SOC Role of Frontline Nivolumab Plus Cabozantinib in Metastatic RCC Confirmed With Long-Term Efficacy Results

María Teresa Bourlon, MD, MSc, MS

Nivolumab (Opdivo) plus cabozantinib (Cabometyx) maintained a superior and clinically meaningful survival benefit alongside durable responses vs sunitinib (Sutent) in the frontline setting for patients with advanced or metastatic renal cell carcinoma (RCC) who did not receive prior treatment, according to updated findings from the phase 3 CheckMate 9ER trial (NCT03141177) presented at the2024 Genitourinary Cancers Symposium.¹

“With 55.6 months of median follow-up, nivolumab plus cabozantinib continues to provide meaningful long-term benefits over sunitinib in terms of progression-free survival [PFS], overall survival [OS], and overall response rate [ORR],” lead study author María Teresa Bourlon, MD, MSc, MS, of the Urologic Oncology Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, in Mexico City, DF, Mexico, stated in an oral presentation of the data. “These extended follow-up results continue to support nivolumab plus cabozantinib as a standard of care for [patients with] previously untreated advanced RCC.”

In the intention-to-treat population (ITT), patients who received the combination (n = 323) achieved a median PFS of 16.4 months (95% CI, 12.5-19.3) vs 8.4 months (95% CI, 7.0-9.7) with sunitinib (n = 328; HR, 0.58; 95% CI, 0.49-0.70). Patients experienced a median OS of 46.5 months (95% CI, 40.6-53.4) vs 36.0 months (95% CI, 29.2-42.8) with the combination vs sunitinib, respectively (HR, 0.77; 95% CI, 0.63-0.95). The ORR in the combination arm was 55.7%, including a partial response (PR) rate of 42.1% and a complete response (CR) rate of 13.6%. Additionally, stable disease (SD) was achieved by 32.2% of patients, and progressive disease (PD) occurred in 6.5% of patients. In the sunitinib group, the ORR was 27.7%, with a PR rate of 23.2% and CR rate of 4.6%. The SD and PD rates were 41.5% and 13.7%, respectively.

The median time to next treatment (TTR) with nivolumab plus cabozantinib was 2.8 months (range, 1.0-22.2) and the median duration of response (DOR) was 22.0 months (range, 18.0-25.2). In the sunitinib arm, the median TTR was 4.3 months (range, 1.7-30.4) and the median DOR was 15.2 months (95% CI, 10.9-19.3).¹

CheckMate 9ER previously met its primary end point of improved PFS, with the combination producing a median PFS of 16.6 months vs 8.3 months with sunitinib, translating to a 49% reduction in the risk of disease progression or death (HR, 0.51; 95% CI, 0.41-0.64; P < .001). Confirmed ORR per BICR was 55.7% with the combination and 27.1% with sunitinib. These data supported the FDA approval of frontline nivolumab plus cabozantinib for the treatment of patients with advanced RCC in January 2021.² Updated data after a median of 44.0 months of follow-up demonstrated continued PFS and OS benefit with nivolumab plus cabozantinib vs sunitinib in the ITT population as well, and improvements in health-related quality of life (HRQoL) benefit were reported.³

CheckMate 9ER Enrollment Criteria

In the current analysis, investigators built upon earlier data by reporting updated efficacy, safety, and HRQoL data in the ITT population and in subgroups (risk status and organ sites of metastases), according to International Metastatic RCC Database Consortium (IMDC).¹

The randomized, open-label study enrolled patients with previously untreated, advanced or metastatic RCC with a clear cell component. Notably, patients were eligible for enrollment regardless of IMDC prognostic risk.

A total of 651 patients were included in the study and randomly assigned in a 1:1 ratio to receive either 240 mg of intravenous nivolumab every 2 weeks plus 40 mg of oral cabozantinib every day or 50 mg of oral sunitinib daily on a 4-week-on, 2-week-off schedule. Treatment continued until disease progression per RECIST 1.1 criteria or unacceptable toxicity. Patients were stratified according to IMDC risk score, geographic region, and PD-L1 expression.

