Background
We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and 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. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status 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 receive either nivolumab or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab–ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab–ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-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 rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at 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 closed to 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 serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patients with nivolumab and 16 (39%; 24–55) of 41 patients with nivolumab–ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25–1·56]). In the ccrcc4 group, objective responses were seen 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 ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33–67) of 36 patients with a 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 the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patients who received nivolumab–ipilimumab. The most common treatment-related grade 3–4 adverse events 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 adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumab group, 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 failure with 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 between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.
Funding
Bristol Myers Squibb, ARTIC.
Molecular selection of patients for systemic therapy
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.
BIONIKK was a biomarker-driven, open-label, non- comparative, randomised, phase 2 trial including patients from 15 centres in France. The ability of a 35-gene expression classifier to identify four distinct profiles of clear-cell renal cell tumours (ccrcc1 to ccrcc4) and to predict sunitinib resistance in the first-line treatment of metastatic renal cell carcinoma was tested. Eligible patients were assigned (1:1) to receive either nivolumab or nivolumab–ipilimumab in the ccrcc1 and ccrcc4 groups, and to receive nivolumab–ipilimumab or VEGFR-TKI (sunitinib or pazopanib) in the ccrcc2 and ccrcc3 groups.
The primary endpoint was the investigator-assessed objective response rate per molecular group and treatment group. By allocating treatment according to tumour molecular group, they enriched the population who achieved an objective response with nivolumab, nivolumab–ipilimumab, and VEGFR tyrosine kinase inhibitors (VEGFR-TKIs). Their results confirm that the response to nivolumab alone or with ipilimumab and to VEGFR-TKIs is different depending on the characteristics of the tumour and its microenvironment (immune-high ccrcc4 tumours are responsive to nivolumab-based therapy, either with or without ipilimumab- immune-enriched tumour microenvironment-; ccrcc1 tumours respond better to nivolumab–ipilimumab due to the need to recruit antitumour cytotoxic T cells and ccrcc2 tumors respond equally to either VEGFR- tyrosine kinase inhibitors (VEGFR-TKIs; sunitinib or pazopanib) and nivolumab–ipilimumab due to the pro-angiogenic and immune-high environment. The feasibility of prospectively selecting patients by their molecular subtype prior to treatment, supports the expansion into larger biomarker-based trial designs.
There were many fascinating findings in this study which deserve notice.
Firstly, despite molecular subtyping and higher response rate, progressive disease figures were high as well, and in highly immunogenic ccrcc4 group progressive disease was detected in 33% in nivolumab and ipilumab group and 38% in nivolumab group, which is much higher than reported 20% progressive disease in original ChecMate 214 trial (1), respectively. However, despite progression, a third of patients did not require a second-line therapy during their follow-up, addressing necessity to continue therapy beyond progression in a subgroup of patients. Only in group 2 with high immunogenic and high angiogenic tumour microenvironment, response rates with nivolumab and ipilimumab and VEGFR-TKIs were high with both therapy classes and progressive disease rates were low, 14% and 17%, respectively. However, the authors subdivided molecular groups further into immune low to intermediate and immune high, distinquishing better responders to nivolumab and ipilimumab and VEGFR-TKI therapy, respectively.
Secondly, 75% of ccrcc4 had sarcomatoid features, receiving nivolumab/ipilimumab and reporting the highest response rates. And the highest response with VEGFR-TKI therapy was evaluated in ccrcc2 group patients in favourable IMDC risk.
Thirdly, this study showed higher response rates than demonstrated in the original CheckMate 214 trial where response rate in ITT population was 39% (1). Here, response rates with the combination between 39% in immune desert group ccrcc1 and 50-51% in ccrcc2 and ccrcc4 immune infiltrated groups were revealed. In pro-angiogenic group (ccrcc2) despite similar response rates with immunotherapy and VEGFR-TKIs, progression free survival was longer with VEGFR-TKIs, suggesting a primary role of VEGFR-TKI on that subgroup.
The 2022 EAU RCC Guidelines recommend three VEGFR-TKI + ICI combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all IMDC risk groups in metastatic first-line RCC, and dual immunotherapy of nivolumab and ipilimumab in IMDC intermediate-and poor-risk groups. This study has promising results which would require evaluation in a larger cohort and validation and may be fascinating to be incorporated in future nomograms to select patients for systemic treatment. Up-to-date, Guideline recommendations remain.