Choueiri Highlights Efficacy of Cabozantinib/Nivolumab in RCC, Next Steps for Research

Partner | Cancer Centers | <b>Dana Farber</b>

Toni Choueiri, MD, discusses the CheckMate-9ER trial, the next steps for nivolumab/cabozantinib, and other cabozantinib regimens under exploration.

The combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) proved to be superior to sunitinib (Sutent) as a first-line treatment for patients with advanced or metastatic renal cell carcinoma (RCC), explained Toni Choueiri, MD, who added that other efforts are further examining cabozantinib in other novel doublet and triplet regimens, as well.

Updated results from the phase 3 CheckMate-9ER trial presented at the 2020 ESMO Virtual Congressshowed that at a median follow-up of 18.1 months, the combination of nivolumab plus cabozantinib significantly improved progression-free survival (PFS) compared with sunitinib, at a median of 16.6 months versus 8.3 months (HR, 0.51; 95% CI, 0.41-0.64; P <.0001) per blinded independent central review (BICR). The median OS was not reached in either arm, leading toa 40% reduction in the risk of death with the combination (HR, 0.60; P = .0010). Moreover, the objective response rate per BICR with the combination was 55.7% versus 27.1% (P <.0001).

Any-grade treatment-related adverse effects (TRAEs) occurred in 97% versus 93% of patients treated in the combination arm and sunitinib arm, respectively. Moreover, 19% of 320 patients received corticosteroids to manage any-grade immune-mediated AEs, added Choueiri. Notably, patients who received the combination experienced significantly better quality of life (QoL) compared with those who received sunitinib.

“If you couple the OS benefit with the QoL benefit [observed with this combination], the message is that patients live longer and better,” said Choueiri. “This is an important combination that, hopefully, will become 1 of our standards [that we will use] to treat patients with RCC in the first-line [setting].”

Cabozantinib is also under exploration in combination with nivolumab and ipilimumab in previously untreated patients with advanced or metastatic RCC in the COSMIC-313 trial (NCT03937219).2 Additionally, in the phase 3 CONTACT-03 trial (NCT04338269), cabozantinib is being examined in combination with atezolizumab in patients with inoperable, locally advanced or metastatic RCC who progressed during or after treatment with an immune checkpoint inhibitor.3

In an interview with OncLive, Choueiri, director of the Lank Center for Genitourinary Oncology; director of the Kidney Cancer Center; senior physician with Dana-Farber Cancer Institute; the Jerome and Nancy Kohlberg Chair; and professor of medicine with Harvard Medical School, discussed the CheckMate-9ER trial, the next steps for nivolumab/cabozantinib, and other cabozantinib regimens under exploration.

OncLive: Could you first start off by discussing the design of the CheckMate-9ER trial?

Choueiri: We presented results from the CheckMate-9ER trial during the 2020 ESMO Virtual Congress. In this trial, we looked at the impact of the combination of a TKI and a checkpoint blocker, cabozantinib and nivolumab, in patients with metastatic RCC who were previously untreated. Patients had metastatic disease and were randomized to either standard sunitinib or to the combination of cabozantinib/nivolumab. Cabozantinib was given at 40 mg daily. This was a phase 3 trial, and the primary end point was PFS by BICR. Secondary end points of the trial included safety, response rate, OS, and QoL.

What were the results presented during the 2020 ESMO Virtual Congress?

Beyond any reason of a doubt, the combination resulted in a significant major clinical benefit over the control arm of sunitinib. The primary end point of PFS was doubled, going from 8.3 months to 16.6 months; this was highly statistically significant. OS was also prolonged, and the risk of death was reduced by 40%; the hazard ratio was 0.6. Responses went from 27% to 56% on BICR. Even when you look at investigator assessment, responses reached 60% and the median PFS per investigator assessment was 19.4 months.

What was the safety profile of the study regimen?

The AEs were manageable. A higher incidence of liver function test abnormalities was observed in the combination [arm]; however, [the number of] deaths from [treatment] were similar on both [arms]. Treatment discontinuation due to AEs were low in both arms. Three percent [of patients on the] combination arm discontinued treatment of both drugs versus 8.8% on the sunitinib [arm].