The study’s primary end point was PFS by blinded independent central review per RECIST 1.1 criteria. Secondary end points included OS, ORR, and safety; HRQoL was a key exploratory end point.

Examining IMDC Subgroup Data: PFS/ORR Benefit Seen With Combination vs Sunitinib

Additional assessment of efficacy according to key subgroups revealed that both PFS and ORR favored the combination vs sunitinib regardless of IMDC risk status. In the favorable-risk population, the median PFS with nivolumab plus cabozantinib (n = 74) was 21.4 months (95% CI, 12.8-24.6) vs 12.8 months (95% CI, 9.4-16.6) with sunitinib (n = 72; HR, 0.69; 95% CI, 0.48-1.00). ORR rates were 66.2% in the combination arm and 44.4% in the sunitinib arm.

“For the IMDC favorable-risk population, PFS and ORR also favored the combination therapy vs sunitinib, but there was no difference between arms for the OS end point in this study,” Bourlon explained during the presentation.

The median OS with the combination was 52.9 months (95% 40.8- not evaluable [NE]) compared with 58.9 (95% CI, 46.1-NE) with sunitinib (HR, 1.10, 95% CI, 0.69-1.75). Further, the median TTR was 2.8 months (range, 1.5-19.8) with the combination and 4.3 months (range, 1.7-30.4) with sunitinib. The combination produced a median DOR of 18.7 months (95% CI, 13.9-22.2) vs 17.8 months (95% CI, 11.1-19.4) with sunitinib.

In the intermediate- to poor-risk subgroups, the median PFS was 15.4 months (95% CI 11.1-18.6) vs 7.1 months (95% CI, 5.7-8.9) with the combination (n = 249) vs sunitinib (n = 256; HR, 0.56; 95% CI, 0.45-0.68); the median OS in these corresponding groups was 43.9 months (95% CI, 34.9-51.9) vs 29.3 months (95% CI, 23.7-36.2) for a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.58-0.91). The ORR was 52.6% with the combination and 23.0% with sunitinib. The combination produced a median TTR of 2.8 months (range, 1.0-22.2) and a median DOR of 23.1 months (95% CI, 17.3-30.5); in the sunitinib arm, these were 4.4 months (range, 1.7-18.1) and 13.8 months (95% CI, 7.1-23.5), respectively.

Further Efficacy Data In Subgroups

Nivolumab plus cabozantinib also produced superior efficacy vs sunitinib in specific subgroups of patients with baseline organ sites of metastases in the liver, bone, or lung. In patients with liver metastases receiving the combination (n = 73) vs sunitinib (n = 55), the median PFS was 10.9 months (95% CI, 7.0-15.2) vs 6.2 months (95% CI, 2.9-8.3), respectively, (HR, 0.54; 95% CI, 0.36-0.81), the median OS was 37.6 months (95% CI, 23.5-49.9) vs 37.6 months (95% CI, 9.8-29.3), respectively (HR, 0.62; 95% CI, 0.41-0.95), and the ORR was 52.1% (95% CI, 40.0%-63.9%) vs 21.8% (95% CI, 11.8%-35.0%), respectively.

Patients with bone metastases given the combination (n = 79) vs sunitinib (n = 73) achieved a median PFS of 13.8 months (95% CI, 8.3-20.1) vs 4.4 months (95% CI, 3.8-8.2), respectively (HR, 0.45 (95% CI, 0.30-0.66). Additionally, the median OS was 34.8 months (95% CI, 21.4-NE) with nivolumab plus cabozantinib vs 20.7 months (95% CI, 12.5-25.7) with sunitinib (HR, 0.57; 95% CI, 0.38-0.84). The ORR was 49.4% (95% CI, 37.9%-60.95) compared with 9.6% (95% CI, 3.9%-18.8%), respectively.

