Biomarker-Driven Assessment of Nivolumab, Nivolumab/Ipilimumab, and VEGFR Tyrosine Kinase Inhibitors in First-Line Treatment of Metastatic Clear Cell RCC

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In the French phase II BIONIKK trial reported in The Lancet Oncology, Vano et al assessed outcomes of first-line treatment with nivolumab with or without ipilimumab and VEGFR tyrosine kinase inhibitors given according to characteristics of molecular subgroups in patients with metastatic clear cell renal cell carcinoma (RCC).

As stated by the investigators, “We previously reported a 35-gene expression classifier identifying four clear cell RCC groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear cell RCC…. Tumors that were less responsive to sunitinib had either a pro-inflammatory and immune-high tumor microenvironment with a high expression of immunosuppressive checkpoints (ccrcc4) or, by contrast, an immune-low tumour microenvironment (ccrcc1). Nearly half of the most responsive tumors to sunitinib expressed an angiogenic-high and immune-high signature (ccrcc2)…. The smallest group with a good response to sunitinib had molecular and pathological features closest to normal kidney tissue (ccrcc3).”

Study Details

In the multicenter, open-label trial, 202 patients were randomly assigned between June 2017 and July 2019 to receive either nivolumab vs nivolumab/ipilimumab in the ccrcc1 and ccrcc4 molecular groups or a VEGFR tyrosine kinase inhibitor (sunitinib or pazopanib) vs nivolumab/ipilimumab in the ccrcc2 and ccrcc3 groups. Treatments consisted of:

  • Nivolumab/ipilimumab as nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for four doses followed by nivolumab at 240 mg every 2 weeks
  • Nivolumab alone at 240 mg every 2 weeks
  • VEGFR tyrosine kinase inhibitors as sunitinib at 50 mg/d for 4 weeks every 6 weeks or pazopanib at 800 mg daily continuously.

The primary endpoint was investigator-assessed response rate.

Key Findings

Median follow-up was 18.0 months (interquartile range = 17.6–18.4 months). In the ccrcc1 group, an objective response was observed in 12 (29%, 95% confidence interval [CI] = 16%–45%) of 42 patients treated with nivolumab and 16 (39%, 95% CI = 24%–55%) of 41 patients treated with nivolumab/ipilimumab (odds ratio [OR] = 0.63, 95% CI = 0.25–1.56).

In the ccrcc4 group, an objective response was observed in 7 (44%, 95% CI = 20%–70%) of 16 patients treated with nivolumab and 9 (50%, 95% CI = 26%–74%) of 18 patients treated with nivolumab/ipilimumab (OR = 0.78, 95% CI = 0.20%–3.01%).

In the ccrcc2 group, an objective response was observed in 18 (50%, 95% CI = 33%–67%) of 36 patients treated with a VEGFR tyrosine kinase inhibitor and 19 (51%, 95% CI = 34%–68%) of 37 patients treated with nivolumab/ipilimumab (OR = 0.95, 95% CI = 0.38%–2.37%).

In the ccrcc3 group, an objective response was observed in 0 of 4 patients treated with a VEGFR tyrosine kinase inhibitor and in 1 (20%, 95% CI = 1%–72%) of 5 patients treated with nivolumab/ipilimumab.

The most common treatment-related grade 3 or 4 adverse events were hepatic failure and lipase increase (3% each) with nivolumab, lipase increase and hepatobiliary disorders (6% each) with nivolumab/ipilimumab, and hypertension (15%) with a VEGFR tyrosine kinase inhibitor.

The investigators concluded, “We demonstrate the feasibility and positive effect of a prospective patient selection based on tumor molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR tyrosine kinase inhibitor in the first-line treatment of metastatic clear cell RCC.”

Yann-Alexandre Vano, MD, of the Institut du Cancer Paris CARPEM, AP-HP Centre, Université de Paris Cité, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb and ARTIC. For full disclosures of the study authors, visit

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