No safety signals beyond what we see with VEGF-targeted therapy and immune checkpoint inhibitors were reported. Nineteen percent of patients who experienced an immune-related AE were [treated with steroids]. When you look at the high-dose steroids—40 mg of prednisone or higher for 1 month or more—the incidence of [these toxicities] were much less. [These were] important findings reported during ESMO.

What did results reveal with regard to quality of life?

One of the interesting things in this study were the QoL metrics. We don't just want the patient to live longer; we also want them to feel better. Two of the QoL metrics were presented [during ESMO]. The Functional Assessment for Cancer Therapy Kidney Symptom Index-19 (FKSI-19), which involves 19 questions, and a subset of FKSI–disease-related symptoms, which includes 6 questions. Patients filled out the questionnaire at baseline, during their visits, and during follow-up in both arms. At the vast majority of the time points, we saw a statistical significance favoring the combination of cabozantinib/nivolumab over sunitinib in terms of QoL.

What are the next steps for the cabozantinib/nivolumab combination?

What’s the next step for the CheckMate-9ER trial? [We are] moving forward and [accruing] patients to another ongoing phase 3 trial called COSMIC-313; this trial is examining nivolumab plus ipilimumab [as a modern control without sunitinib, versus the [triplet] combination comprised of nivolumab, ipilimumab, and cabozantinib. Two of the 3 drugs were [examined in the] CheckMate-9ER trial. This study is accruing [to examine] a triplet versus a doublet regimen in an intermediate-risk population.

Similarly, the PDIGREE [trial] is combination study that involves the 3 drugs but they are being given in a different sequence. It's an academic Alliance-led study that is being done in the United States. First, patients are given nivolumab/ipilimumab and if they achieve a complete response (CR), they could stop [treatment] after 1 year. If a patient has disease progression, they could be switched to cabozantinib. The 70% of patients who do not have progressive disease and do not have a CR will get randomized to nivolumab maintenance, which is what we do normally with nivolumab/ipilimumab or nivolumab/cabozantinib. That's the PDIGREE study and that is also currently accruing patients.

Were any other studies presented during the meeting that you wanted to highlight?

Another interesting oral presentation about therapeutics was reported during the meeting. In a poster, [investigators combined] cabozantinib with another checkpoint inhibitor, the PD-L1 inhibitor atezolizumab (Tecentriq). Monty Pal, MD, of City of Hope, and Bradley McGregor, MD, of Dana-Farber Cancer Institute, presented both studies.

Pal showed in a population of patients with RCC, at a different dose of 40 mg or 60 mg, response rates were over 50%; 90% or more patients demonstrated tumor shrinkage. Most importantly, the combination was well tolerated; as such, it was moved to a phase 3 trial called CONTACT-3. In this trial, which is being done in the post-immunotherapy setting, patients who experienced prior checkpoint inhibitor and progressed will be randomized to control cabozantinib versus cabozantinib plus atezolizumab.

What’s your take-home message regarding this trial and its findings?

Overall, it’s to have options and to keep the field moving. We want patients to be able to hear about the options available to them and for oncologists be familiar with [those options]. The 3 drugs I mentioned—nivolumab, cabozantinib, and atezolizumab—overall, are drugs that are available and approved for use in other malignancies. For example, nivolumab and cabozantinib [are FDA approved] in RCC and atezolizumab [is approved] for use in many other malignancies. Putting them together in RCC seems to be the natural thing. I’m glad that [these agents] made it to the next step.


  1. Choueiri TK, Powles T, Burotto M, 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. Presented at 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract 6960_PR.
  2. Study of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma (COSMIC-313). Updated August 28, 2020. Accessed October 7, 2020.
  3. Exelixis announces initiation of CONTACT-03 phase 3 pivotal trial of cabozantinib in combination with atezolizumab in previously treated metastatic renal cell carcinoma. News release. Exelexis, Inc. July 20, 2020. Accessed October 7, 2020.