Cabozantinib Approved in Japan for Advanced Hepatocellular Carcinoma

The Japanese Ministry of Health, Labor, and Welfare has approved cabozantinib for the treatment of patients with unresectable hepatocellular carcinoma that has progressed on prior systemic therapy.

The Japanese Ministry of Health, Labor, and Welfare has approved cabozantinib (Cabometyx) for the treatment of patients with unresectable hepatocellular carcinoma (HCC) that has progressed on prior systemic therapy.1

The approval is based on results of the phase 3 CELESTIAL (XL184-139) and the phase 2 Japanese Cabozantinib-2003 (NCT03586973) trials. In CELESTIAL, the median overall survival (OS) with cabozantinib was 10.2 months vs 8.0 months with placebo, representing a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92; P = .0049).2,3

“Hepatocellular carcinoma causes approximately 30,000 deaths in Japan each year and is a leading cause of cancer-related death worldwide,” said Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, which partners in the development of cabozantinib with Takeda Pharmaceutical Company Limited. “The approval of Cabometyx in Japan is an exciting next step toward bringing this treatment to liver cancer patients who otherwise have limited treatment options following prior systemic therapy. We’re proud to collaborate with Takeda as we work to bring this treatment to patients in Japan.”

In January 2019, the FDA approved cabozantinib as a treatment for patients with HCC who received prior sorafenib (Nexavar), also based on the CELESTIAL trial findings.

In the trial, 707 patients were randomized to receive cabozantinib at 60 mg daily (n = 470) or placebo (n = 237). All patients had an ECOG performance status of 0 or 1, a Child-Pugh score of A, and had progressed on at least 1 prior systemic therapy for advanced HCC, with 70% having received only prior sorafenib.

Baseline characteristics were balanced between arms. The median age was 64 years and 82% of patients were male. The baseline etiologies included hepatitis B virus infection (38%) and hepatitis C virus infection (24%). Over three-fourths of patients had extrahepatic spread (78%) and 30% had macrovascular invasion, with 27% of patients having both. Twenty-five percent of patients were enrolled in Asia and 27% had received 2 prior systemic therapies.

The median progression-free survival (PFS) was 5.2 months vs 1.9 months for placebo (HR, 0.44, 95% CI, 0.36-0.52; P <.0001). The objective response rate (ORR) was 4% with cabozantinib compared with 0.4% with placebo (P = .0086). The disease control rate with the multikinase inhibitor was 64% compared with 33% for placebo when those with stable disease were included.

In a subgroup analysis of those who received only prior sorafenib for advanced HCC, the median OS was 11.3 months with cabozantinib compared with 7.2 months for placebo (HR, 0.70; 95% CI, 0.55-0.88). The median PFS in this group was 5.5 months with cabozantinib versus 1.9 months with placebo (HR, 0.40; 95% CI, 0.32-0.50).

Regarding safety, more patients discontinued therapy due to treatment-related adverse events (AEs) with cabozantinib (16%) versus placebo (3%). The most common grade 3/4 AEs with cabozantinib versus placebo were palmar-plantar erythrodysesthesia (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%).

There was a higher incidence of grade 5 AEs in the cabozantinib arm compared with placebo. Overall, 6 patients had a grade 5 AE in the cabozantinib arm, which included hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism, and hepatorenal syndrome. One patient in the placebo group died of hepatic failure.

In the 2-cohort, multicenter, phase 2 Cabozantinib-2003 trial, investigators evaluated the efficacy and safety of cabozantinib in approximately 32 Japanese patients with advanced HCC who received prior systemic therapy. Cohort A included patients who received prior sorafenib (n = 17) while cohort B included those who did not previously receive the TKI (n = 15). Cabozantinib was administered at 60 mg daily.

To be eligible for enrollment, patients must have been at least 20 years old, had investigator-assessed measurable disease as per RECIST v1.1 criteria, had disease that was not amenable to curative treatment approaches, received 1 or 2 prior anti-cancer therapies, had radiographic progression following systemic anticancer therapy, had an ECOG performance status of 0 or 1, a Child-Pugh Score of A, adequate organ and marrow function at screening, and antiviral therapy per local standard of care if they had actives hepatitis B virus infection.

Those with fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma, had anti-cancer therapy within 14 days before the first day of study drug treatment, had radiation therapy within 28 days, received prior cabozantinib, received prior treatment within 28 days with any investigational treatment, had known brain metastases or cranial epidural disease, and concomitant anticoagulation could not enroll on the study.

The primary endpoint was 24-week PFS rate; secondary endpoints include PFS, ORR, DCR, and OS.

Exelixis is eligible to receive a $15 million milestone payment from Takeda upon the first commercial sale of cabozantinib for unresectable HCC, which is expected to occur in the fourth quarter of 2020, as per the terms of Exelixis and Takeda’s collaboration and license agreement.


  1. Exelixis announces partner Takeda receives approval in Japan for Cabometyx (cabozantinib) for the treatment of unresectable hepatocellular carcinoma that has progressed after prior systemic therapy. News release. Exelixis, Inc. November 27, 2020. Accessed November 30, 2020.
  2. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2018;36 (suppl 4S; abstr 208). doidoi:10.1200/JCO.2018.36.4_suppl.207
  3. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Eng J Med. 2019;379(1):54-63. doi: 10.1056/NEJMoa1717002