Adding cabozantinib to nivolumab-ipilimumab delays disease progression in previously untreated advanced RCC patients with intermediate/poor IMDC risk

Results of the phase III COSMIC-313 study show that adding cabozantinib to an immune checkpoint inhibitor combination of nivolumab and ipilimumab significantly delays the time to progression of previously untreated advanced renal cell carcinoma patients with an intermediate or poor risk IMDC score. The triplet was generally tolerable, although it did come with a higher incidence of adverse events than nivolumab-ipilimumab alone. Of note, the benefit of adding cabozantinib seemed to be largely restricted to patients with an intermediate IMDC score, an observation that requires further validation.

Introduction

In recent years, dual immune checkpoint inhibition (ICI) with nivolumab and ipilimumab (Nivo-Ipi) has become an established standard of care in the first line treatment of patients with renal cell carcinoma (RCC) of IMDC intermediate or poor risk. However, despite the fact that this treatment combination prolongs the survival of patients compared to sunitinib, about 20% of patients will have disease progression as a best response. In an attempt to reduce this proportion of unresponsive patients, investigators have looked into combining Nivo-IPI with cabozantinib (Cabo), a tyrosine kinase inhibitor that is currently being used as single agent, or in combination with Nivo in the treatment of advanced RCC. Previously, phase I data with this triplet combination proved to be active and feasible in patients with untreated advanced RCC forming the basis for a larger, phase III evaluation of this treatment regimen. In the phase III COSMIC-313 study, the combination of Cabo-Nivo-Ipi was therefore compared to Placebo-Nivo-Ipi in the first line treatment of IMDC intermediate or poor risk advanced RCC patients.

Study design

COSMIC-313 is a global, double-blind, randomized phase III study that enrolled previously untreated patients with clear cell advanced RCC of IMDC intermediate or poor risk. In the study, patients were randomized to receive Cabo (40 mg qd) or matched placebo, stratified by region and IMDC risk. In addition, patients in both arms received Nivo (3 mg/kg IV q3w) + Ipi (1 mg/kg IV q3w) for 4 cycles followed by Nivo (480 mg IV q4w) for up to 2 years. The primary endpoint of the study was progression-free survival (PFS) by blinded independent radiology review per RECIST 1.1 in the first 550 randomized patients (PITT population), with secondary objectives including overall survival (OS) in all randomized patients (ITT population); objective response rate (ORR) and safety.

Results

In total, 855 patients were randomized in the study, 428 to Cabo-Nivo-Ipi and 427 to Placebo-Nivo-Ipi. The median follow-up for the presented analysis was 20.2 and 17.7 months for the PITT and ITT population, respectively. The median age of patients in the study was 61 years and three quarters were male. In both treatment arms, 75% of patients had an IMDC intermediate risk, while the remaining quarter had IMDC poor risk disease. About 60% of patients in the study had a Karnofsky performance status of 100-90 and two thirds underwent a prior nephrectomy.

The final analysis of the PFS in the PITT population demonstrated a significant benefit for patients treated with the Cabo-Nivo-Ipi combination compared to those in the control arm, with a median PFS that was not reached vs. 11.3 months (HR[95%CI]: 0.73[0.57-0.94]; p= 0.013). At 12 months, this translated into a PFS rate of 57% and 49% for Cabo-Nivo-Ipi and Placebo-Nivo-Ipi, respectively. This benefit in PFS was seen irrespective of age, sex, Karnofsky performance statue and whether or not the patient underwent a prior nephrectomy. In contrst, the subgroup analysis did suggest that the benefit of adding cabozantinib seemed to be limited to IMDC intermediate risk patients (median PFS not reached vs. 11.4 months; HR[95%CI]: 0.63[0.47-0.85]), without a benefit in IMDC poor patients (median PFS 9.5 vs. 11.2 months; HR[95%CI]: 1.04[0.65-1.69]). Adding Cabo to Nivo-Ipi also resulted in a numerically higher ORR (43% vs. 36%). As what was seen for PFS, this benefit seemed to be restricted to IMDC intermediate patients (ORR: 45% vs. 35%), with a similar ORR for both regimens in IMDC poor patients (37% vs. 38%). Interestingly, the incidence of progressive disease as best response was markedly lower in the Cabo-Nivo-Ipi arm compared to the control group at 8% and 20%, respectively (disease control rate: 86% vs. 72%).

A higher proportion of patients in the control arm received 4 doses of IPI compared to the Cabo-Nivo-Ipi arm (73% vs. 58%). Dose reductions due to adverse events were reported in 54% of patients treated with the triple combination as compared to only 20% with Placebo-NIVO-Ipi. Treatment discontinuation of all treatment components due to the same treatment-related adverse event (TRAE) occurred in 12% of patients in the experimental arm as compared to 5% in the control arm. The incidence of grade 3/4 TRAEs was 73% with Cabo-Nivo-Ipi vs. 41% with Placebo-Nivo-Ipi. This difference was mainly driven by a higher incidence of elevated liver transaminases, but also (low-grade) diarrhea and skin toxicity occurred more frequently with the triple combination.

Conclusions

The phase III COSMIC-313 study is the first to use an ICI doublet as the control arm and demonstrated that adding the TKI Cabo to this ICI doublet results in a significant improvement in PFS and a numerically higher ORR. While a subgroup analysis of this study was mostly consistent with the overall study results, it does seem that the benefit of adding Cabo to Nivo-Ipi was much more pronounced in patients with IMDC intermediate risk advanced RCC. Not surprisnly, the triple combination was associated with a higher incidence of TRAEs, but overall the toxicity of the triplet was manageable and consistent with what is known from the individual components. Follow-up for the secondary endpoint of OS is ongoing.

Reference

Choueiri T, Powles T, Albiges L, et al. Phase 3 study of cabozantinib in combination with nivolumab and ipilimumab in previously untreated advanced renal cell carcinoma of IMDC intermediate or poor risk (COSMIC-313). Presented at ESMO 2022; Abstract LBA8.