Long-term results show sustained benefit from the immunotherapy-TKI combination for patients with metastatic renal cell carcinoma regardless of risk profile or PD-L1 status.
Patients receiving first-line treatment for advanced renal cell carcinoma (RCC) or metastatic RCC who received the PD-1 inhibitor nivolumab (Opdivo) and the tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx; Exelixis) had a 30% reduction in the risk of death after 44 months compared with those treated with sunitinib, according to new data.1
Long-term results from the CheckMate 9ER trial (NCT03141177) were presented in an oral abstract session at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), held February 16-18, 2023. They showed sustained benefit for patients with mRCC from the immunotherapy-TKI combination regardless of risk profile or PD-L1 status; this second finding was contained in a separate biomarker analysis.2
Both abstracts were highlighted in a news release from Bristol Myers Squibb, maker of nivolumab.3 “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,” Mauricio Burotto, MD, medical director, Bradford Hill Clinical Research Center, Santiago, Chile, and lead author on the updated results from CheckMate 9ER, said in the release.
CheckMate 9ER involved 323 patients randomized to the combination and 328 patients treated with sunitinib. Progression-free survival (PFS) was the primary end point; among the secondary end points were overall survival (OS) and objective response rate (ORR). Superiority of the nivolumab and cabozantinib combination over sunitinib in first-line treatment of mRCC had been previously demonstrated.4 The new analysis shared at ASCO GU evaluated patients after a minimum of 36.5 months and a median of 44 months.1
In the latest results, PFS and OS were maintained in the nivolumab-cabozantinib combination compared with sunitinib in intent-to-treat patients. Median PFS was 16.6 months vs 8.4 months for sunitinib (HR, 0.58; 95% CI, 0.48-0.71; P = .0001). Median OS was 49.5 months vs 35.5 months (HR, 0.70; 95% CI, 0.56-0.87; P = .0014).
ORR was higher with the nivolumab combination than with sunitinib, 55.7% vs 28.4%; across the 2 arms, 12% vs 5% achieved a complete response, respectively. Median duration of response was 23.1 months vs 15.2 months, favoring nivolumab plus cabozantinib. Responses were comparable among patients regardless of risk status, as determined by International mRCC Database Consortium (IMDC) Risk Score.
Treatment-related adverse events (TRAEs) of any grade were seen in 97% of patients taking the nivolumab combination, compared with 93% taking sunitinib; grade 3 TRAEs or higher were seen in 67% vs 55% of patients, respectively. TRAEs led to stopping only cabozantinib in 10% of patients, stopping only nivolumab in 10% of patients, and stopping the combination in 7% of patients; 28% of patients stopped at least 1 of the therapies in the combination; and 11% of patients stopped taking sunitinib.
“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,” Burotto said in the release.3 “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.”
Biomarker analysis. A separate abstract presented by Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, Massachusetts, offered an exploratory post hoc analysis from CheckMate 9ER after 44 months. In their abstract, the authors stated that earlier work had investigated how underlying biomarkers determined response to anti–PD-L1 and anti-VEGF therapy in advanced RCC, but not in first-line treatment.
In this analysis, PFS and OS were evaluated based on tumor PD-L1 expression (< 1% or ≥ 1%), CD8% (low, medium, or high, by tertiles), and CD8 topology phenotype (cold, excluded, or inflamed). The authors reported, “Biomarkers previously found to be predictive of anti–PD-L1 and anti-VEGF outcomes, including established gene expression signatures, were not necessarily predictive of efficacy with anti–PD-1 and anti-VEGF targeted therapy, suggesting that key determinants of response to anti–PD-1 vs anti–PD-L1 therapies may differ.”2
In an email to The American Journal of Managed Care®, Choueiri went further and said, “Here, we show that PD-1–based first-line combinations should not use PD-L1 status to pick therapy,” and that PD-1–based therapy compared with PD-L1 options in first-line treatment for mRCC “may have different biomarkers [that] may be specific to the actual drugs.”
Are these results likely to be seen in other cancers? Choueiri said this would be “variable,” because “RCC is very different tumors where the immune response has not been linked to commonly anticipated biomarkers such as PD-L1 and [tumor mutation burden].”
Real-world setting. An abstract from German investigators presented real-world data for 67 patients (62.7% male) with advanced RCC or mRCC treated with the nivolumab-cabozantinib combination; the median age was 67.6 years.5 Data were collected retrospectively from 8 GU cancer centers from patients with mRCC who received 40 mg cabozantinib orally and 240 mg or 430 mg of nivolumab intravenously. Nephrectomy was performed in 56.7% of the patients (n = 38).
IMDC scores were 0 for 11 patients (16.4%), equal to or greater than 1 in 45 patients (67.1%), and missing for 11 patients (16.4%). For 20 patients (29.9%), dose reductions or interruptions were required. Partial response was seen in 46.3% of patients (n = 31), with stable disease in 32.8% (n = 22), and progressive disease in 4.5% (n = 3) as the best response. Data were missing for 14.9% of patients (n = 10). Median follow-up was 8.3 months, median treatment duration was 6.0 months, and PFS rate at 6 months was 81.9%. AEs for all grades were seen in 82.1% of patients, with 47.8% (32 patients) seeing AEs of grade 3 to 5. Elevated liver enzymes (40.3%), diarrhea (22.4%), and hand-foot syndrome (20.9%) were the 3 most frequent AEs.
More than 431,000 new cases of RCC are diagnosed worldwide each year, accounting for 179,000 deaths, with the highest rates of the disease in North America and Europe. Up to 30% of patients already have advanced or metastatic RCC when they receive their diagnosis.6
1. 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
2. Choueiri TK, Motzer RJ, Powles T, et al. Biomarker analysis from the phase 3 CheckMate 9ER trial of nivolumab + cabozantinib v sunitinib for advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41(suppl 6):608. doi:10.1200/JCO.2023.41.6_suppl.608
3. 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. http://bit.ly/3YAK6hy
4. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888-898.
5. Hilser T, Darr C, Niegisch G, et al. Cabozantinib + nivolumab in adult patients with advanced or metastatic renal cell carcinoma: a retrospective, non-interventional study in a real-world cohort. J Clin Oncol. 2023;41(suppl 6):628. doi:10.1200/JCO.2023.41.6_suppl.628
6. Global health estimates 2020: deaths by cause, age, sex, by country and by region, 2000-2019. World Health Organization. 2020. Accessed February 26, 2023. https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death