CheckMate 9ER Trial of Nivolumab/Cabozantinib Continues to Elicit Clinical Benefit in RCC

Mauricio Burotto, MD

Updated results from the phase 3 CheckMate 9ER trial (NCT03141177) of nivolumab (Opdivo) plus cabozantinib (Cabometyx) showed a continued clinically meaningful improvement in long-term survival and in responses vs treatment with sunitinib (Sutent) monotherapy in patients with advanced renal cell carcinoma (RCC), according to a presentation at the 2023 Genitourinary Cancers Symposium.

With a median follow-up of 44.0 months (range, 36.5-56.5), median progression-free survival (PFS) in the intent-to-treat (ITT) population by blinded independent central review (BICR) was 16.6 months (95% CI, 12.8-19.8) with nivolumab plus cabozantinib vs 8.4 months (95% CI, 7.0-9.7) with sunitinib (HR, 0.58; 95% CI, 0.48-0.71). Additionally, PFS rate was 47.7% vs 27.0% at 18 months and 21.0% vs 11.6% at 36 months in each respective cohort.

In subgroups based on International Metastatic RCC Database Consortium (IMDC) risk scores, the median PFS in the intermediate-/poor-risk group was 16.4 months (95% CI, 11.2-19.3) with nivolumab plus cabozantinib vs 7.1 months (95% CI, 5.7-8.9) with sunitinib (HR, 0.55; 0.45-0.69). Additionally, PFS rate in this subgroup was 45.8% vs 23.8% at 18 months and 20.5% vs 10.0% at 36 months in each respective cohort.

Among patients with favorable-risk disease, the median PFS was 21.4 months (95% CI, 13.1-24.8) with nivolumab plus cabozantinib vs 13.9 months (95% CI, 9.6-18.5) with sunitinib (HR, 0.75; 0.50-1.13). PFS rate in this subgroup was 54.0% vs 38.6% at 18 months and 25.4% vs 16.1% at 36 months in each respective cohort.

Moreover, the median PFS in the poor-risk group was 9.9 months (5.9-17.7) vs 4.2 months (95% CI, 2.9-5.6) in the combination group and control group, respectively (HR, 0.38; 95% CI, 0.25-5.6). The 18-month and 36-month PFS rates were 37.8% vs 7.2% and 28.6% vs 2.4%, respectively.

Lastly, the intermediate-risk group had a median PFS of 17.5 months (95% CI, 12.3-20.3) and 8.5 months (95% CI, 7.0-10.4) in the combination and single-agent groups, respectively (HR, 0.61; 95% CI, 0.48-0.79). The 18-month and 36-month PFS rates were 48.5% vs 29.3% and 18.5% vs 12.1% in each respective group.

“These results continue to support nivolumab plus cabozantinib as first-line treatment for patients with advanced or metastatic RCC,” presenting author Mauricio Burotto, MD, a medical oncologist at Bradford Hill Clinical Research Center in Santiago, Chile, said in the presentation.

Investigators of the randomized, open-label, phase 3 CheckMate 9ER trial assessed nivolumab plus cabozantinib compared with sunitinib alone as treatment for clear cell, advanced, or metastatic RCC. Patients were randomly assigned 1:1 to receive 240 mg of nivolumab intravenously every 2 weeks plus 40 mg of cabozantinib orally once a day or 50 mg of sunitinib orally once a day using a 4 weeks on, 2 weeks off schedule.

The primary end point of the trial was PFS per blinded independent central review based on RECIST v1.1 criteria. Key secondary end points included overall survival (OS), overall response rate (ORR) per RECIST v1.1 criteria, and safety.

Patients who had previously untreated advanced or metastatic RCC, a clear cell component, or who were part of any IMDC risk group were eligible for enrollment on the trial.

Investigators included a total of 651 patients in the overall population. Baseline characteristics were generally consistent across IMDC risk subgroups, although notably fewer patients in the poor-risk group received a prior nephrectomy in the nivolumab plus cabozantinib (48%) and sunitinib (51%) cohorts, according to Burotto.

The median OS in the ITT population was 49.5 months (95% CI, 40.3-not evaluable [NE]) with nivolumab plus cabozantinib vs 35.5 months (95% CI, 29.2-42.3) with sunitinib (HR, 0.70; 95% CI, 0.56-0.87). Additionally, OS rate was 79.0% vs 68.8% at 18 months and 58.7% vs 49.5% at 36 months in each respective cohort.

