Treating Renal Cell Carcinoma With Tyrosine Kinase Inhibition

Reviewing Updated Survival and Subgroup Data of CheckMate9ER for RCC

During a Targeted Oncology case-based roundtable event, Eric Jonasch, MD, discussed the efficacy of the CheckMate 9ER regimen for patients with renal cell carcinoma.

TARGETED ONCOLOGYTM: What were the outcomes of the phase CheckMate 9ER trial (NCT03141177) of frontline immunotherapy plus tyrosine kinase inhibitor (IO/TKI) treatment for advanced renal cell carcinoma (RCC)?

ERIC JONASCH, MD: The CheckMate 9ER study, [like] all of the IO/TKI studies, ended up having similar eligibility criteria: patients with previously untreated clear cell renal cell carcinoma, stratification factors are typically [geographic location], plus IMDC [International Metastatic RCC Database Consortium] risk strata, and patients were randomly assigned 1:1 to receive 40 mg of cabozantinib [Cabometyx] daily plus [240 mg] nivolumab [Opdivo] every 2 weeks versus sunitinib [Sutent]. The primary end point in this study was PFS, but the secondary end points were all the usual ones.

It met its primary end point [of PFS]. There are updated data: at 33 months median follow-up, there was a 16.6-month versus an 8.3-month median PFS, with the hazard ratio [HR] that is [favoring cabozantinib/nivolumab] of 0.56 [95% CI, 0.46-0.68].1 The median OS with updated 33-month follow-up data, is 37 months [for cabozantinib/nivolumab] versus 34 months [for sunitinib], but looking at the [Kaplan-Meier] curves, it ends up looking like…at 24 months, 70% [given cabozantinib/nivolumab] versus 60% [given sunitinib] are alive, so there's definitely a survival difference between the 2 arms.

[Looking at] OS by subgroup based on the IMDC prognostic, there are poor risk, intermediate, and favorable. The favorable-risk [group’s confidence interval] is…very much overlapping 1.0.2 The directionality is much better for the intermediate- and poor-risk groups compared with the favorable-risk group from an OS perspective. [Patients with or without] bone metastases favored the combination, and [for both patients with or without having] a primary nephrectomy, the directionality was towards the combination.

[For the favorable-risk group had] a very wide confidence interval [HR, 0.84; 95% CI, 0.35-1.97] because it's a small sample set, but still…the OS didn't turn out to be positive [for showing benefit in this subgroup due to not reaching] a pre-specified input.

In terms of objective response rate [ORR], the combination had a 56% ORR versus 28% ORR for sunitinib.1 In terms of CR, there was a 12% CR rate for the combination versus 5% for sunitinib. A big question was, for IO/TKI, is this [response] durable or not?

Progressive disease as best response was 13.7% for sunitinib versus [6.2%]. So there were only [about] 6% of patients who were primary refractory [to cabozantinib/nivolumab] versus 13% for sunitinib, so there is a big difference there.

[Looking at] sites of metastases, for those with liver metastases, PFS [HR was 0.51; 95% CI, 0.33-0.79], and OS [HR was 0.47; 95% CI, 0.27-0.82].3 For those with bone metastases, PFS [HR was 0.38; 95% CI, 0.25-0.59] and OS [HR was 0.64; 95% CI, 0.39-1.06]. For those with lung metastases, PFS [HR was 0.51; 95% CI, 0.40-0.64] and OS [had an HR of 0.63; 95% CI, 0.46–0.86]. So even by organ metastasis sites, you can see that this is favoring the combination arm.

What stood out about the safety of this combination?

[In terms of] the safety data, the most common adverse event [in both arms] was diarrhea; we also see hypertension, and some transaminitis.1 With the cabozantinib/nivolumab, and also axitinib [Inlyta] plus pembrolizumab [Keytruda], you'll see the transaminitis that occurs more commonly with the combination. Very often, you can stop the TKI and the transaminitis is going to be better. You're not going to get this high level of grade 3/4 transaminitis with cabozantinib alone. There is some interaction between the drugs, but typically, you can manage it by managing the TKI.


1. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(6_suppl):350. doi:10.1200/JCO.2022.40.6_suppl.350

2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

3. Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(15_suppl):4553. doi:10.1200/JCO.2021.39.15_suppl.4553