ESMO 2020: Renal Cell Carcinoma

The CheckMate-9ER Trial: Possible New Combination Therapy for Advanced RCC

In the phase 3 CheckMate-9ER trial of patients with advanced renal cell carcinoma (aRCC), first-line treatment with nivolumab plus cabozantinib demonstrated superior progression-free survival (PFS), overall survival (OS), and objective response rates (ORR) compared with sunitinib.

The safety profile of the nivolumab plus cabozantinib combination was manageable and consistent with the known single agent adverse profiles of both drugs. The results support the combination of nivolumab plus cabozantinib as a new immune checkpoint inhibitor (CPI) with a tyrosine kinase inhibitor (TKI) option for patients with aRCC. Results were reported at the recent ESMO Virtual Congress 2020.

Patients with aRCC were randomized 1:1 to nivolumab 240 mg plus cabozantinib 40 mg (n=323) vs sunitinib 50 mg PO for 4 weeks (n=328) until disease progression or unacceptable toxicity. At 18.1 months median follow up, all three efficacy endpoints (PFS, OS, ORR) were met. The combination arm demonstrated improvements in PFS (HR 0.51 [95% CI, 0.41–0.64], p<0.0001) and OS (HR 0.60 [98.89% CI, 0.40–0.89]; p=0.0010) vs sunitinib. Results were consistent across prespecified International Metastatic RCC Database Consortium (IMDC) risk and PD-L1 subgroups.

The objective response rate (95% CI) was significantly higher in the combination arm vs sunitinib (55.7% [50.1–61.2] vs 27.1% [22.4–32.3]; p<0.0001); while 8.0% vs 4.6% of patients had a complete response. The median duration of response was 20.2 months vs 11.5 months for the combination arm vs sunitinib.

Any-grade treatment-related adverse events (AEs) occurred in 96.6% vs 93.1% of patients treated with the combination vs sunitinib (60.6% vs 50.9% ≥grade 3).

Of interest is that the survival benefit of nivolumab plus cabozantinib (<3 months) was seen much earlier than with the combination of nivolumab plus ipilimumab (CheckMate-214, 6 months).

COSMIC-021 Study: Combination Therapy for Clear Cell RCC Shows Robust Clinical Activity

The combination of cabozantinib and atezolizumab demonstrated robust clinical activity in previously untreated patients with advanced clear cell renal carcinoma (ccRCC) with an acceptable safety profile at two doses of cabozantinib evaluated. Results were reported at the recent European Society of Medical Oncology (ESMO) Virtual Congress 2020.

Cabozantinib, a standard-of-care for treatment of advanced RCC, promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors and has shown encouraging activity in combination with immune checkpoint inhibitors in tumor types including ccRCC, urothelial carcinoma, metastatic castration-resistant prostate cancer (mCRPC), and hepatocellular carcinoma.

COSMIC-021 is a multicenter phase 1b study evaluating the combination of cabozantinib and atezolizumab in various solid tumors.

Patients with ccRCC were enrolled in the dose escalation (n=10) and expansion stage (n=60) study. Patients were enrolled sequentially to receive atezolizumab 1200 mg with either cabozantinib 40 mg (n=34) or 60 mg (n=36) in each stage. Eligible patients had ECOG performance status of 0-1. None had received prior systemic anticancer therapy for advanced RCC.

As of July 21, 2020, 30 patients were enrolled with a median follow-up of 13.0 months (range 8-20), including 16 patients (53%) that remained on treatment.

The confirmed objective response rate (ORR) per RECIST v1.1 was 33% (80% CI: 22–47), and 10 patients had partial responses (papillary, [n=6]; chromophobe, [n=1]; ccRCC, [n=1]; translocation, [n=1]; and unclassified, [n=1]); there were no complete responses, although partial responses occurred in all International Metastatic RCC Database Consortium (IMDC) risk groups. The disease control rate (DCR=complete response + partial response + stable disease) rate was 93% or more.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 71% of the cabozantinib 40 mg group and 64% of the cabozantinib 60 mg group, with no grade 5 TRAEs at either dose. In the cabozantinib 40 mg group, ORR was 47%, DCR was 94%, median progression free response (PFS) was 19.5 months and 12 months, and the PFS rate was 67%. For cabozantinib 60 mg, the ORR was 58%, DCR was 92%, median PFS was 20.4 months, and the 12-month PFS rate was 71%.

The phase 3 CONTACT-03 trial of cabozantinib plus atezolizumab immune checkpoint inhibitor-pretreated RCC patients, including those with papillary or unclassified ccRCC is currently ongoing.

