COSMIC-313: Adding cabozantinib to nivo-ipi may improve PFS in advanced RCC

The combination of nivolumab, ipilimumab, and cabozantinib improved progression-free survival (PFS) in patients with previously untreated, advanced renal cell carcinoma (RCC) of intermediate or poor risk as per IMDC* criteria, results of the phase III COSMIC-313 trial showed.

“This was the first study to use an immuno-oncology doublet standard of care as the control,” presented study author Professor Toni Choueiri from the Dana–Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, US, at ESMO 2022.

“There was a 27 percent decrease in the risk of progression or death favouring the triplet [vs doublet combination],” he said.

Participants were 855 patients with advanced clear-cell RCC, IMDC intermediate or poor risk, and Karnofsky Performance Status ≥70 percent with no prior receipt of systemic therapy. They were randomized 1:1 to receive oral cabozantinib (40 mg QD; median age 61 years, 76 percent male) or placebo (median age 60 years, 73 percent male), in addition to four cycles of intravenous nivolumab (3 mg/kg Q3W) and ipilimumab (1 mg/kg Q3W). This was followed by cabozantinib (40 mg QD) + nivolumab** (480 mg Q4W) among patients in the triplet group and placebo + nivolumab** (480 mg Q4W) in the doublet group.

Seventy-five percent of patients were categorized as intermediate IMDC risk and 65 percent had previously undergone nephrectomy.

After a median 20.2-months follow-up***, PFS was significantly improved with the triplet vs doublet regimen (median not reached vs 11.3 months; hazard ratio [HR], 0.73, 95 percent confidence interval [CI], 0.57–0.94; p=0.013), with 12-month PFS rates of 57 percent vs 49 percent. [ESMO 2022, abstract LBA8]

The results were consistent across subgroups assessed.

Objective response rate (ORR) was 43 and 36 percent in the triplet and doublet groups, respectively. Three percent of each group (n=7 and 9, respectively) achieved complete response, 41 and 32 percent, respectively, achieved partial response, and 43 and 36 percent, respectively, had stable disease. Eight and 20 percent, respectively, experienced progressive disease. Disease control rate was 86 percent vs 72 percent. Time to objective response was comparable between groups (median 2.4 vs 2.3 months), while duration of response was not reached in either group.

The PFS and ORR benefits appeared specific to those of IMDC intermediate risk and not poor risk. In the intermediate risk group, PFS was not reached with the triplet and a median 11.4 months with the doublet regimen (HR, 0.63, 95 percent CI, 0.47–0.85), while the corresponding values were 9.5 vs 11.2 months in the poor risk group (HR, 1.04, 95 percent CI, 0.65–1.69). Similarly, the ORR benefit with the triplet vs doublet regimen was seen in those with intermediate risk (45 percent vs 35 percent) but was similar between groups in those with poor risk (37 percent vs 38 percent).

Grade 3–4 treatment-related adverse events (TRAEs) occurred in more triplet than doublet recipients (73 percent vs 41 percent). Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were the most common grade 3–4 TRAEs in the triplet group (26 and 20 percent, respectively), while elevated ALT, AST, and lipase levels were the most common in the doublet group (6, 5, and 6 percent, respectively). AE-related dose reduction of cabozantinib or placebo occurred more frequently in the triplet than doublet group (54 percent vs 20 percent), as did discontinuation of any treatment due to TEAEs (45 percent vs 24 percent).

At 100 days after the last dose, grade 5 TRAEs were documented in five patients in the triplet and four in the doublet group. More patients in the triplet than doublet group required high-dose corticosteroids for AEs (58 percent vs 35 percent).

“The safety profile of [the triplet regimen] was generally manageable and consistent with the profiles of the treatment components,” noted Choueiri. Overall survival (OS) is immature at present, with follow-up ongoing.

The results are potentially practice changing and this combination could be an additional treatment option in this population, though it is too early to tell, he concluded.

“If the study meets the prespecified OS endpoint, we will see the triplet regimen utilized in a broader array of patients. However, we will need to attend to toxicity and quality of life,” pointed out discussant Professor Sumanta Pal from the City of Hope Comprehensive Cancer Center, Los Angeles, California, US. [https://ascopost.com/issues/october-25-2022/cosmic-313-triplet-therapy-is-active-in-renal-cell-carcinoma-but-toxicities-pose-a-challenge/]

“[Even] if the study doesn’t meet the primary endpoint, I am optimistic we can identify a subset that benefits from this triplet therapy,” said Pal.