The combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) continues to show significant benefits for patients with metastatic clear cell renal cell carcinoma (RCC), except for those in the favorable-risk group, according to updated findings from the phase 3 CheckMate 9ER trial (NCT03141177). The data, presented at the 2024 Genitourinary Cancers Symposium, reinforce previous results, aligning with similar outcomes observed in trials of other TKI and immunotherapy combinations.
Consistent Efficacy Across Trials
Adam E. Singer, MD, PhD, from UCLA Health, noted the similarities between CheckMate 9ER and other trials such as KEYNOTE-426 (axitinib/pembrolizumab) and CLEAR (lenvatinib/pembrolizumab). All three trials demonstrated the superiority of combination regimens over sunitinib (Sutent) in terms of progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) in the intention-to-treat (ITT) populations.
"It’s interesting that [there were] similar findings across the trials [demonstrating that] the IMDC favorable-risk category [groups did not experience an] improvement in OS compared with sunitinib," Singer commented. Despite this, response rates were consistently higher in the combination arms across all three trials.
CheckMate 9ER Detailed Findings
CheckMate 9ER, a randomized phase 3 trial, compared cabozantinib plus nivolumab to sunitinib monotherapy in patients with metastatic clear cell RCC. The combination significantly improved PFS and OS for the ITT population. However, in the IMDC favorable-risk subgroup, while PFS showed a trend favoring the doublet (HR = 0.72), the OS was not significantly different.
Comparing Combination Regimens
Currently, first-line treatment options include combinations of VEGFR/TKI inhibitors (axitinib, cabozantinib, or lenvatinib) with immunotherapy checkpoint inhibitors (pembrolizumab or nivolumab). These combinations generally prove more tolerable than sunitinib monotherapy. Data from CheckMate 9ER presented at the 2024 ASCO Annual Conference indicated that patients could remain on the cabozantinib/nivolumab combination longer than sunitinib.
Furthermore, a post-discontinuation benefit was observed, with patients discontinuing sunitinib initiating subsequent therapies sooner than those discontinuing cabozantinib/nivolumab, potentially due to the long half-lives of the immunotherapy components.
Managing Toxicities
The adverse effect (AE) profiles are similar across TKI combinations, with axitinib generally causing fewer AEs than lenvatinib or cabozantinib. Common AEs include diarrhea, nausea, anorexia, hypertension, and fatigue, along with hypothyroidism, proteinuria, dysphonia, and hand-foot syndrome. The addition of immunotherapy components introduces immune-mediated AEs, thyroid issues, pruritus, and diarrhea, consistent with the known profiles of nivolumab and pembrolizumab.
Nivolumab/Ipilimumab in Intermediate/Poor-Risk RCC
The combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) has been a preferred regimen for patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)-classified intermediate/poor-risk RCC, based on the phase 3 CheckMate 214 trial (NCT02231749). The trial demonstrated benefits in overall response rate (ORR) and progression-free survival (PFS) vs sunitinib in patients with IMDC intermediate- or poor-risk disease.
Extended follow-up data from CheckMate 214, with a median follow-up of approximately 8 years, have provided insights into long-term outcomes, including duration of response, long-term PFS, and OS. A new investigational end point, treatment-free survival, has emerged as a key measure of benefit, highlighting the potential of nivolumab plus ipilimumab to generate durable responses without ongoing treatment.