The BIONIKK Trial: First Randomized Clinical Trial Based on Molecular Profiling for Treatment in Metastatic Clear Cell RCC

Sunitinib was the standard first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) for many years; however, recent clinical trials have shown superior efficacy of various treatment combinations including nivolumab and ipilimumab in International Metastatic RCC Database Consortium (IMDC) intermediate or poor-risk disease.

A recent transcriptomic analysis of primary frozen ccRCC specimens revealed molecular subgroups that could be summarized by a 35 gene signature. These signatures predicted outcomes to sunitinib treatment. The purpose of the BIONIKK trial was test response to first-line sunitinib, nivolumab, and combination nivolumab plus ipilimumab based on those gene signatures.

Between 2017 and 2019, 308 patients across 15 centers in France were screened. Two-hundred and two patients were randomized to the different arms, with 154 patients ultimately being evaluable in the target cohort. An additional 33 patients were included in an additional cohort (ACE) after IDMC review suggested continuation of the study.

The objective response rate (ORR, primary endpoint) for combination nivolumab and ipilimumab was numerically higher than nivolumab alone in the ccRCC1 group (immune-low). ORR was numerically comparable between nivolumab and nivolumab plus ipilimumab in the immune-high ccRCC4 group, representing a much higher than previously published ORR for nivolumab.

The ORR was also numerically similar between sunitinib and nivolumab plus ipilimumab in the ccRCC2 angio-high group. Numbers were small in the ccRCC3 cohort, with responses only in the nivolumab plus ipilimumab group.

Presenting author, Yann-Alexandre Vano, MD, PhD, Universite de Paris, Paris, France, stated that BIONIKK represents the first randomized clinical trial based on molecular profiling for treatment in mccRCC.

The chosen tumor profiling method of RNA expression signatures enriched response rates in tumors classified as “immune-high” (ccRCC4) to nivolumab to that numerically similar with combination nivolumab and ipilimumab. As hypothesized, the “immune-low” ccRCC1 group had increased ORR with combination nivolumab and ipilimumab, and tyrosine kinase inhibitors (i.e. sunitinib) are effective in the “angio-high” patient population.

This study provides evidence that prospective molecularly based clinical trials are feasible in mccRCC.

Checkmate 214 Trial: 4-Year Follow-Up

The CheckMate 214 trial examined the combination of nivolumab plus ipilimumab vs sunitinib for previously untreated clear cell advanced RCC. Published results showed that overall survival (OS) and objective response rates (ORR) were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced RCC.1

At the recent European Society of Medical Oncology (ESMO) Virtual Congress 2020, investigators presented 4-year follow-up and subgroup analysis of patients without nephrectomy.

Laurence Albiges, MD, PhD, from Institut Gustave Roussy in Paris, France presented long-term data from the CheckMate-214 trial comparing nivolumab and ipilimumab to sunitinib, with a focus on a group of patients who had not had their kidney removed (nephrectomy).

After 42 months of follow-up, 56% of patients on nivolumab/ipilimumab and 47% on sunitinib were alive. Thirteen percent stayed on their nivolumab + ipilimumab treatments and 7% stayed on their sunitinib treatment. Thirty one percent of patients on nivolumab + ipilimumab and 12% on sunitinib survived without further drug treatment.

In the intention-to-treat (ITT) population, combination nivolumab + ipilimumab continued to demonstrate superiority (HR 0.69, 95% CI, 0.59–0.81). In subgroups, those with intermediate- or poor-risk had improved survival with nivolumab + ipilimumab (HR 0.65, 95% CI, 0.54–0.78) while there was no appreciable difference among those with favorable-risk disease (HR 0.93, 95% CI, 0.62–1.40). Similar benefits in objective response rate were also seen.

In post hoc analyses of patients without a history of nephrectomy, primary tumor responses were more common among patients receiving nivolumab + ipilimumab. No complete responses were seen.

Among patients with a target kidney lesion, median OS was longer among those randomized to nivolumab + ipilimumab (26.1 months, 95% CI, 13.9–35.4) compared with sunitinib (14.3 months, 95% CI, 9.7–22.6) (HR 0.63, 95% CI, 0.40–1.00).

In an exploratory efficacy analysis restricted to 249 favorable-risk participants, there was no significant difference between the groups with regard to OS; and both PFS and ORR appeared to be significantly poorer with the combination than sunitinib, with median PFS of 17.8 months vs 27.7 months and ORRs of 29% vs 54%. The complete response rate remained higher with combination immunotherapy than sunitinib, at 13% and 6%, respectively.

The incidence of treatment-related AEs, treatment-related select immune-related AEs, and corticosteroid use declined over time.


  1. Morzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma. NEJM 2018; 378:1277-1290.