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Advanced or metastatic kidney cancer patients treated with the PD-1 checkpoint inhibitor nivolumab (Opdivo) plus cabozantinib (Cabometyx) lived twice as long without disease progression compared to patients receiving an older standard, a phase III study found.

For the primary endpoint in , median progression-free survival (PFS) in patients with previously untreated renal cell carcinoma (RCC) improved from 8.3 months with sunitinib (Sutent) to 16.6 months with nivolumab-cabozantinib (HR 0.51, P<0.0001), reported Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston.

With a follow-up of 18.1 months, the median overall survival (OS) had not been reached for either study arm, but was significantly improved with the combination (HR 0.60, P=0.001).

"The combination was generally well-tolerated with low rates of treatment-related discontinuation, with patients on the combination of cabozantinib and nivolumab having significantly better quality of life," Choueiri said during a press briefing ahead of the 2020 European Society for Medical Oncology (ESMO) virtual congress.

"These results, we believe, support nivolumab plus cabozantinib as a potential first-line option in patients with advanced renal cell carcinoma," he added.

Patients on the combination were twice as likely to respond, with an objective response rate of 55.7% versus 27.1% with sunitinib, including complete responses (CRs) in 8.0% vs 4.6%.

The 8.0% CR rate with nivolumab-cabozantinib is higher than previously reported CR rates with other approved immunotherapy plus tyrosine kinase inhibitor (TKI) combinations in advanced RCC -- pembrolizumab (Keytruda) plus axitinib (Inlyta), or avelumab (Bavencio) plus axitinib -- though still below the 10.5% CR rate established by nivolumab plus ipilimumab (Yervoy) in CheckMate-214, another first-line option for patients with intermediate- and poor-risk disease.

"The question is, 'What is the only drawback of this trial?'" said ESMO-invited discussant Dominik Berthold, MD, of Lausanne University Hospital in Switzerland. "Well I guess it's the fact that it's not first in class in this situation."

Nivolumab plus cabozantinib certainly appears to be a new option for the first-line treatment of advanced RCC, said Berthold.

"What we still need to learn here is, are there any patient populations who may benefit more from this combination than the other combinations?" he added, noting that long-term follow-up will be key. "Cabozantinib is quite a unique TKI, which may target bone metastases for example."

The CheckMate 9ER trial randomized 651 patients with previously untreated advanced or metastatic clear cell RCC 1:1 to either intravenous nivolumab (240 mg every other week) plus oral cabozantinib (40 mg daily) or standard oral sunitinib (50 mg daily, 4 weeks on followed by 2 weeks off). Patients were treated until disease progression or unacceptable toxicity. The trial allowed for any International Metastatic RCC Database Consortium (IMDC) risk group, and about 75% were intermediate- or high-risk, while about 25% were poor-risk.

Choueiri reported consistent benefit with the combination across subgroups, including IMDC risk groups, PD-L1 expression, presence of bone metastases, as well as age, sex, and region of the world.

In patients on nivolumab-cabozantinib, treatment-related adverse events (AEs) led to discontinuation of one or both therapies in 15.3% (3.1% both, 5.6% nivolumab only, and 6.6% cabozantinib only) versus 8.8% of those on sunitinib. In the combination arm, more than 50% of patients required a dose reduction of cabozantinib due to AEs.

"Overall it seems that the combination has a somewhat manageable safety profile in patients with advanced RCC," said Choueiri.

Frequency of common treatment-related AEs of any grade were similar between the two arms. Grade 3/4 treatment-related AEs with the combination versus sunitinib, respectively, included hypertension (11% vs 12%), hand-foot syndrome (8% for each), diarrhea (6% vs 4%), fatigue (3% vs 4%), stomatitis (2% each), mucosal inflammation (<1% vs 3%), and increased levels of aspartate transaminase (3% vs <1%) and alanine aminotransferase (5% vs <1%).

The study also looked at health-related quality of life, and found that patients on the combination maintained scores from baseline on the Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (FKSI-19) total score at all time points (through 91 weeks), while those on sunitinib experienced deterioration from baseline. Between-arm differences were significantly improved with the combination at nearly all time points. Improvements in FKSI disease-related symptoms improved with the combination, while with sunitinib, patients saw worsening symptoms.

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