Selecting Patients for Treatment With Nivolumab ± Ipilimumab by Molecular Phenotype Yielded Positive Outcomes in Clear Cell RCC

Results from the phase 2 BIONIKK trial highlighted the feasibility and positive impact of selecting patients with metastatic clear cell renal cell carcinoma for treatment with nivolumab plus or minus ipilimumab and a VEGFR-tyrosine kinase inhibitor based on molecular phenotype.

Selecting individuals for treatment with nivolumab (Opdivo) plus or minus ipilimumab (Yervoy) plus a VEGFR-tyrosine kinase inhibitor based on molecular phenotype appeared feasible with a impact on patients with first-line metastatic clear cell renal cell carcinoma, according to the phase 2 BIONIKK trial (NCT02960906) published in The Lancet Oncology.

Several tumor groups were included in the study from ccrcc1—low-tumor microenvironment—to ccrcc4—high-tumor microenvironment. These groups were determined based on variable sensitivity to frontline sunitinib (Sutent). Those in ccrcc2 had the highest response to sunitinib and those in ccrcc3 had a good molecular response to sunitinib with the closest pathological features to normal kidney tissue.

After a median follow-up of 18.0 months, the objective response rate (ORR) in the ccrcc1 group was 29% (95% CI, 16%-45%) for nivolumab alone and 39% (95% CI, 24%-55%) for nivolumab plus ipilimumab (OR, 0.63; 95% CI, 0.25-1.56). In the ccrcc4 group, the ORR was 44% (95% CI, 20%-70%) for nivolumab alone and 50% (95% CI, 26%-74%) in nivolumab plus ipilimumab (OR, 0.78; 95% CI, 0.20-3.01). In the ccrcc2 group, the ORR was 50% (95% CI, 33%-67%) for VEGEFR-TKI vs 51% (95% CI, 34%-68%) for nivolumab plus ipilimumab (OR, 0.95; 95% CI, 0.38-2.37). No ORR was reported in the ccrcc3 group for those who received a VEGFR-TKI and was 20% (95% CI, 1%-72%) for those who received nivolumab plus ipilimumab.

Those in the nivolumab plus ipilimumab group received nivolumab intravenously at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab intravenously at 240 mg every 2 weeks. Those assigned to nivolumab alone received nivolumab at 240 mg intravenously every 2 weeks. Those assigned to VEGFR-TKI groups received oral sunitinib at 50 mg every day for 4 weeks or continuous oral pazopanib (Votrient) at 800 mg every day.

A total of 303 patients were screened, of whom 236 had a molecular group determination. Moreover, 202 patients were randomized to the different groups, including 61 in the nivolumab alone group, 101 in the nivolumab plus ipilimumab group, and 40 in the VEGFR-TKI group.

After the median follow-up, 59 patients continued receiving treatment. Additionally, 40 patients had died, 4 had withdrawn by investigator’s decision, and 3 had withdrawn consent.

The primary end point of ORR was met in 33% (95% CI, 21%-46%) of patients in receiving nivolumab alone with 3 complete responses (CRs); 45% (95% CI, 35%-55%) receiving nivolumab plus ipilimumab with 10 complete responses; and 45% (95% CI, 29%-62) with e VEGFR-TKI with 1 CR. The median duration of response was not reached for any group, except for those receiving VEGFR-TKIs in the ccrcc2 group.

The median follow-up was 16.2 months for progression-free survival (PFS), with 7 patients died and 121 progressed. Progression occurred in 69% of patients receiving nivolumab, 66% receiving nivolumab plus ipilimumab, and 53% with a VEGFR-TKI.

The median PFS was 5.3 months (95% CI, 2.4-9.1) with nivolumab alone, 10.4 months (95% CI, 7.7-13.8) with nivolumab plus ipilimumab, and 13.5 months (95% CI, 7.8–not reached [NR]) with VEGFR-TKI. The median PFS in the ccrcc1 cohort was 5.2 months (95% CI, 2.4-9.1) with nivolumab and 7.7 months (95% CI, 5.0-12.9) with nivolumab plus ipilimumab (HR, 1.27; 95% CI, 0.77-2.11). In the ccrcc4 cohort, the median PFS was 7.8 months (95% CI, 2.3–not evaluable [NE]) with nivolumab and 13.0 months (95% CI, 2.5-NE) with nivolumab plus ipilimumab (HR, 1.37; 95% CI, 0.57-3.29). In the ccrcc2 cohort, the median PFS was 14.4 months (95% CI, 10.6-NE) with VEGFR-TKI and 11.1 months (95% CI, 7.7-23.2) with nivolumab plus ipilimumab (HR, 0.75; 95% CI, 0.40-1.39). In the ccrcc3 cohort, the median PFS was 3.2 months (95% CI, 1.8-4.9) with a VEGFR-TKI and 16.1 months (95% CI, 2.0-NE) with nivolumab plus ipilimumab.

At the median follow-up for overall survival (OS) was 18.0 months, during which 40 patients had died, 4 had withdrawn due to investigator decision, and 3 withdrew consent. The median OS was not reached in any of the treatment groups. The median duration of treatment was 7.4 months for those receiving nivolumab alone, 8.4 months for nivolumab plus ipilimumab, and 8.1 months for VEGFR-TKI.

Common grade 3 and 4 treatment-related adverse effects (AEs) were hepatic failure (3%) and lipase increase (3%) in the nivolumab group, lipase increase (6%) and hepatobiliary disorders (6%) for the nivolumab plus ipilimumab group, and hypertension (15%) for VEGFR-TKI group. Serious AEs of any grade occurred in 3% of patients in the nivolumab group, 38% in the nivolumab plus ipilimumab group, and 25% with VEGFR-TKIs, with the most common being hypophysis (2%) and Meniere’s disease (2%) in the nivolumab alone group, adrenal insufficiency (6%) in the nivolumab plus ipilimumab group, and thrombotic microangiopathy (5%) and hepatic cytolysis (5%) in the VEGFR-TKIs group.

During treatment, 40 patients died, 29 deaths of which were related to disease progression, including 24% of those in the nivolumab group, 12% in the nivolumab plus ipilimumab group, and 8% with a VEGFR-TKI. Three deaths were related to the study treatment.

Reference

Vano YA, Elaidi R, Bennamoun M, et al. 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. Lancet Oncol. 2022;23(5):612-624. doi:10.1016/S1470-2045(22)00128-0