First-line cabozantinib-atezolizumab boosts PFS in advanced HCC

The combination of cabozantinib and atezolizumab in the first-line setting significantly improved progression-free survival (PFS) compared with sorafenib in patients with advanced hepatocellular carcinoma (HCC), according to results of the phase III COSMIC-312 trial presented at ESMO Asia 2021.

Participants in this global, open-label trial were 837 patients (median age 64 years) with advanced HCC (BCLC* stage B or C) who were not amenable to curative treatment or locoregional therapy, and had Child-Pugh class A, ECOG performance status ≤1, and no prior exposure to systemic therapy for HCC. They were randomized 2:1:1 to receive oral cabozantinib (40 mg QD) plus intravenous atezolizumab (1,200 mg Q3W; n=432), oral sorafenib (400 mg BID; n=217), or oral cabozantinib (60 mg QD; n=188) until loss of clinical benefit or intolerable toxicity.

The intention-to-treat (ITT) population comprised all randomized patients while the prespecified ITT population comprised the first 372 patients assigned to cabozantinib plus atezolizumab or sorafenib. These two groups were followed for a median 13.3 and 15.8 months, respectively.

In terms of HCC aetiology, 30 percent of patients had hepatitis B (HBV), 31 percent hepatitis C without HBV, and 39 percent non-viral aetiology. Extrahepatic disease and/or macrovascular invasion was present in 69 percent.

In the prespecified ITT population, PFS, as per blinded independent review committee, was significantly improved with cabozantinib plus atezolizumab compared with sorafenib (median 6.8 vs 4.2 months; hazard ratio [HR], 0.63, 99 percent confidence interval [CI], 0.44–0.91; p=0.0012). [ESMO Asia 2021, abstract VP10-2021]

After a median 13.6 months follow-up, interim overall survival in the ITT population was not significantly different between patients assigned to cabozantinib plus atezolizumab and sorafenib (median 15.4 vs 15.5 months; HR, 0.90, 96 percent CI, 0.69–1.18; p=0.438), though follow-up for this outcome is ongoing.

At a median 13.1 months follow-up, interim analysis of cabozantinib vs sorafenib in the ITT population showed that median PFS was 5.8 vs 4.3 months (HR, 0.71, 99 percent CI, 0.51–1.01; p=0.0107), with follow-up ongoing.

Objective response rate was 11, 3.7, and 6.4 percent in patients in the cabozantinib plus atezolizumab, sorafenib, and cabozantinib groups, respectively, with a median time to objective response of 4.0, 3.5, and 4.2 months, respectively. Duration of response was a median 10.6, 8.8, and 15.1 months, respectively, and disease control rate 78, 65, and 84 percent, respectively.

Patients in the cabozantinib plus atezolizumab and sorafenib groups were exposed to their respective treatments for a median 7.6 and 4.2 months, respectively. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 53.8 and 31.9 percent, respectively, and grade 5 TRAEs in 1.9 and 0.5 percent. Sixty, 44, and 67 percent of cabozantinib plus atezolizumab, sorafenib, and cabozantinib recipients, respectively, required dose reductions of cabozantinib or sorafenib due to AEs. TRAEs led to discontinuation of cabozantinib and atezolizumab in 6.1 percent, cabozantinib and/or atezolizumab in 14 percent, and sorafenib in 7.7 percent. Twenty, 37, and 29 percent of cabozantinib plus atezolizumab, sorafenib, and cabozantinib recipients, respectively, received subsequent systemic anticancer therapies.

The most common grade ≥3 AEs with cabozantinib plus atezolizumab vs sorafenib were palmar-plantar erythrodysesthesia (7.9 percent vs 8.2 percent), hypertension (7.0 percent vs 6.3 percent), and increased aspartate aminotransferase (6.5 percent vs 2.4 percent) and alanine aminotransferase levels (6.3 percent vs 1.9 percent). Grade ≥3 haemorrhage occurred in 2.8 and 4.8 percent of cabozantinib plus atezolizumab and sorafenib recipients, respectively, while immune-mediated grade ≥3 AEs that warranted use of systemic steroids occurred in 4.4 and 0.5 percent, respectively.

“AEs associated with cabozantinib plus atezolizumab were manageable, and the safety profile of the combination was consistent with that of each agent,” noted the authors.

“Cabozantinib plus atezolizumab showed statistically significant and clinically meaningful improvement of PFS vs sorafenib in patients with advanced HCC not previously treated with systemic therapy,” said Dr Robin Kate Kelley from the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California, US, and co-authors.

“The combination of cabozantinib plus atezolizumab may be a new option for first-line systemic treatment of patients with advanced HCC,” she said.