First-line treatment of advanced/metastatic RCC

Both CheckMate 9ER and COSMIC-021 showed efficacy of first-line combination therapy with an immune checkpoint inhibitor and tyrosine kinase inhibitor (TKI). In addition, the BIONIKK trial suggests that a 35-gene signature could be helpful to select the optimal first-line treatment in renal cell cancer (RCC).

Both nivolumab and cabozantinib are approved as single agent therapies for treatment of patients with advanced clear cell RCC, based on improvements in overall survival (OS) in phase 3 clinical trials [1,2]. CheckMate 9ER evaluated first-line treatment with the combination of nivolumab and cabozantinib [3]. In this phase 3 trial, 651 patients (22.6% favourable risk, 57.6% intermediate risk, 19.7% poor risk; 24.9% PD-L1 ≥1%) were 1:1 randomised to nivolumab (240 mg every 2 weeks plus cabozantinib (40 mg daily), or sunitinib (50 mg daily for 4 weeks on/2 weeks off). Primary endpoint is progression-free survival (PFS). Secondary endpoints are OS, objective response rate (ORR), and safety.

With 18.1 months median follow-up, all 3 efficacy endpoints were met. Nivolumab plus cabozantinib significantly improved PFS with a median PFS of 16.6 versus 8.3 months with sunitinib (HR 0.51; 95% CI 0.40-0.64; P<0.0001). The benefit of nivolumab plus cabozantinib was observed in all prespecified subgroups. Median OS was not yet reached in both study arms, but current HR was 0.60 (P=0.0010) in favour of nivolumab plus cabozantinib. ORR was significantly higher with nivolumab plus cabozantinib (55.7% vs 27.1%; P<0.0001). A complete response was achieved in 8.0% and 4.6% of the patients, respectively. Median duration of response was 20.2 versus 11.5 months for nivolumab plus cabozantinib versus sunitinib. Nivolumab plus cabozantinib was well tolerated with a low rate of treatment-related discontinuations.

In the phase 1b COSMIC-021 basket trial, cabozantinib was combined with atezolizumab [4]. A total of 70 patients with advanced RCC who had no prior systemic therapy for advanced RCC were enrolled (n=10 in the dose escalation phase, n=60 in the extension phase). According to IMDC criteria, 30% were classified as favourable, 67% were intermediate, and 3% were poor risk. Patients were treated with atezolizumab (1,200 mg every 3 weeks) and either cabozantinib 40 mg daily (n=34) or 60 mg daily (n=36). Results are summarised in the Table. Baseline PD-L1 expression and high CD8-positive cell count were associated with greater tumour reduction and overall response. A phase 3 study (CONTACT-03) is ongoing.

Table: Primary and secondary endpoints of COSMIC-021 [4]



In the phase 2 BIONIKK trial, the first-line treatment for patients with metastatic RCC was selected using a 35-gene signature of the tumours. Based on this genetic signature, metastatic RCC was divided into 4 subgroups (ccrcc1-4) with distinct tumour micro-environment composition and distinct outcomes with sunitinib [5]. In the study, 3 treatment options were available:

• A (nivolumab 240 mg every 2 weeks)


• B (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks)


• C (sunitinib or pazopanib)

Patients with a ccrcc1 or ccrcc4 tumour were randomised between A and B, patients with a ccrcc2 or ccrcc3 tumour were randomised between B and C. A total of 202 patients were randomised from whom 154 were evaluable for response [6]. ORR outcomes for each subgroup and treatment are listed in the Figure.

Figure: Objective response rates in evaluable patients of BIONIKK



After a median follow-up of 16 months, both in ccrcc1 and ccrcc4 tumours, nivolumab/ipilimumab was associated with a better median PFS compared with nivolumab monotherapy (8.0 vs 4.6 months and 12.2 vs 7.8 months, respectively). In ccrcc3 tumours, TKI was associated with a better median PFS compared to nivolumab/ipilimumab (not reached vs 10.4 months). In conclusion, BIONIKK provides evidence that gene expression signatures in mRCC may enable to enrich response rates.

1. Motzer RJ, et al. N Engl J Med. 2015;373:1803-1813.


2. Choueiri TK, et al. J Clin Oncol 2017;35(6):591-7.


3. Choueiri TK, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: First results from the randomized phase III CheckMate 9ER trial. ESMO Virtual Congress 2020, abstract 696O.


4. Pal S, et al. Cabozantinib (C) in combination with atezolizumab (A) as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from the COSMIC-021 study. ESMO 2020 Virtual Meeting, abstract 702O.


5. Beuselinck B, et al. Clin Cancer Res 2015;2:1329-1339.


6. Vano YA, et al. Results from the phase II biomarker driven trial with nivolumab (N) and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer (m-ccRCC) patients (pts): The BIONIKK trial. ESMO 202 Virtual Meeting, abstract LBA25.

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Posted on 25 November, 202024 November, 2020