Cabozantinib Plus Atezolizumab Extends PFS for Frontline HCC in COSMIC-312 Trial

The combination of cabozantinib plus atezolizumab resulted in improved progression-free survival in patients with hepatocellular carcinoma whose disease has not previously been treated vs sorafenib monotherapy.

Patients with treatment-naïve hepatocellular carcinoma (HCC) who were treated with cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) experienced a statistically significant progression-free survival (PFS) benefit vs those treated with sorafenib (Nexavar) in the phase 3 COSMIC-312 trial (NCT03755791), according to the company responsible for the small molecule inhibitor, Exelixis, Inc.1

These results indicate that the trial met 1 of its dual primary end points at the preplanned primary analysis. Overall survival (OS), the other primary outcome measure, was also assessed, with data indicating a trend toward cabozantinib/atezolizumab superiority, although the association was not statistically significant.

“While we are encouraged by the data supporting the potential for the combination of cabozantinib and atezolizumab to reduce the risk of disease progression or death, we are disappointed by the interim result of lack of significant improvement on [OS vs] the comparator arm,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, said in a press release. “As these data continue to mature, we are working to understand the potential impact of various contributing factors on the results, including patient demographics, subsequent anti-cancer therapy and the impact of COVID-19 on the trial. We anticipate presenting the results at a future medical conference.”

In the intention to treat population, the risk of disease progress or death was reduced by 37% with the use of cabozantinib plus atezolizumab vs standard-of-care sorafenib (HR, 0.63; 99% CI, 0.44-0.91; P = .0012).

Of note, no new safety signals were reported with any of the drugs and the toxicity profiles appeared to be consistent with the known profiles of each individual agent.

The trial will continue as planned and the OS final analysis is expected in early 2022. Given the known data, the investigators anticipate that the likelihood of a statistically significant OS benefit with the experimental regimen is low.

The multicenter, randomized, open-label controlled trial is currently ongoing with a recruitment goal of 740 patients. Patients with previously untreated histologically or cytologically confirmed HCC or those with cirrhosis who have a clinical diagnosis by CT or MRI per American Association for the Study of Liver Diseases 2018 or European Association for the Study of Liver 2018 criteria were randomized in a 2:1:1 fashion to cabozantinib/atezolizumab, cabozantinib alone, or sorafenib.

Treatment with the combination includes oral cabozantinib at 40 mg daily plus intravenous atezolizumab at 1200 mg every 3 weeks. Single-agent cabozantinib is administered at 60 mg daily. Patients in the control arm will receive oral sorafenib at 200 mg twice daily.

Patients must have disease that cannot be treated with curative treatment or locoregional therapy, such as surgery or transarterial chemoembolization, respectively. Tumors must be measurable per RECIST 1.1 criteria, have a Barcelona Clinic Liver Cancer stage category B or C, and have a Child-Pugh Score of A.

Patients with known fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma; who underwent prior systemic therapy for HCC, radiation therapy for bone metastases within 2 weeks and any radiation within 8 weeks or randomization; had known brain or cranial epidural disease unless adequately controlled; and were receiving concomitant oral anticoagulants are not eligible for treatment on the trial.

Cabozantinib’s mechanism of action involves inhibition of MET, VEGFR, and TAM kinases.2 The agent is currently approved by the FDA to treat HCC as of December 2017 following treatment with sorafenib in the frontline setting but is not currently indicated for frontline disease.3


  1. Exelixis and Ipsen announce cabozantinib in combination with an immune checkpoint inhibitor significantly improved progression-free survival in phase 3 COSMIC-312 pivotal trial in patients with previously untreated advanced liver cancer. News release. Exelixis, Inc. June 28, 2021. Accessed June 28, 2021.
  2. Rimassa L, Cheng A, Braiteh F, et al. Phase 3 (COSMIC-312) study of cabozantinib in combination with atezolizumab vs sorafenib in patients with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy. Ann Oncol. 2019;30(suppl 4):IV65-IV66. doi:10.1093/annonc/mdz155.237
  3. FDA grants regular approval to Cabometyx for first-line treatment of advanced renal cell carcinoma. News release. FDA. December 19, 2017. Accessed June 28, 2021.