Study shows feasibility of mRCC treatment selection based on tumor gene expression

The results of the BIONIKK study published in The Lancet Oncology suggest that biomarker-based treatment selection based on tumor molecular phenotype may be on the horizon in the metastatic renal cell carcinoma (RCC) treatment paradigm.1

The study (NCT02960906) specifically examined this precision medicine pathway in the treatment selection between nivolumab (Opdivo) with or without ipilimumab (Yervoy) and a VEGFR tyrosine kinase inhibitor (TKI) as first line for patients with metastases. RCC cell (ccRCC).

First-line treatment for ccRCC has changed dramatically since 2015, when the immune checkpoint inhibitor (ICI), nivolumab, gained FDA approval. Since then, ICI alone and in combinations have entered the space and provide options for patients with RCC subtypes.

Previous research has shown that treatment with sunitinib (Sutent) in patients with a good response to the agent had molecular and pathological characteristics closest to normal kidney tissue (ccrcc3), the researchers hypothesized that the Immune-elevated ccrcc4 tumors would respond to nivolumab-based treatment, either with or without ipilimumab (Yervoy), due to the immune-enriched tumor microenvironment. In addition, ccrcc1 tumors would have a better response to the combination of nivolumab and ipilimumab compared to nivolumab alone due to the need to recruit antitumor cytotoxic T cells.

“To our knowledge, this is the first study to show the feasibility of prospective patient and treatment selection based on tumor gene expression in metastatic renal cell carcinoma. By assigning treatment based on tumor molecular group, we enriched the objective response population with nivolumab, nivolumab-ipilimumab, and VEGFR tyrosine kinase inhibitors (VEGFR-TKIs),” the authors wrote. of the study directed by Yann-Alexandre Vano, physician. oncologist at the European Hospital Georges-Pompidou.

To conduct the Phase 2, open-label, non-comparative, randomized, biomarker-based BIONIKK trial (NCT02960906), patients with ccRCC from 15 university hospitals and cancer centers in France were recruited. Individuals eligible for the study were patients 18 years of age or older who had newly diagnosed or recurrent stage IV RCC, an ECOG performance status of 0-2, 1 or more measurable lesions according to RECIST v1.1, and had not received prior systemic therapy for metastatic disease.

In terms of molecular clustering, the presence of a sarcomatoid component and the expression of PD-L1 were assessed centrally by an expert uropathologist on selected samples of formalin-fixed and paraffin-embedded tumors for all patients. Specimens were selected according to certain criteria, which included tumors with ≥60% viable tumor cells, ≤20% necrosis, highest grade, and highest immune infiltrate. Additionally, the presence of a sarcomatoid component was identified and PD-L1 expression was assessed using the PD-L1 22C3 antibody. Tumors with TC ≥ 1% were positive for PD-L1.

Patients with ccrcc1 and ccrcc4 disease received either nivolumab 3 mg/kg or nivolumab with ipilimumab 1 mg/kg. Individuals with disease in the ccrcc2 and ccrcc3 groups received 1 of 2 VEGFR TKIs (sunitinib 50 mg/day for 4 weeks every 6 weeks or oral pazopanib [Votrient] 800 mg per day continuously).

The primary endpoint of the study was objective response rate (ORR) as assessed by the investigator according to RECIST v1.1. Secondary endpoints of the study included ORR at week 22, progression-free survival (PFS), overall survival, duration of response (DOR), duration of treatment, as well as safety and tolerability.

A total of 61 patients received nivolumab monotherapy, 101 received the combination of nivolumab and ipilimumab, and 40 received a VEGFR TKI.

Among patients with ccrcc1, those treated with nivolumab alone had an ORR of 29% (95% CI, 16%-45%) versus 39% (95% CI, 24%-55%) with nivolumab plus ipilimumab ( odds ratio [OR], 0.63; 95% CI, 0.25-1.56). Patients with ccrcc4 disease had an ORR of 44% (95%, 20%-70%) on nivolumab monotherapy versus 50% (95% CI, 26%-74%) in patients treated with nivolumab/ipilimumab (OR, 0.78; 95% CI, 0.20-3.01).

Responses were higher in patients with ccrcc2 compared to the other phenotypes and lower in patients with ccrcc3 disease. Specifically, people with ccrcc2 treated with a VEGFR TKI had an ORR of (50% (95%, 33%-67%) versus 51% (95% CI, 34%-68%) with nivolumab plus ipilimumab ( OR, 0.95 (0.38-2.37) Among ccrcc3 patients, ORR was 0 with VEGFR TKI treatment versus 20% (95% CI, 1% to 72%; OR, no assessable [NE]).

DORs were not achieved (NR) in any treatment arm, but ranged from 6.0 months to 11.8 months, depending on the phenotype and the treatment administered. The shortest time to response was observed in patients with ccrcc4 disease treated with nivolumab monotherapy, with a time to response of 2.2 months (range: 2.2-NR). The longest time to response was observed in patients with ccrcc2 disease treated with a VEGFR TKI at 4.9 months (range, 2.8-16.5).

PFS was assessed in the ccrcc1, ccrcc2, and ccrcc4 groups. In patients with ccrcc1 disease who received the combination of nivolumab and ipilimumab, the median PFS was 7.7 months (95% CI, 5.0-12.9) versus 5.2 months ( 95% CI, 2.4-9.1) in those treated with nivolumab alone (risk ratio [HR] 1.27 (95% CI, 0.77-2.11).

Median PFS in patients with ccrcc4 treated with ICI combination was 13.0 months (95% CI, 2.5-NE) versus 7.8 months (95% CI, 2.3-NE) with nivolumab alone (HR, 1.37 (95% CI, 0.57-NE) 3.29)

Finally, patients in the ccrcc2 group treated with nivolumab plus ipilimumab had a median PFS of 11.1 months (95% CI, 7.7-23.2) versus 14.4 months (10.6-NE) ​​with VEGFR TKI treatment (HR, 0.75; 95% CI, 0.40-1.39).

Safety was assessed based on treatment with nivolumab monotherapy, nivolumab plus ipilimumab, and VEGFR TKI, and grade 1/2 adverse events (AEs) were observed in 76%, 54%, and 30%, respectively. In the nivolumab alone group, the most frequent low-grade AEs were fatigue (50%), pruritus (24%) and maculopapular rash (17%). For patients treated with the ICI combination, the most common grade 1/2 AEs were fatigue (50%), pruritus (31%) and diarrhea (32%). Finally, in the VEGFR TKI arms, the most frequent grade 1/2 AEs were fatigue (65%), diarrhea (53%) and oral mucositis (43%).

“Our results confirm that the response to nivolumab alone or combined with ipilimumab and VEGFR-TKIs is different depending on the characteristics of the tumor and its microenvironment. The ability to prospectively select patients based on their molecular group for treatment choice paves the way for broader biomarker-based trial designs,” wrote Vano et al.


1. Vano Y, Elaidi R, Bennamoun M, et al. Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line therapy for metastatic clear cell renal cell carcinoma (BIONIKK): open-label, non-comparative, randomized, biomarker-driven phase 2 trial [Published online ahead of print April 04, 2022]. Lancet Oncol. doi: 10.1016/s1470-2045(22)00128-0

Martin E. Berry