The addition of a second immunotherapy, ipilimumab (Yervoy), to the combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) produced durable responses and longer progression-free survival (PFS) than cabozantinib plus nivolumab alone in patients with advanced hepatocellular carcinoma (HCC), the most common type of liver cancer. The overall survival (OS) was not yet reached in the triplet arm.
However, as can be expected, the triplet regimen with 2 immunotherapies was associated with a higher rate of treatment-emergent adverse events in the CheckMate-040 study, reported Thomas Yau, MD, MBBS, MRCP, Associate Professor, Department of Medicine, University of Hong Kong, China, at the 2020 Gastrointestinal Cancers Symposium.
With a median follow-up of approximately 19 months in each, the median PFS was 5.4 months in the doublet arm versus 6.8 months in the triplet arm. The median OS was 21.5 months with the 2-drug combination and was not reached with the 3-drug combination.
In the CheckMate-040 clinical trial, patients with advanced HCC who had not received sorafenib (Nexavar) therapy or those who had received sorafenib treatment (and had disease progression or did not tolerate sorafenib) were randomized to cabozantinib 40 mg daily plus nivolumab 240 mg every 2 weeks, or to cabozantinib 40 mg daily plus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 6 weeks. Treatment continued until disease progression or intolerable adverse events.
In all, 38.9% of the patients in the doublet arm and 42.9% of the patients in the triplet arm had vascular invasion; 47.2% and 65.7% of the patients, respectively, had extrahepatic spread; and 77.8% who were randomized to the doublet and 85.7% who were randomized to the triplet arm had Barcelona Clinic Liver Cancer stage C disease. Previous exposure to sorafenib was documented in more than half of the patients in each arm (53% in the doublet and 66% in the triplet arm).
The median duration of therapy was 7.1 months in the doublet arm and 7.8 months in the triplet arm, and 19% and 29%, respectively, continue to receive treatment. Disease progression was the reason for treatment discontinuation in 64% and 46% of patients, respectively.
The overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1, the primary efficacy end point, was higher in the triplet arm compared with the doublet (29% vs 19%, respectively). By investigator assessment, the best ORR was a partial response in 7 (19%) patients in the doublet arm and 10 (29%) in the triple arm. In addition, 20 patients in the doublet arm had stable disease, for a disease control rate of 75%, compared with 19 (54%) patients with stable disease in the triplet arm, for a disease control rate of 83%.
The median duration of response was 8.3 months, and the median time to response was 4.8 months with the doublet; the median duration of response was not reached with the triplet and the median time to response was 3.5 months.
Risk versus Benefit
Grade 3 or 4 treatment-emergent adverse events was 71% in the triplet arm versus 47% in the nivolumab plus cabozantinib arm and led to treatment discontinuation in 20% and 11% of patients, respectively.
“Investigation with longer duration of follow-up may be necessary to better assess the true benefit–risk ratio of both the doublet and triple combination in patients with advanced HCC,” Dr Yau emphasized.
No new safety signals were observed in either arm. The rate of treatment discontinuation because of immune-related adverse events was 11% in the triplet arm and in 6% in the doublet arm, said Dr Yau.