Cabozantinib May Be a Match for Regorafenib in Second line Advanced HCC


Based on data from a matching-adjusted indirect comparison study, cabozantinib the safety and efficacy of cabozantinib may be comparative to regorafenib in advanced hepatocellular carcinoma.

Cabozantinib (Cabometyx) demonstrated an improvement in the median progression-free survival (mPFS) when compared with regorafenib (Stivarga) as a second-line treatment of patients with advanced hepatocellular carcinoma (HCC), a matching-adjusted indirect comparison (MAIC) study showed. This is the first study to compare the efficacy and safety of cabozantinib and regorafenib in the second-line setting of advanced HCC.1

“Hepatocellular carcinoma is a devastating disease with only a few treatment options available to improve survival for patients with advanced disease, though we have seen significant progress with multiple new treatments demonstrating efficacy in the past few years,” said Katie Kelley, MD, associate professor of Clinical Medicine, Department of Medicine (Hematology/Oncology) at the University of California, San Francisco, in the press release. “This MAIC analysis brings further insight into the comparative effectiveness of the key new second-line treatments for advanced hepatocellular carcinoma, particularly in relation to important endpoints like progression-free survival. The results published today may help clinicians in making informed treatment decisions for their patients.”

The study examined data the phase 3 CELESTIAL trial (NCT01908426) of cabozantinib versus placebo in patients with HCC who received prior treatment with sorafenib (Nexavar) and the phase 3 RESORCE trial (NCT01774344) of regorafenib after sorafenib in HCC. Overall, 379 patients were assessed in RESORCE, and 331 patients were evaluated in CELESTIAL.1,2

Results were published in Advances in Therapy and showed a mPFS increase of 80.6% with cabozantinib. The mPFS was 5.6 months (95% CI, 4.9-7.3) versus 3.1 months (95% CI, 2.8-4.2) in the cabozantinib and regorafenib groups, respectively (P =.0005). The median overall survival (OS) was 11.4 months with cabozantinib versus 10.6 months with regorafenib. However, this difference was not statistically significant.1

In previously reported findings of the CELESTIAL trial, the mPFS was 5.2 months versus 1.9 months with cabozantinib versus placebo (HR, 0.44; 95% CI, 0.36-0.52; P <.0001), and the median OS was 10.2 months versus 8.0 months, respectively (HR, 0.76; 95% CI, 0.63-0.92; P =.0049).

Results from RESORCE showed higher alpha-fetoprotein (AFP) level response with regorafenib compared with placebo. The median OS was 12.0 months (95% CI, 9.9-14.6) in patients with an AFP response versus 7.0 months (95% CI, 6.2-7.9) in those who did not achieve an AFP response (HR, 0.57; 95% CI, 0.40-0.82), according to result presented at the 2019 International Liver Cancer Association (ILCA) Annual Meeting.3

Both arms in the MAIC study combined had a 5% occurrence of grade 3 or 4 treatment-emergent adverse events (TEAEs) which included increased aspartate transaminase, diarrhea, elevated bilirubin, fatigue, hypertension, and palmar-plantar erythrodysesthesia syndrome. The frequency of grade 3/4 TEAEs was not statistically different between the 2 study arms (P =.8558).2

Based on these study data, Kelley et al consider cabozantinib to be comparative to regorafenib for the treatment of advanced HCC. This study provides more clarity on which targeted therapies provided optimal treatment for patients with advanced HCC, as many different tyrosine kinase inhibitors are now available in the treatment landscape.

A head-to-head, randomized, controlled trial is recommended to confirm the similarity of efficacy and safety between cabozantinib and regorafenib in this patient population.

“The recent rapid development of new second-line treatments for patients with advanced hepatocellular carcinoma has led to the generation of information mainly based on placebo-controlled trials. While alternative methodological approaches such as MAIC are not substitutes for evidence-based prospective clinical trials, the publication of the MAIC for cabozantinib versus regorafenib provides healthcare professionals with timely new insights into the comparative effectiveness of current treatment approaches,” said Amauri Soares, vice president, Medical Affairs Oncology, Ipsen, in a statement.1


1. Ipsen announces publication of first matching-adjusted indirect comparison of cabometyx® (cabozantinib) versus regorafenib in advanced hepatocellular carcinoma in advances in therapy [news release]. Paris, France: Ipsen; May 19, 2020. Accessed May 19, 2020.

2. Kelley RK, Mollon P, Blanc JF, et al. Comparative efficacy of cabozantinib and regorafenib for advanced hepatocellular carcinoma. Adv Ther. 2020. Published Online May 18, 2020. doi: 10.1007/s12325-020-01378-y

3. Bruix J, Reig M, Merle P, et al. Alpha-fetoprotein (AFP) response and outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with regorafenib or placebo in the phase 3 RESORCE trial. Poster presented at: 2019 ILCA Annual Conference; September 20-22, 2019; Chicago, IL. Abstract P-013.

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