3%, and 38.5% of patients were alive and free of subsequent therapy. In the favorable-risk population, the 3-year OS rate was 96.8%, and 65.6% of patients were alive and free of subsequent treatment. Among the intermediate- and poor-risk population, the 3-year OS rate was 56.6%, and 27.1% of patients were alive and free of subsequent treatment.

“Future studies may look at both partitioned survival and quality of life, not just during the treatment period, but for a defined period of at least 3 years and conceivably until death, and could employ not just objective criteria for treatment cessation but also for initiating subsequent systemic therapy, thereby providing an even more complete and robust measure of how various regimens perform and are experienced by patients. Such data may not only add further depth of knowledge about how treatments perform, but also identify properties that distinguish one treatment regimen from another that might be useful in assessing the overall value of a treatment approach for a particular population,” the authors concluded.

References

1. Atkins MB, Jegede OA, Haas NB, et al. Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A). J Immunother Cancer. 2024;12(4):e008293. doi:10.1136/jitc-2023-008293
2. 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