Previously, the primary analysis of the phase III CheckMate 9ER trial showed superior progression-free survival, overall survival (OS), and objective response of nivolumab plus cabozantinib vs. sunitinib in previously untreated patients with advanced renal cell carcinoma (aRCC). With extended follow-up and preplanned final OS analysis, the combination confirmed its superior efficacy, further supporting its use in the first-line treatment of aRCC.
The primary analysis of the phase III CheckMate 9ER trial (median follow-up 18.1 months) showed improved efficacy outcomes of nivolumab plus cabozantinib vs. sunitinib in the first-line setting of patients with advanced renal cell carcinoma (aRCC). The results reported at this time were the final analysis of progression-free survival (PFS, primary endpoint) and objective response, and the first interim analysis of overall survival (OS). Compared with sunitinib, nivolumab plus cabozantinib significantly improved PFS (HR[95%CI]: 0.51[0.41-0.64]; p< 0.001), OS (HR[98.89%CI]: 0.60[0.40-0.89]; p= 0.001), and objective response (55.7 vs. 27.1%; p< 0.001). Based on these results, nivolumab plus cabozantinib is recommended as a new standard of care for first-line treatment of aRRC. In this article, the preplanned final OS analysis with an extended follow-up of 32.9 months is presented, as well as updated PFS, objective response and safety outcomes.
The open-label, randomised phase III CheckMate 9ER trial included adult patients (≥18 years) with advanced or metastatic RCC with a clear-cell component, including sarcomatoid features. Eligible patients had to have a Karnofsky performance status of 70% or higher, no previous systemic therapy, measurable disease according to RECIST 1.1, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every two weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily for four weeks followed by two weeks off in each 6-week cycle. Patients received nivolumab treatment for up to a maximum of two years or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurred first. Crossover between treatment groups was not permitted. Prespecified and post-hoc analyses in subgroups of clinical interest at baseline included patients with sarcomatoid features, previous nephrectomy, liver metastasis, bone metastasis, and lung metastasis. The primary endpoint was PFS. OS was a secondary endpoint. Other secondary endpoints included objective response (including time to and duration of response), and safety and tolerability.
Between September 2017 and May 2019, 651 RCC patients were randomised to nivolumab plus cabozantinib (N= 323) or sunitinib (N= 328). With a median follow-up of 32.9 months, median OS was 37.7 vs. 34.3 months in the nivolumab plus cabozantinib and sunitinib arms, respectively (HR[95%CI]: 0.70[0.55-0.90], p= 0.0043), and 24-month OS was 70% vs. 60%. The OS benefit with nivolumab plus cabozantinib was maintained across subgroups of clinical interest, including patients with sarcomatoid features, previous nephrectomy, and different sites of metastases. The updated median PFS was 16.6 vs. 8.3 months (HR[95%CI]: 0.56[0.46-0.68], p< 0.0001), and 24-month PFS was 39.5% vs. 20.9%. The proportion of patients with a confirmed objective response was also higher in the nivolumab plus cabozantinib group (56% vs. 28%), including more patients with a complete response (12% vs. 5%). Patients in the nivolumab plus cabozantinib arm had shorter median time to response (2.8 vs. 4.2 months) and longer median DoR (23.1 vs. 15.1 months). A higher proportion of patients had target lesion shrinkage with nivolumab plus cabozantinib, regardless of target lesion organ site. Consistent with the primary analysis, all-cause adverse events of any grade occurred at similar frequencies in both arms. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 65% vs. 54% of patients in the nivolumab plus cabozantinib and sunitinib groups. The most common grade 3-4 TRAEs were hypertension (13% vs. 12%), palmar–plantar erythrodysaesthesia (8% vs. 8%), and diarrhoea (7% vs. 5%). Treatment-related serious AEs of any grade occurred in 22% vs. 10% of the patients. Since the primary analysis, there were no new deaths related to treatment with nivolumab plus cabozantinib, while one additional death occurred with sunitinib.
Long-term follow up results of the CheckMate 9ER trial, including the final OS analysis, demonstrate superior efficacy of nivolumab plus cabozantinib vs. sunitinib for the first-line treatment of patients with advanced RCC, further supporting the use of this combination in this setting. The benefit of the combination was maintained among multiple baseline subgroups of clinical interest, including patients with sarcomatoid features, previous nephrectomy, and different sites of metastases. No new safety signals were identified with nivolumab plus cabozantinib treatment.
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