The combination of cabozantinib (Cabometyx), a second-generation tyrosine kinase inhibitor (TKI), plus nivolumab (Opdivo), an immune checkpoint inhibitor, significantly improved overall survival (OS) and doubled the objective response rates (ORR) compared with the current standard, sunitinib (Sutent), in treatment-naïve patients with advanced renal-cell carcinoma (RCC), according to the results of the phase 3 CheckMate-9ER clinical trial. The results were presented at the European Society for Medical Oncology (ESMO) virtual Congress 2020 and were featured at the meeting press conference.
With a median follow-up of 18.1 months, the median progression-free survival (PFS) was 16.6 months with nivolumab plus cabozantinib versus 8.3 months with sunitinib (P <.0001), representing a 49% reduction in the risk for disease progression or death. The combination had a manageable safety profile, with a low rate of treatment-related discontinuations.
“With expanding options for patients with advanced RCC, the overall efficacy, safety, and quality of life benefits, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” said lead investigator Toni K. Choueiri, MD, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School, Boston, MA.
“These results, we believe, support nivolumab and cabozantinib as a potential first-line option in patients with advanced renal-cell carcinoma,” Dr Choueiri added.
Based on these results, in August 2020, the manufacturer of cabozantinib submitted a supplemental new drug application to the FDA with this drug combination for advanced RCC. Both drugs are currently indicated, independently, for patients with RCC. In 2015, nivolumab was approved by the FDA for metastatic RCC, and in 2018 it received a new indication, in combination with ipilimumab (Yervoy), for first-line treatment of patients with intermediate- or poor-risk RCC; this combination has the longest follow-up of any other combination in this patient population. And in December 2017, cabozantinib was approved by the FDA for first-line treatment of patients with advanced RCC.
Several immune checkpoint inhibitor combinations are now being studied in patients with RCC, including axitinib (Inlyta) plus a tyrosine kinase inhibitor (TKI), and pembrolizumab (Keytruda) plus a TKI. Earlier trials found that nivolumab and cabozantinib had good activity, and that was the impetus for the phase 3 CheckMate-9ER trial.
The CheckMate-9ER study included 651 treatment-naïve patients with advanced RCC who were randomized in a 1:1 ratio to the combination of nivolumab plus cabozantinib versus sunitinib in the first-line setting or to sunitinib. To qualify for the study, patients must have had advanced or metastatic disease with a clear-cell component and must not have received previous therapy. Patients from all International Metastatic RCC Database Consortium (IMDC) risk scores were allowed in the study.
Patients in the combination arm received nivolumab at 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg daily. Patients in the sunitinib arm received oral sunitinib, given at 50 mg daily on a 4-weeks-on and 2-weeks-off cycle. The treatment was continued until disease progression or unacceptable toxicity.
The drug combination showed a PFS benefit across most subgroups, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.
The median OS was not reached in either arm, but a 40% reduction in the risk for death was observed with the combination (P = .0010) at this relatively early time point.
The ORR was doubled with nivolumab plus cabozantinib compared with sunitinib—55.7% versus 27.1%, respectively (P <.0001).
The incidence of the most common, any-grade and high-grade treatment-related adverse events was similar in the 2 treatment arms. More than 50% of patients who received the combination required dose reductions of cabozantinib because of adverse effects. Treatment-related adverse events led to treatment discontinuations in 15.3% of patients in the combination arm and in 8.8% of those receiving sunitinib. Specifically, 3.1% of patients discontinued nivolumab and cabozantinib because of adverse events, 5.6% discontinued only nivolumab, and 6.6% discontinued only cabozantinib.
The overall rate of serious adverse events was similar between the 2 groups; however, liver toxicity was more common with the cabozantinib and nivolumab combination. In addition, 19% of patients who received the combination required corticosteroids because of immune-related adverse events, and 4% needed corticosteroids for at least 30 days.
“Overall, it seems that the combination has a manageable safety profile in patients with advanced RCC,” said Dr Choueiri.
The combination also improved health-related quality of life compared with sunitinib. Quality of life was maintained over time with nivolumab plus cabozantinib, whereas patients who were randomized to sunitinib had a deterioration in quality of life over time, as measured by the Functional Assessment for Cancer Therapy-Kidney Symptom Index 19 total score. The between-arm differences were significant at nearly all time points; the disease-related symptoms also improved with nivolumab plus cabozantinib.
Dominik Berthold, MD, Head, Specialised Consultation for Urological Cancers Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Switzerland, commented on the CheckMate-9ER study, calling these results “pretty impressive,” but he noted that other combinations of checkpoint inhibitor and TKI are already being used for advanced RCC. “We also have the combination of ipilimumab and nivolumab with high response rates, and now, longer follow-up data,” Dr Berthold said.
“Nivolumab and cabozantinib is certainly an option for these patients. What we still need to learn is, are there any patient populations who may benefit more from this combination than the other combinations? Cabozantinib is quite a unique TKI, which may better target bone metastases, for example. We will learn more with longer follow-up,” Dr Berthold suggested.