Deep Responses Demonstrate Association With Prolonged Survival to Nivolumab/Cabozantinib in mRCC

Andrea B. Apolo, MD

Patients with treatment-naïve advanced renal cell carcinoma (RCC) who received nivolumab (Opdivo) plus cabozantinib (Cabometyx) achieved deeper objective responses leading to improved progression-free survival (PFS) and overall survival (OS) rates vs those who received sunitinib (Sutent), according to findings from an exploratory analysis of the phase 3 CheckMate 9ER trial (NCT03141177), which were presented at the 2022 International Kidney Cancer Symposium.

At a 6-month post-randomization landmark, 293 patients were alive and 236 were also progression free in the nivolumab plus cabozantinib (NIVO+CABO) arm, and 253 patients were alive and 157 were also progression free in the sunitinib (SUN) arm. Of these, 14%, 11%, and 13% of patients in the NIVO+CABO arm achieved complete response (CR), partial response (PR) 1 or PR2, respectively, vs 7%, 4%, and 7% in the SUN arm.

In total, 38% of patients in the NIVO+CABO arm had a best reduction in target tumors of at least 60% vs 17% of patients in the SUN arm. Additionally, 5% of patients in the NIVO+CABO arm had progressive disease (PD) vs 15% of those in the SUN arm, and 34% and 24% of the NIVO+CABO arm had stable disease (SD) and PR3, respectively, vs 49% and 19% of the SUN arm.

“This exploratory post hoc analysis sought to evaluate the relationship between depth of response and clinical outcomes in patients participating in CheckMate 9ER randomized to either nivolumab plus cabozantinib or sunitinib using data from the most recent database lock (32.9-month median follow-up),” lead study author Andrea B. Apolo, MD, of the Center for Cancer Research, National Cancer Institute, National Institutes of Health in Bethesda, Maryland, and colleagues, wrote.

In the CheckMate 9ER trial, after a median follow-up of 18.1 months, nivolumab plus cabozantinib demonstrated efficacy benefits over sunitinib in patients with untreated advanced RCC. After an extended median follow-up of 32.9 months, the patients who received nivolumab plus cabozantinib experienced sustained improvements in OS, PFS, and overall response rate (ORR).

To be eligible for enrollment to CheckMate 9ER, patients needed to have previously untreated advanced or metastatic RCC with a clear cell component. Patients in any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk group were allowed.

A total of 651 patients were randomized 1:1 to either the NIVO+CABO arm (n = 323) or the SUN arm (n = 328). The NIVO+CABO arm received intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg daily. The SUN arm received oral sunitinib at 50 mg daily in a cycle of 4 weeks on and 2 weeks off.

The primary end point of this study was PFS by blinded independent central review per RECIST v1.1 criteria. Key secondary end points were OS, ORR, and safety.

The exploratory analysis included patients with best overall response data at baseline and post baseline. Patients were categorized into depth of response subgroups based on their best overall response and best tumor reduction threshold. These subgroups and their respective populations in the NIVO+CABO and SUN arms included CR (n = 40; n = 17); PR1, defined as PR with the best percentage of reduction in the sum of diameters for target lesions by at least 80% (n = 33; n = 9); PR2, defined as PR with the best percentage of reduction in the sum of diameters for target lesions by between 60% and under 80% (n = 38; n = 18); PR3, defined as PR with the best percentage of reduction in the sum of diameters for target lesions by under 60% (n = 69; n = 49); SD (n = 99; n = 123); and PD (n = 14; n = 37).

The end points analyzed for each depth of response subgroup were PFS and OS in patients who were progression free and/or alive at the 6-month post-randomization landmark; time to and duration of objective response; and treatment-related adverse effects (TRAEs) occurring within 30 days after the 6-month OS landmark analysis.

In patients who were alive at the 6-month landmark, the distribution of IMDC prognostic risk groups was generally similar within subgroups. CR and PR1 differed the most between the subgroups. Of the patients who achieved CR, 27.5%, 67.5%, and 5.0% of the NIVO+CABO arm and 47.1%, 47.1%, and 5.9% of the SUN arm were favorable, intermediate, and poor risk, respectively. Of the patients who achieved PR1, 24.2%, 63.6%, and 12.1% of the NIVO+CABO arm were favorable, intermediate, and poor risk, respectively, and 77.8% and 22.2% of the SUN arm were intermediate and poor risk, respectively.

Deeper responses led to PFS improvements in both arms. In the NIVO+CABO arm, the median PFS was not reached (NR; 95% CI, 26.0-not estimable [NE]), 24.3 months (17.0-NE), 24.8 months (95% CI, 13.4-NE), 10.4 months (95% CI, 5.5-14.0), and 6.3 months (95% CI, 4.0-10.6) in the CR, PR1, PR2, PR3, and SD subgroups, respectively. In the SUN arm, the median PFS was NR (95% CI, 15.9-NE), 6.5 months (95% CI, 0.9-NE), 12.0 months (95% CI, 7.9-NE), 15.9 months (95% CI, 6.8-21.6), and 5.2 months (95% CI, 3.7-6.7) in the CR, PR1, PR2, PR3, and SD subgroups, respectively.