In IMDC subgroups, the median OS in the combined intermediate-/poor-risk group was 49.5 months (95% CI, 34.9-NE) in the nivolumab plus cabozantinib cohort vs 29.2 months (95% CI, 23.7-36.0) in the sunitinib cohort (HR, 0.65; 95% CI, 0.51-0.83). Additionally, OS rate in this subgroup was 76.8% vs 63.6% at 18 months and 55.7% vs 43.6% at 36 months in each respective cohort.

According to Burotto, there was no difference in OS between the nivolumab plus cabozantinib and sunitinib arms for patients with favorable-risk disease. The median OS was not reached (95% CI, 40.7-NE) in the nivolumab plus cabozantinib arm and 47.6 months (95% CI, 43.6-NE) in the sunitinib arm (HR, 1.07; 95% CI, 0.63-1.79). OS rate at 18-months and 36-months was 86.3% vs 87.3% and 68.4% vs 70.1% for each respective cohort.

In the poor-risk group, the median OS was 34.8 months (95% CI, 21.4-NE) and 10.5 months (95% CI, 6.8-20.7) in the combination and monotherapy groups, respectively. Moreover, the 18-month and 36-month OS rates were 70.3% vs 43.3% and 46.8% vs 25.1% in each respective group.

Lastly, the median OS was 49.5 months (95% CI, 37.6-NE) compared with 36.2 months (95% CI, 25.7-46.0) in the nivolumab and sunitinib groups, respectively. The 18-month and 36-month OS rates were 78.9% vs 71.0% and 58.7% vs 50.4% in each respective group.

In the ITT population, ORR was 55.7% (95% CI, 50.1%-61.2%) in the nivolumab plus cabozantinib cohort vs 28.4% (95% CI, 23.5%-33.6%) in the sunitinib cohort (odds ratio [OR], 3.3; 95% CI, 2.4-4.6). This included a complete response rate of 12.4% and partial response rate of 43.3% in the combination group vs 5.2% and 23.2% in the sunitinib group, respectively.

Additionally, the median time to response was 2.8 months (range, 1.0-22.3) vs 4.2 months (range, 1.7-30.4), and the median duration of response was 23.1 months (95% CI, 20.2-27.9) vs 15.2 months (95% CI, 9.9-20.7) in each respective cohort.

Of note, the ORRs with nivolumab plus cabozantinib vs sunitinib in the favorable-, intermediate, poor-, and intermediate-/poor-risk subgroups were 66.2% vs 44.4%, 57.4% vs 28.7%, 37.7% vs 10.3%, and 52.6% vs 23.8%, respectively.

The median duration of therapy was 21.8 months (interquartile range [IQR], 8.8-34.0) in the nivolumab plus cabozantinib arm and 8.9 months (IQR, 2.9-20.7) in the sunitinib arm. The treatment discontinuation rate due to any-grade treatment-related adverse effects (TRAEs) was 27.5% and 10.6% in each respective arm and discontinuation due to disease progression occurred in 48.1% vs 62.8% of patients, respectively.

Thirty-six percent of patients receiving nivolumab plus cabozantinib and 45% of patients receiving sunitinib had any subsequent therapy in the ITT population. For patients who discontinued study treatment for any reason, 44% and 51% of patients in each respective arm received any subsequent therapy.

In a post hoc analysis, the baseline characteristics of those who completed 2 years of therapy with nivolumab were consistent with those observed in the ITT population, according to Burotto.

The median time to subsequent therapy 20.6 months (95% CI, 7.9-NE) for patients who completed 2 years of treatment with nivolumab plus cabozantinib.

“This prolonged period of time reflects the efficacy of nivolumab after treatment discontinuation,” Burotto said.

Investigators observed any-grade AEs in 97% of patients receiving nivolumab plus cabozantinib and 93% of those receiving sunitinib. Frequent any-grade AEs in each respective arm included diarrhea (59% vs 46%), palmar-plantar erythrodysesthesia (PPE; 39% vs 42%), and hypertension (33% vs 34%). Grade 3 or higher AEs were seen in 67% and 55% of each respective cohort, with the most frequent toxicities including hypertension (13% vs 13%), PPE (8% vs 8%), and diarrhea (7% vs 5%).

No new deaths associated with treatment have been reported since the last database lock.

Overall, 22% of patients receiving nivolumab plus cabozantinib had corticosteroid treatment with at least 40 mg of prednisone per day to manage any-grade immune-mediated AEs (IMAEs). Additionally, 13% and 5% of patients received corticosteroids continuously for at least 14 days and at least 30 days, respectively.

High-grade IMAEs in the experimental group included diarrhea (3%) and alanine transaminase increase (3%) compared with hypothyroidism (<1%) and hepatotoxicity (<1%) in the control arm.

Reference

Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603