Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial
Mené en France sur 202 patients atteints d'un carcinome rénal à cellules claires de stade métastatique, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité de trois stratégies thérapeutiques de première ligne selon le phénotype moléculaire de la tumeur (nivolumab en monothérapie, nivolumab en combinaison avec l'ipilimumab, inhibiteurs de tyrosine kinase anti-VEGFR)
Background : We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironmentsand sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab–ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab–ipilimumab,and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.
Methods : This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligiblepatients were aged 18 years or older, had an Eastern Cooperative Oncology Group performancestatus of 0–2, and had previously untreated metastatic clear-cell renal cell carcinoma.Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receiveeither nivolumab or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKIor nivolumab–ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab–ipilimumabreceived intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for fourdoses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned tonivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned toVEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib(800 mg daily continuously). The primary endpoint was the objective response rateby investigator assessment per Response Evaluation Criteria in Solid Tumors version1.1. The primary endpoint and safety were assessed in the population who receivedat least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closedto enrolment.
Findings : Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab–ipilimumab,40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a seriousadverse event before the first study dose and one patient was excluded from analysesdue to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In theccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patientswith nivolumab and 16 (39%; 24–55) of 41 patients with nivolumab–ipilimumab (oddsratio [OR] 0·63 [95% CI 0·25–1·56]). In the ccrcc4 group, objective responses wereseen in seven (44%; 95% CI 20–70) of 16 patients with nivolumab and nine (50% 26–74)of 18 patients with nivolumab–ipilimumab (OR 0·78 [95% CI 0·20–3·01]). In the ccrcc2group, objective responses were seen in 18 (50%; 95% CI 33–67) of 36 patients witha VEGFR-TKI and 19 (51%; 34–68) of 37 patients with nivolumab–ipilimumab (OR 0·95[95% CI 0·38–2·37]). In the ccrcc3 group, no objective responses were seen in thefour patients who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patientswho received nivolumab–ipilimumab. The most common treatment-related grade 3–4 adverseevents were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab,lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab–ipilimumab,and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverseevents occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumabgroup, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related:one due to fulminant hepatitis with nivolumab–ipilimumab, one death from heart failurewith sunitinib, and one due to thrombotic microangiopathy with sunitinib.
Interpretation : We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment betweennivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment ofmetastatic clear-cell renal cell carcinoma.
The Lancet Oncology , résumé, 2021