Dylann Cohn-Emery

The combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) showed strong efficacy in patients with renal cell carcinoma (RCC) in both patients with prior nephrectomy and those who had not received the procedure, according to an exploratory subgroup analysis of the CheckMate 9-ER trial.

Findings from the analysis shared during the 2021 ESMO Congress showed the immunotherapy/TKI combo significantly improved response and survival outcomes compared with sunitinib (Sutent), regardless of prior nephrectomy status.

“Overall survival [OS] benefits with nivolumab plus cabozantinib versus sunitinib [Sutent] were observed in patients with prior nephrectomy and OS probabilities were higher with nivolumab plus cabozantinib in the subgroup without prior nephrectomy,” Camillo Guglielmo Porta, MD, said in his presentation.

In this first-line phase 3 study, patients with advanced RCC in the intent-to-treat (ITT) achieved superior OS, PFS, and ORR with nivolumab plus cabozantinib compared with sunitinib after a minimum follow-up of 10.6 months, this efficacy was also maintained after 16.0 months of minimum follow-up. Patients on the trial were randomized 1:1 to nivolumab at 240 mg every 2 weeks and cabozantinib at 40 mg once daily versus sunitinib at 50 mg once daily 4 weeks in a 6-week cycle.

Patients with advanced RCC who do not receive nephrectomy up front usually have a poor prognosis and these patients have limited data with targeted therapies and immunotherapy combinations. The CheckMate 9ER exploratory post hoc analysis assessed efficacy outcomes with nivolumab/cabozantinib versus sunitinib in patients with baseline nephrectomy status after a minimum of 16-months follow-up.

Out of 651 patients in the ITT population, 455 had prior nephrectomy—222 in the nivolumab/cabozantinib arm and 233 in the sunitinib arm—and 196 did not have prior nephrectomy—101 receiving nivolumab/cabozantinib and 95 receiving sunitinib. The baseline characteristics of these 2 groups were similar, but more patients had International Metastatic RCC Database Consortium favorable-risk disease in those with prior nephrectomy in both treatment arms.

The hazard ratio for progression favored nivolumab/cabozantinib over sunitinib regardless of nephrectomy status, with a longer median PFS of 19.4 months versus 8.9 months, respectively, with prior nephrectomy (HR, 0.50; 95% CI, 0.39-0.64) and 11.3 months compared with 7.0 months without prior nephrectomy (HR, 0.62; 95% CI, 0.43-0.89).

Additionally, the PFS probabilities were higher with nivolumab/cabozantinib at 62% versus 37% at 12 months and 54% versus 27% at 19 months, respectively, with prior nephrectomy. Without prior nephrectomy, the PFS probabilities were 47% versus 35% and 33% versus 18% at 12 and 18 months, respectively.

In the nivolumab/cabozantinib group, OS probabilities were also consistently higher. Patients with prior nephrectomy had higher 12- and 18-month OS probabilities with nivolumab/cabozantinib. However, the OS probabilities at 12 and 18 months did not show a notable difference between arms were observed.

The median OS was not reached (NR) with nivolumab/cabozantinib and sunitinib in the subgroup with prior nephrectomy (HR, 0.54; 95% CI, 0.37-0.78). Patients without prior nephrectomy had a median OS of 23.8 months (95% CI, 21.4-NR) with nivolumab/cabozantinib and 29.5 months (95% CI, 19.4-29.5) with sunitinib (HR, 0.87; 95% CI, 0.57-1.35).

With nivolumab/cabozantinib, the ORR was higher in both subgroups. With prior nephrectomy, the ORR was 60.8% compared to 30.5% with nivolumab/cabozantinib and sunitinib, respectively. The ORR was 41.6% versus 23.2% without prior nephrectomy. The median time to response was shorter and there was a notably higher with nivolumab/cabozantinib in both subgroups.

“Notable efficacy benefits were also observed with nivolumab plus cabozantinib versus sunitinib in patients when there was prior nephrectomy within 3 months of trial enrollment,” Porta, an adjunct professor at the University of Pavia in Italy, said.

There were 54 out of the 222 patients (24.3%) who underwent nephrectomy within 3 months of enrollment in the nivolumab/cabozantinib group, and 72 of the 233 (30.9%) patients in the sunitinib group also underwent nephrectomy. The ORR was higher with nivolumab/cabozantinib at 50.0%, with 5.6% of patients achieving complete response and 44.4% achieving partial response, in this subgroup. The sunitinib arm had an ORR of 22.2% in this subgroup, with a 2.8% complete response rate and 19.4% partial response rate.

In patients without prior nephrectomy, 61.4% given nivolumab/cabozantinib and 66.3% given sunitinib had target kidney lesions. The ORR was higher nivolumab/cabozantinib than sunitinib at 35.5% and 20.6%, respectively. No patients achieved complete response in this subgroup. A 30% or more reduction in target kidney lesions was achieved in 50.9% of patients in the nivolumab/cabozantinib arm and 29.4% in the sunitinib arm. The median reduction was 30% versus 16%, respectively.

