Nivolumab/Cabozantinib Combo Joins RCC Lineup

Oncology Live®Vol. 22/No. 4
Volume 22
Issue 04

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Patients with metastatic renal cell carcinoma have a new frontline treatment alternative following FDA approval of the combination of nivolumab plus cabozantinib combination.

Toni Choueiri, MD

Toni Choueiri, MD

Patients with metastatic renal cell carcinoma (RCC) have a new frontline treatment alternative following FDA approval of the combination of nivolumab (Opdivo) plus cabozantinib (Cabometyx) combination. The doublet induced a 40% reduction in the risk for death compared with sunitinib (Sutent).1

The combination pairing the immune checkpoint inhibitor (ICI) nivolumab with the VEGF inhibitor cabozantinib was approved on January 22, 2021, based on findings from the phase 3 CheckMate 9ER trial (NCT03141177). The regimen improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus sunitinib in patients with RCC.

“It’s going to be another option for frontline clear cell RCC. It’s not the only combination that is approved, but I think there are some distinctions, especially with the quality-of-life data,” said principal investigator Toni K. Choueiri, MD. He is the director of the Lank Center for Genitourinary Oncology and a senior physician at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.

The approval follows a trend of combination therapies incorporating ICIs for first-line RCC therapy. In less than 2 years, the FDA has approved frontline combinations of axitinib (Inlyta), a VEGF inhibitor, with the ICIs pembrolizumab (Keytruda) or avelumab (Bavencio). Dual therapy with the ICIs nivolumab and ipilimumab (Yervoy), a CTLA-4 inhibitor, also is approved for previously untreated intermediate- or poor-risk advanced RCC.2

The nivolumab/cabozantinib option, Choueiri said, has shown activity across all risk groups in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Overall, at a median follow-up of 18.1 months, the median PFS with the combination was 16.6 months (95% CI, 12.5-24.9) versus 8.3 months (95% CI, 7.0-9.7) with sunitinib monotherapy (HR, 0.51; 95% CI, 0.41- 0.64; P < .0001). The median OS had not yet been reached in either treatment arm (HR, 0.60; 98.89% CI, 0.40-0.89; P = .0010).

Previous study findings showed that nivolumab promotes antitumor responses by preventing cancer from evading immune detection. Cabozantinib, on the other hand, has antiangiogenic and immunomodulatory properties thought to counteract tumor-induced immunosuppression. Both agents are approved in monotherapy settings in RCC.

In CheckMate 9ER, investigators randomly assigned 651 patients with advanced clear cell RCC to first-line nivolumab in combination with cabozantinib (n = 323) or sunitinib (n = 328). To be eligible for enrollment, patients had to be treatment naïve and have advanced or metastatic disease with a clear cell component.

Results from CheckMate 9ER, presented during the 2020 European Society for Medical Oncology Virtual Congress, demonstrated that the doublet induced activity across several subgroups. These spanned age, sex, PD-L1 expression, bone metastases, IMDC risk groups, and geographic region.

The doublet also showed a favorable safety profile. Incidence of any-grade and high-grade treatment-related adverse effects (TRAEs) were similar between the 2 arms. Of patients who received cabozantinib or nivolumab, 15.3% reported TRAEs that resulted in treatment discontinuation compared with 8.8% of those in the sunitinib arm.1

Nineteen percent of participants in the investigational arm required corticosteroids due to immune-associated toxicities, with 4% of them needing corticosteroids for at least 30 days. Choueiri said that the rate of complete treatment discontinuation due to AEs and use of steroids, especially after 14 and 28 days, was generally low for the combination. Moreover, one should expect a greater incidence of toxicities with 2 drugs rather than with 1, he said.

“One thing to mention is that the dose of cabozantinib in CheckMate 9ER is not the same dose when we use cabozantinib as monotherapy,” Choueiri said. “The approved indication of cabozantinib monotherapy in first-line and second-line RCC is 60 mg orally once a day. With the combination, it’s 40 mg once a day. Even with that, the efficacy end points were met. It’s possible that the toxicity could be lower and the quality of life better because of that adjustment, [compared with] a full dose of sunitinib.”

Additionally, Choueiri noted, the nivolumab/cabozantinib combination resulted in improved health-related quality-of-life (QOL) scores compared with sunitinib. Health-related QOL was maintained over time with the doublet versus sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index (FKSI)-19 total score and on the FKSI disease-related symptom subscale. The differences between arms were found to be significant at most time points over 91 weeks.1

“QOL is the voice of the patient. We can grade toxicities as much as we want—these are questionnaires that the patients answer about how they feel,” Choueiri said. “It is still very hard to extrapolate and say, ‘This is the only superior combination for QOL against sunitinib versus the other combination,’ simply because the combinations have not been compared head-to-head.”

He continued: “There is not one questionnaire and one QOL metric. There are many, and there isn’t a real hardcore consensus on what constitutes a clinically meaningful QOL,” he said. “Also, you may not have general improvement in QOL, but there are [important] elements that are part of it, like fatigue, that could be different. So you’ll have to dig into this very closely.”

Investigators will present patient-reported outcomes from this trial at the 2021 Genitourinary Cancers Symposium in February. Moving forward, Choueiri said, patients with RCC will have “an embarrassment of riches” in terms of treatment options, giving rise to questions on sequencing.

“The question is, if someone went with 1 regimen of VEGF-IO [immunooncology], could they switch to another VEGF-IO knowing that it does have OS benefit, but now [they are] treated so it’s not the same indication?” Choueiri said. “It’s going to get a bit complicated in RCC. That’s why our group and several others remain interested in targets and drugs outside the VEGF receptor and the PD-1/PD-L1 and CTLA-4 blockade.”


  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 3 CheckMate 9ER trial. Ann Oncol. 2020;31(suppl 4):S1159. doi:10.1016/j.annonc.2020.08.2257
  2. Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated January 22, 2021. Accessed January 29, 2021.
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