Deeper responses also led to 12-month PFS improvements in both arms. In the NIVO+CABO arm, the 12-month PFS rates were 94.9%, 81.3%, 72.1%, 46.7%, and 33.5% in the CR, PR1, PR2, PR3, and SD subgroups, respectively. In the SUN arm, the 12-month PFS rates were 82.4%, 37.5%, 53.2%, 57.0%, and 22.6% in the CR, PR1, PR2, PR3, and SD subgroups, respectively.

A greater proportion of patients who were alive and progression free at the 6-month landmark had deeper responses with nivolumab plus cabozantinib than with sunitinib, at 46.2% (n = 109) vs 27.4% (n = 43), respectively.

Increasingly deeper responses generally led to OS improvements in both arms. In the NIVO+CABO arm, the median OS was NR (95% CI, NE-NE), NR (95% CI, 28.9-NE), NR (95% CI, 31.7-NE), NR (95% CI, 30.5-NE), 28.7 months (95% CI, 17.8-NE), and 10.1 months (95% CI, 4.8-25.1) in the CR, PR1, PR2, PR3, SD, and PD subgroups, respectively. In the SUN arm, the median OS was NR (95% CI, 30.2-NE), NR (95% CI, 19.7-NE), NR (95% CI, NE-NE), NR (95% CI, 25.1-NE), NR (95% CI, 24.6-NE), and 13.7 months (95% CI, 6.5-18.6) in the CR, PR1, PR2, PR3, SD, and PD subgroups, respectively.

Deeper responses also led to improved 18-month OS outcomes in both arms. In the NIVO+CABO arm, the 18-month OS rates were 97.5%, 97.0%, 83.5%, 78.3%, 59.6%, and 35.7% in the CR, PR1, PR2, PR3, SD, and PD subgroups, respectively. In the SUN arm, the 18-month OS rates were 100.0%, 100.0%, 88.2%, 75.3%, 68.0%, and 39.1% in the CR, PR1, PR2, PR3, SD, and PD subgroups, respectively.

A greater proportion of patients who were alive at the 6-month landmark had deeper responses with nivolumab plus cabozantinib vs sunitinib, at 37.9% (n = 111) vs 17.4% (n = 44), respectively.

In the NIVO+CABO arm, the median duration of response (DOR) numerically improved with each incremental increase in depth of response. This improvement did not occur in the SUN arm.

Specifically, in those who received nivolumab plus cabozantinib, the median time to response was 2.8 months (range, 1.0-22.3), 2.8 months (range, 1.5-6.8), 2.8 months (range, 2.3-7.1), and 2.9 months (range, 1.9-11.0) in the CR, PR1, PR2, and PR3 subgroups, respectively. The median DOR was NR (95% CI, 28.2-NE), 26.2 months (95% CI, 20.2-NE), 24.9 months (95% CI, 16.6-NE), and 10.8 months (95% CI, 7.0-17.2) in the CR, PR1, PR2, and PR3 subgroups, respectively.

In those who received sunitinib, the median time to response was 3.4 months (range, 1.9-30.4), 3.5 months (range, 1.7-7.1), 4.2 months (range, 2.8-11.2), and 5.7 months (range, 1.7-20.2) in the CR, PR1, PR2, and PR3 subgroups, respectively. The median DOR was NR (95% CI, 16.1-NE), 7.0 months (95% CI, 2.8-23.5), 15.2 months (95% CI, 9.9-NE), and 10.9 months (95% CI, 6.9-19.4) in the CR, PR1, PR2, and PR3 subgroups, respectively.

The incidence of any-grade and grade 3 or 4 TRAEs was generally consistent across the subgroups. In the NIVO+CABO arm, 65%, 70%, 74%, 62%, 68%, and 62% experienced grade 3 or 4 TRAEs in the CR, PR1, PR2, PR3, SD, and PD arms, respectively. In the SUN arm, 59%, 56%, 67%, 65%, 56%, and 35% experienced grade 3 or 4 TRAEs in the CR, PR1, PR2, PR3, SD, and PD arms, respectively.

“As observed in prior studies of other immunotherapy-based treatments, these results suggest that, in general, depth of response may be a useful early indicator of durable efficacy and improved prognosis among patients with untreated advanced RCC receiving nivolumab plus cabozantinib,” the study authors concluded.

Reference

Apolo AB, Choueiri TK, Burotto M, et al. Association between depth of response and clinical outcomes: exploratory analysis in patients with previously untreated advanced renal cell carcinoma in CheckMate 9ER. Presented at: 2022 International Kidney Cancer Symposium; November 4-5, 2022; Austin, TX. Abstract 38.