“As a whole, these data together with other ongoing studies exploring the role in sequencing nephrectomy will continue to inform us about optimal metastatic kidney cancer treatment strategies. Overall, however, these results continue to support nivolumab plus cabozantinib as a first-line treatment option for patients with advanced RCC,” Porta concluded.

1. Porta C, Burotto M, Suarez C, et al. First-line nivolumab + cabozantinib vs sunitinib in patients (pts) with advanced renal cell carcinoma (aRCC) in subgroups based on prior nephrectomy in the CheckMate 9ER trial. Presented at: 2021 European Society for Medical Oncology Congress; September 16-21, 2021; virtual. Abstract 663P.

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The findings come from an exploratory subgroup analysis of the pivotal CheckMate 9-ER trial shared during the 2021 ESMO Congress. 

Nivolumab/cabozantinib efficacy in RCC unaffected by prior nephrectomy status

A subanalysis of the phase 3 TIVO-3 trial presented during the 2021 Genitourinary Cancers symposium showed that tivozanib hydrochloride (Fotivda) significantly increased quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) versus sorafenib (Nexavar) when used in the third- or fourth-line setting for patients with metastatic renal cell carcinoma (RCC).

Based on previously reported data from the TIVO-3 study, the FDA accepted a new drug application (NDA) for the use of the VEGF tyrosine kinase inhibitor tivozanib in patients with relapsed/refractory RCC. The agency is scheduled to decide on the NDA on or before March 31, 2021.

“The difference in Q-TWiST in TIVO-3 was primarily driven by benefits of tivozanib in TWiST, partially offset by superiority of sorafenib in time after progression or relapse [REL],” the investigators wrote in their abstract for the 2021 American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium.

To quantify the net health benefits of tivozanib, the investigators applied Q-TWiST methods because of the similar survival of the 2 agents reported previously.

Investigators calculated mean Q-TWiST by applying utility coefficients of 0.5, 1.0, and 0.5 to the 36-month restricted mean health states of time with toxicity, time without symptoms and toxicity, and REL, respectively.

 The relative Q-TWiST gain was defined as the mean absolute Q-TWiST difference divided by the sorafenib mean overall survival (OS).

The mean Q-TWiST was 15.04 months for tivozanib versus 12.78 months for sorafenib (

=.0493). The relative gain for tivozanib was 11.2%. With more follow-up, there were better Q-TWiST means. Q-TWiST at 36 months of follow-up, which was the primary end point of this analysis, the mean was 2.25 (95% CI, 0.01-4.51) in favor of tivozanib. Mean TWiST was significantly longer for tivozanib versus sorafenib (10.30 months vs 5.35 months; TABLE).

For this multicenter, randomized, controlled, open-label trial, 350 patients were split evenly between the 2 drugs and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy.2 These patients had to progress on 2 or 3 prior systemic regimens, at least 1 of which had to be a VEGFR tyrosine kinase inhibitor other than sorafenib or tivozanib.

Patients either received 1.5 mg of tivozanib mg orally once a day on 4-week cycles or sorafenib at 400 mg orally twice a day continuously. The primary end point was progression-free survival (PFS) by independent review in the intention-to-treat population.

In the previous report of TIVO-3, tivozanib increased PFS compared with sorafenib but did not show a difference in OS. The PFS difference at a 19-month median follow-up was significant between tivozanib and sorafenib at 5.6 and 3.9 months, respectively (HR, 0.73; 95% CI, 0.56-0.94; 

The most common grade 3/4 treatment-related adverse events (TRAEs) in the originally published data were hypertension in 20% of patients receiving tivozanib and 14% of patients receiving sorafenib. Serious TRAEs were observed in 11% versus 10% of patients respectively, but no treatment-related deaths were reported.

“As a third- or fourth-line treatment for RCC, tivozanib significantly increased Q-TWiST relative to sorafenib, primarily through an increase in TWiST, which is generally considered to be the state with highest utility to patients. Consequently, Q-TWiST may be considered an alternative patient-centered measure of benefit of tivozanib in these settings,” the investigators wrote in their conclusion.

1. Szarek M, Needle MN, Rini BI, et al. Q-TWiST analysis of tivozanib (T) versus sorafenib (S) in patients with advanced renal cell carcinoma (RCC) in the TIVO-3 study. 

2021;39(suppl 6):298. doi:10.1200/JCO.2021.39.6_suppl.298

2. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. 

. 2020;21(1):95-104. doi: 10.1016/S1470-2045(19)30735-1

The FDA is scheduled to decide on a new drug application for tivozanib by March 31, 2021, for use in relapsed/refractory renal cell carcinoma. 

Dylann Cohn-Emery

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