Cabozantinib/Atezolizumab Combo Shows No Survival Benefit in Advanced HCC

Cabozantinib plus atezolizumab did not outperform sorafenib in improving overall survival in advanced hepatocellular carcinoma.

A final analysis of phase 3 COSMIC-312 trial revealed that cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) did not improve or decrease overall survival (OS) outcomes vs sorafenib (Nexavar) in patients with previously untreated advanced hepatocellular carcinoma (HCC), according to a press release. In light of these findings, and despite promising previously reported progression-free survival rates, the manufacturers no longer intend to submit a supplemental new drug application to the FDA for this indication.1

“Exelixis has a longstanding commitment to patients with liver cancer, exemplified by the 2019 approval of [cabozantinib] for previously treated advanced liver cancer, and we remain steadfast in our journey to further therapies for this and other difficult-to-treat cancers,” said Vicki L. Goodman, MD, executive vice president of product development and medical affairs, and chief medical officer at Exelixis. “We are grateful to the investigators and patients who participated in the COSMIC-312 trial and contributed greatly to this research.”

The COSMIC-312 trial was a global, multicenter, randomized, phase 3 study designed to evaluate the safety and efficacy of cabozantinib plus atezolizumab against sorafenib in previously untreated adult patients with advanced HCC.2

The trial evaluated the outcomes of 840 patients. Eligible participants include those with histological or cytological HCC diagnoses, whose disease were not amenable to a curative approach, and with measurable disease per RECIST v1.1 criteria, Barcelona Clinic Liver Cancer stage category B or C disease, and an ECOG performance status of 0 to 1.

Patients with fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma, or who had received previous systemic anticancer previously or had undergone radiation, whether for bone metastasis or another reason, within 8 weeks of randomization, were not eligible to participate. Furthermore, patients with known brain metastases or cranial epidural diseases, or who were receiving concomitant anticoagulation with oral anticoagulants, were also not eligible to enroll.

The study randomized patients 2:1:1 into 1 of 3 arms: cabozantinib at a daily dose of 40 mg plus atezolizumab at 1200 mg every 3 weeks; sorafenib alone at a twice-daily dose of 400 mg; or cabozantinib monotherapy at a daily dose of 60 mg.

The main objectives of the study were to evaluate PFS and OS in the experimental arm vs the control arm. Secondary objectives included evaluating the PFS in the single-agent arm vs the control arm.

The co-primary end points of the trial were PFS and OS in the experimental arm vs the control arm. The secondary end point focused on PFS in the single-agent arm vs the control arm.

Cabozantinib tablets are currently approved to treat patients with renal cell carcinoma (RCC) both as a frontline treatment in combination with nivolumab (Opdivo) and for those with advanced RCC. It is also approved as a treatment for patients with HCC who previously received sorafenib. Lastly, cabozantinib is approved for patients 12 years of older with locally advanced or metastatic differentiated thyroid cancer and who have already received VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

The most common adverse events (AEs) associated with cabozantinib as a monotherapy include diarrhea, fatigue, palmar-plantar erythrodysesthesia (PPE), decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation. These AEs are reported in more than 20% of patients who receive cabozantinib. Patients who report PPE need to hold treatment until condition improves to a grade 1; approximately 45% of patients who receive this agent experience this AE. If conditions improve, they may then resume treatment at a reduced dose.

Cabozantinib plus nivolumab is associated with the following AEs: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

If a patient receives cabozantinib in addition with a strong CYP3A4 inhibitor, cabozantinib dosage should be reduced and the patient should avoid grapefruits or grapefruit juice.If a patient receives cabozantinib in addition with a strong CYP3A4 inducer, cabozantinib dosage should be reduced and the patient should avoid St. John’s Wort.


  1. Exelixis announces final overall survival results from phase 3 COSMIC-312 trial of cabozantinib in combination with an immune checkpoint inhibitor in patients with previously untreated advanced liver cancer. Exelis. News release. March 14, 2022. Accessed March 15, 2022.
  2. Study of cabozantinib in combination with atezolizumab versus sorafenib in subjects with advanced HCC who have not received previous anticancer therapy (COSMIC-312). Updated June 4, 2021. Accessed March 15, 2022.