First-line nivolumab-cabozantinib improves PFS, OS, ORR in advanced clear cell RCC

The combination of nivolumab and cabozantinib in the first-line setting conferred greater survival outcomes and responses compared with sunitinib in patients with clear cell advanced renal cell carcinoma (RCC), results of the phase III CheckMate 9ER trial showed.

“The results with combination therapy were statistically significant and clinically meaningful. The risk of progression or death was cut by almost 50 percent, death was cut by 40 percent, and the response rate doubled,” said study author Professor Toni Choueiri from the Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, US.

Patients with previously untreated advanced or metastatic clear cell RCC (n=651) were randomized 1:1 to receive intravenous nivolumab (240 mg Q2W) plus oral cabozantinib (40 mg QD; median age 62 years, 77 percent male) or oral sunitinib (50 mg QD on 4-week-on, 2-week-off cycles; median age 61 years, 71 percent male). Of these, 22.6, 57.6, and 19.7 percent had favourable, intermediate, and poor risk score*, respectively, and 24.9 percent had PD-L1 expression ≥1 percent. Patients were followed up for a median 18.1 months.

Progression-free survival was significantly improved with nivolumab-cabozantinib compared with sunitinib (median 16.6 vs 8.3 months; hazard ratio [HR], 0.51, 95 percent confidence interval [CI], 0.41–0.64; p<0.0001). [ESMO 2020, abstract 696O_PR]

Overall survival improved by 40 percent with nivolumab-cabozantinib vs sunitinib (median not reached in either group; HR, 0.60, 98.89 percent CI, 0.40–0.89; p=0.0010).

Objective response rate (ORR) was greater with nivolumab-cabozantinib vs sunitinib (55.7 percent vs 27.1 percent; p<0.0001). More patients on nivolumab-cabozantinib than sunitinib achieved complete response (8.0 percent vs 4.6 percent) and partial response (PR; 47.7 percent vs 22.6 percent). Among patients with PR or better, response duration was longer with nivolumab-cabozantinib than sunitinib (median 20.2 vs 11.5 months), with shorter time to response (median 2.8 vs 4.2 months).

The findings were consistent across multiple subgroups including presence of bone metastases, IMDC risk, and PD-L1 expression.

Nivolumab-cabozantinib and sunitinib recipients were treated for a median 14.3 and 9.2 months, respectively, with 56.3 and 51.6 percent, respectively, requiring at least one dose reduction of either cabozantinib or sunitinib. Treatment discontinuation occurred in 44.4 and 71.3 percent of nivolumab-cabozantinib and sunitinib recipients, respectively, 27.8 and 48.1 percent due to disease progression, and 15.3 and 8.8 percent due to adverse events (AEs). Among nivolumab-cabozantinib recipients, AEs led 5.6 percent to discontinue nivolumab only, 6.6 percent cabozantinib only, and 3.1 percent both. Receipt of subsequent therapy following discontinuation was similar between groups.

Any-grade treatment-related AEs were comparable in nivolumab-cabozantinib and sunitinib recipients (97 percent vs 93 percent), with 61 and 51 percent, respectively, experiencing grade ≥3 AEs. AST and ALT elevations were more common in the nivolumab-cabozantinib than sunitinib group. Most immune-related AEs were low grade and warranted corticosteroid treatment in 19 percent of patients. One treatment-related death occurred in the nivolumab-cabozantinib group and two in the sunitinib group.

“Quality of life was maintained over time with nivolumab-cabozantinib compared with the consistent deterioration from baseline with sunitinib as measured by FKSI-19** total score,” Choueiri pointed out.

Choosing the right option

“These results support nivolumab-cabozantinib as a potential first-line option for patients with aRCC,” noted Choueiri.

Despite the positive findings, questions remain on the better choice of combination therapy, two immunotherapies or immunotherapy plus an anti-angiogenic drug. This could also influence second-line therapy, commented Dr Dominik Berthold from Lausanne University Hospital, Lausanne, Switzerland, who was not affiliated with the study. 

“If you start with a combination of immune therapy only, it becomes an automatic choice to use an anti-angiogenic drug in the second line. But if you begin with a combination of two mechanisms of action, such as immune therapy and an anti-angiogenic drug, then the second-line choice is less clear. More data are needed on the most suitable order of therapy,” he highlighted.

Long-term durability of response and efficacy of the combination in non-clear cell RCC are yet unknown, said Berthold.

“Presently, the only possible, though highly empiric, driver of our therapeutical choice should be the biological aggressiveness of the tumour,” suggested discussant Professor Camillo Porta from the University of Pavia, Italy.