Japanese Approval Sought for Cabozantinib in Advanced HCC

A new drug application has been filed with the Japanese Ministry of Health, Labor and Welfare for manufacturing and marketing approval of cabozantinib for the treatment of patients with unresectable hepatocellular carcinoma following progression on prior systemic therapy.

Michael M. Morrissey, PhD

A new drug application has been filed with the Japanese Ministry of Health, Labor and Welfare (MHLW) for manufacturing and marketing approval of cabozantinib (Cabometyx) for the treatment of patients with unresectable hepatocellular carcinoma (HCC) following progression on prior systemic therapy.1

The application is based on the results of the phase III CELESTIAL and phase II Japanese Cabozantinib-2003 trials (NCT03586973). In CELESTIAL, data showed that cabozantinib led to a 24% reduction in the risk of death compared with placebo in patients with previously treated advanced HCC (HR, 0.76; 95% CI, 0.63-0.92; P = .005).2 The median overall survival (OS) with cabozantinib was 10.2 months versus 8.0 months for placebo.

“We are excited about the progress our partner Takeda has made on advancing cabozantinib toward regulatory approval in Japan for patients with advanced liver cancer,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, which has a collaboration and license agreement with Takeda on cabozantinib, stated in a press release. “This regulatory filing is an important milestone for patients in Japan who currently have limited treatment options after they have progressed following systemic therapy. We look forward to our continued collaboration as Takeda works to bring cabozantinib to patients in need of new therapies.”

In the CELESTIAL trial, 707 patients were randomized 2:1 to receive cabozantinib at 60 mg once 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 ≥1 prior systemic therapy for advanced HCC, with 70% having received only prior sorafenib (Nexavar).

Baseline characteristics were balanced between the arms. The median age was 64 years old and 83% were male. The baseline etiologies included hepatitis B virus infection (38%) and hepatitis C virus infection (23.5%). Over three-fourths of patients had extrahepatic spread (78%) and 30.5% had macrovascular invasion. A quarter of patients were enrolled in Asia (25%) and 27% had received 2 prior systemic therapies.

The median, investigator-assessed PFS was 5.2 months compared with 1.9 months for placebo, which demonstrated a 56% reduction in the risk of progression or death with cabozantinib (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). When including those with stable disease, the disease control rate (DCR) with the multikinase inhibitor was 64% compared with 33% for placebo.

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).

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, bronchoesophageal 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 II 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 ≥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.

As a result of this latest application submission, per the terms of Exelixis and Takeda’s collaboration and license agreement with cabozantinib, Exelixis is eligible to receive a $10 million milestone payment from Takeda, which is anticipated to be received in the first quarter of 2020.

In April 2019, Takeda applied for approval to manufacture and sell cabozantinib as a treatment for patients with unresectable and metastatic renal cell carcinoma (RCC) in Japan. Following the HCC regulatory filing, Exelixis will be eligible to receive further development, regulatory, and first-sale milestone payments of up to $76 million from Takeda related both to patients with previously treated and previously untreated RCC, and also those with previously treated HCC. Exelixis is eligible to receive additional development, regulatory, and first-sale milestones for potential future cabozantinib indications, and is also eligible for sales revenue milestones and royalties on net sales of cabozantinib in Japan, Exelixis stated in the press release.

Takeda fully funds cabozantinib development activities that are exclusively for the benefit of Japan and is responsible for 20% of associated costs with international cabozantinib clinical trials, allowing the company to opt into those trials.

In the United States, cabozantinib is currently approved for the treatment of patients with HCC who have been previously treated with sorafenib. The agent is also indicated for the treatment of patients with medullary thyroid cancer, advanced RCC following 1 prior antiangiogenic therapy, and for the first-line treatment of patients with advanced RCC.


  1. Exelixis announces partner Takeda files new drug application in Japan for Cabometyx (cabozantinib) for advanced hepatocellular carcinoma [news release]: Alameda, CA. Exelixis. Published January 29, 2020. https://bit.ly/2S3a7W1. Accessed January 29, 2020.
  2. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Eng J Med. 2018;379(1):54-63. doi: 10.1056/NEJMoa1717002.