CheckMate-9ER Data Continues to Show Benefit With Nivolumab + Cabozantinib in RCC

The combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) demonstrated survival and response rate benefits as a first-line treatment for patients with advanced renal cell carcinoma (RCC) compared with sunitinib (Suntent), according to 3-year follow-up results from the phase 3 CheckMate-9ER trial (NCT03141177).

In addition, improvements in median progression-free survival (PFS) and overall survival (OS) were sustained with the combination of nivolumab and cabozantinib in patients with RCC regardless of PD-L1 status in an exploratory biomarker analysis.

For these updated, 3-year results from the CheckMate-9ER study, patients had a median follow-up of 44 months, which represents the longest reported follow-up in any phase 3 trial evaluating an immunotherapy-tyrosine kinase inhibitor regimen within this patient population.

“In this analysis, PFS benefit with nivolumab and cabozantinib vs sunitinib was largely independent of PD-L1 and c-MET status. Also, select gene signatures evaluated in this analysis, some of which were previously found to be predictive of anti-PD-L1 and anti-VEGF outcomes, were not necessarily predictive of efficacy with anti-PD-1 and anti-VEGF therapies. For the near future, we will continue exploratory biomarker discovery from CheckMate-9ER. Our goal is to find a predictive biomarker or even composite model of nivolumab plus cabozantinib efficacy,” Toni K. Choueiri, MD, medical director, International Strategic Initiatives, director, Lank Center for Genitourinary Oncology, director, Kidney Cancer Center, senior physician, at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg chair and professor of Medicine, Harvard Medical School, told Targeted Oncology^TM.

The phase 3 CheckMate-9ER study is an open-label, randomized, multi-national trial where 651 patients with previously untreated advanced or metastatic RCC are being evaluated. Among those enrolled, 23% are favorable-risk, 58% are intermediate-risk, and 20% are poor-risk. A total of 323 patients were randomized to receive nivolumab plus cabozantinib vs 328 to sunitinib.

Investigators are evaluating the primary end point of PFS and the secondary end points of OS and objective response rate (ORR).

Findings being presented at ASCO GU have shown there to be a median follow-up of 44.0 months with 36.5 months minimum. The combination of nivolumab and cabozantinib led to superior OS, PFS, ORR, duration of response (DoR), and complete response (CR) rates compared with sunitinib, and there were no new safety signals seen with extended follow-up.

Benefits in ORR were maintained. Nearly double the number of patients responded to treatment with the combination (55.7%) compared with sunitinib (28.4%). More durable responses were also observed with the combination regimen, with a median DoR of 23.1 months vs 15.2 months with sunitinib.

The combination continued to show a 30% reduction in the risk of death (HR 0.70; 95% CI, 0.56-0.87), and an improvement in median OS at 49.5 months vs 35.5 months with sunitinib, respectively). Since the previous data cutoff, the median OS also improved by 11.8 months at 32.9 months median follow-up. PFS benefits were sustained with the combination and the median PFS continued to double at 16.6 months vs 8.4 months with sunitinib (HR 0.58; 95% CI, 0.48-0.71).

Regarding the CR rates, 12.4% of patients given the combination had a CR vs 5.2% of those treated with sunitinib. Additionally, 97% of patients treated with nivolumab and cabozantinib had a treatment-related adverse event (TRAE) of any grade while 93% of patients treated with sunitinib had a TRAE. Grade 3 TRAEs were seen in 67% vs 55% of patients in the combination vs sunitinib arm, respectively.

“Despite the progress made through science and medicine, there remains a need for treatment options that can durably extend survival for patients with metastatic renal cell carcinoma, especially for those classified as higher risk,” said Mauricio Burotto, MD, medical director, Bradford Hill Clinical Research Center, Santiago, Chile, in the press release “With these updated results from CheckMate-9ER, we’ve now seen nivolumab in combination with cabozantinib durably extend survival and sustain response benefits compared to sunitinib for over 3 years, regardless of patients’ risk classification. These results reinforce the importance of this immunotherapy-tyrosine kinase inhibitor regimen for patients and its potential to help change survival expectations for patients with this challenging cancer.”

Then in the exploratory post-hoc analysis of the CheckMate-9ER study at a median follow-up of 44.0 months, PFS and OS improvements were observed in patients administered the combination, regardless of the patients PD-L1 status.

In this post-hoc analysis, PFS and OS were evaluated by tumor PD-L1 expression as either <1% or ≥1%, CD8% (low, medium, high by tertiles), and CD8 topology phenotype. PFS and OS were also assessed for association using Kaplan-Meier methods with log-rank test and Cox proportional hazard models.

The biomarkers that were found to be predictive of anti-PD-L1 and anti-VEGF outcomes in previous studies were not necessarily predictive of efficacy with anti-PD-1 and anti-VEGF targeted therapies. This showed that key determinants of response to anti-PD-1 vs anti-PD-L1 therapies may differ.

The fully updated findings from the 3-year follow-up and post-hoc analysis will be presented at the American Society of Clinical Oncology (ASCO) 2023 Genitourinary Cancers Symposium from February 16-18, 2023.

“We have a strong heritage of bringing immunotherapy-based combinations to patients with advanced renal cell carcinoma and transforming patient outcomes with Opdivo-based combinations across several cancer types,” added Dana Walker, MD, MSCE, vice president, development program lead, genitourinary cancers of Bristol Myers Squibb, in the press release. “The updated data from CheckMate-9ER further reinforce the use of [nivolumab] in combination with [cabozantinib] for the first-line treatment of patients with advanced renal cell carcinoma. We remain committed to collaboration across the scientific community and our ongoing exploration of combination approaches with our proven cancer agents in the pursuit of solutions that may help improve long-term outcomes for as many patients as possible.”

“With 44 months median follow-up, the compelling survival benefit further reinforces the value of the [cabozantinib] and [nivolumab] combination regimen as a first-line option for patients with advanced kidney cancer,” concluded Vicki L. Goodman, MD, executive vice president, product development & medical affairs, and chief medical officer of Exelixis, in the press release. “We are pleased to share these long-term findings at ASCO GU and remain steadfast in our longstanding commitment to improving outcomes for patients living with advanced kidney cancer.”

REFERENCE:

Opdivo® (nivolumab) in combination with CABOMETYX® (cabozantinib) shows durable survival with over three years of follow-up in the CheckMate -9ER trial in first-line advanced renal cell carcinoma. News release. Bristol Myers Squibb. February 13, 2023. Accessed February 14, 2023. https://bit.ly/3xjrGpE