Lastly, in patients with lung metastases the combination (n = 241) elicited a median PFS of 16.4 months (95% CI, 12.3-21.4) vs 8.3 months (95% CI, 6.9-9.7) with sunitinib (n = 251; HR, 0.56; 95% CI, 0.46-0.69). The median OS was 47.5 months (95% CI, 40.6-56.1) vs 32.6 months (95% CI, 24.9-39.7), respectively (HR, 0.73; 95% CI, 0.58-0.92). The ORR was 57.3% (95% CI, 50.8%-63.6%) with the combination compared with 28.3% (95% CI, 22.8%-34.3%) with sunitinib.

HRQoL and Safety Findings Remain Consistent With Prior Data

Evaluation of HRQoL was also consistent with previous follow-up data. “In the ITT population, the mixed model analysis of repeated measures favored nivolumab plus cabozantinib vs sunitinib, as most measures were stable or improved,” Bourlon emphasized, adding that, “changes from baseline in HRQoL favored nivolumab and cabozantinib vs sunitinib in patients with intermediate -and poor-risk disease, according to IMDC [risk status].”

Notably, no differences in HRQoL measures were observed between arms in patients who had IMDC favorable risk disease.

A total of 11% and 6% of patients in the combination vs sunitinib arms, respectively, remained on treatment at the time of data cutoff. Among those who proceeded to subsequent treatment (49% in the combination arm; 55% in the sunitinib arm), options included radiotherapy (18%; 14%), surgery (8%; 6%), or systemic therapy (38%; 50%).

“A higher percentage of patients in the [combination] arm received subsequent radiotherapy or surgery, and a lower proportion of patients [given the] combination therapy received subsequent systemic therapy,” Bourlon summarized.

Regarding safety, no new toxicity concerns were observed, and the regimen’s safety profile was consistent with prior results reported. Any grade treatment-related adverse effects (AEs) led to treatment discontinuation in 28% of patients in the combination arm and 11% of patients in the sunitinib arm. Any grade AEs occurred in 98% of patients in the combination arm, 68% of which were grade 3 or 4; these rates were 93% and 55%, respectively, in the sunitinib arm.

Common any grade AEs in combination arm vs sunitinib included diarrhea (59% vs 46%), palmar-plantar erythrodysesthesia (39% vs 42%), hypertension (34% vs 35%), fatigue (28% vs 32%), hypothyroidism (37% vs 31%), nausea (25% vs 28%), mucosal inflammation (21% vs 26%), stomatitis (18% vs 24%), dysgeusia (22% vs 21%), anemia (11% vs 21%), thrombocytopenia (7% vs 20%), decreased appetite (22% vs 18%), increased alanine aminotransferase (27% vs 12%), increased aspartate aminotransferase (28% vs 8%), and rash (21% vs 7%).

Editor’s Note: Dr Bourlon reports the following disclosures: a leadership role with Bristol Myers Squibb; receiving honoraria from Bristol Myers Squibb and Tecnofarma; serving in a consulting or advisory role for Asofarma; Astellas Pharma; Bayer; Bristol Myers Squibb; Eisai; Ferring; Gilead Sciences; Janssen Oncology; Merck; MSD Oncology; Novartis; and Pfizer; serving on a Speakers’ Bureau for Asofarma; Astellas Pharma; AstraZeneca; Bayer; Bristol Myers Squibb; Eisai; Ferring; Ipsen; Janssen Oncology; Medicamenta; Merck; MSD Oncology; Pfizer; and Tecnofarma; receiving research funding from Janssen Oncology (Inst) and Pfizer; providing expert testimony for Asofarma; receiving funding for travel or accommodations from Asofarma; Bristol Myers Squibb (Mexico); Janssen-Cilag; MSD Oncology; and Pfizer.

References

1. Bourlon MT, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Results from 55-month follow-up of the CheckMate 9ER trial. J Clin Oncol. 2024;42(4):362. doi:10.1200/JCO.2024.42.4_suppl.362
2. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed February 1, 2024. bit.ly/3UwczWU
3. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603