Second-Line Cabozantinib Proves Effective in HBV+ Liver Cancer

Tim Meyer, MD, PhD

Cabozantinib (Cabometyx) improved survival outcomes as second-line therapy for patients with hepatocellular carcinoma (HCC) who also had a history of hepatitis B virus (HBV) infection, demonstrating efficacy against a highly prevalent cause of the malignancy, according to study findings presented at the 2018 International Liver Cancer Association (ILCA) Annual Conference.

The data were reported as part of a subgroup analysis of the phase III CELESTIAL trial, in which cabozantinib reduced the risk of death by 24% compared with placebo in patients who had progressed on at least 1 prior systemic therapy for advanced HCC.^1,2

Similarly, the multikinase inhibitor showed improved overall survival (OS) in patients with an HBV etiology, although the medians were lower than the full population, lead investigator Tim Meyer, MD, PhD, said in presenting the data at ILCA.¹

“The benefit for cabozantinib is maintained,” said Meyer, a professor and director of the University College of London Experimental Cancer Medicine Centre in the United Kingdom, adding that no new safety signals were observed. “The absolute survival is worse in this patient population generally, so the hepatitis B—infected patients have a poor prognosis.”

In CELESTIAL, 707 patients were randomized 2:1 to receive cabozantinib at 60 mg daily (n = 470) or placebo (n = 237). In this population, median OS with cabozantinib was 10.2 versus 8.0 months for placebo (HR, 0.76; 95% CI, 0.63-0.92; P = .005). The median progression-free survival (PFS) was 5.2 months compared with 1.9 months for placebo, which was a 56% reduction in the risk of progression or death with the targeted therapy (HR, 0.44; 95% CI, 0.36-0.52; P <.001).

In all, 267 patients (38%) randomized during the trial had HBV; 178 were in the cabozantinib arm and 89 in the placebo group. This group comprised 79% of participants from Asia (n = 175), an area that included Hong Kong, South Korea, Singapore, and Taiwan; 22% of those from Europe and the Pacific (n = 365); and 29% of those from North America (n = 167).

Among all patients classified with HBV etiology, the median OS was 9.7 months (95% CI, 7.9-12.3) for cabozantinib compared with 6.1 months (95% CI, 4.8-7.7) with placebo, a 31% reduction in the risk of death (HR, 0.69; 95% CI, 0.51-0.94). The median PFS was 4.4 months with cabozantinib (95% CI, 3.7-5.6) versus 1.8 months (95% CI, 1.7-1.8) with placebo, which was a 69% reduction in risk (HR, 0.31; 95% CI, 0.23-0.42).

Drilling down further into the study details, Meyer also presented data for patients whose HBV status was confirmed through serology. When the study was launched, Meyer explained, central testing for HBV status via serology was not required and classification by investigators was permitted. As a result, serology testing was not conducted for approximately 35% of the participants who were classified as HBV-positive in both arms.

Of those who were tested by serology, 53% of the cabozantinib group and 58% of the placebo arm were positive for hepatitis B surface antigen (HBsAG) or hepatitis B core antibody (HBcAb). The median OS in the cabozantinib arm for this patient subgroup (n = 95) was 8.9 months (95% CI, 6.4-11.6) versus 5.5 months (95% CI, 4.4-7.8) in the placebo group (n = 52), for an HR favoring cabozantinib of 0.58 (95% CI, 0.37-0.89). The median PFS was 4.3 months (95% CI, 3.5-6.4) with cabozantinib versus 1.8 months (95% CI, 1.7-1.9) with placebo (HR, 0.40; 95% CI, 0.27-0.61).

The baseline characteristics of patients with HBV were balanced between the treatment arms. Patients who received cabozantinib had a median age of 59 years (range, 22-83), 47% had alpha-fetoprotein (AFP) levels ≥400 ng/mL, and 90% had extrahepatic spread (EHS) or macrovascular invasion (MVI). In the placebo arm, the median age was 60 years (34-79), 54% had AFP ≥400 ng/mL, and 91% had EHS or MVI.

In terms of prior therapies, 71% of patients in both arms received 1 prior therapy before joining the trial and about 29% had received 2. All patients had previously taken sorafenib (Nexavar), an established frontline standard in HCC.

Meyer said cabozantinib’s mechanism of action may account for its efficacy as a second-line therapy. The drug targets MET, SXL, and VEGF receptors. “It is known to be active against MET and AXL, which distinguishes it from sorafenib, and MET is known to be a resistance escape pathway so that may be relevant for its activity in the second line,” he said.

Based on the data from CELESTIAL, the FDA has accepted a supplemental new drug application for cabozantinib for patients with previously treated advanced HCC, according to Exelixis, the company developing the therapy. The FDA is scheduled to render a decision by January 14, 2019.

Cabozantinib was initially approved by the FDA as a treatment for patients with medullary thyroid cancer in 2012. In April 2016, the agent received a new indication as advanced renal cell carcinoma (RCC) following 1 prior antiangiogenic therapy. This approval was further expanded in December 2017 to patients with advanced RCC in the first-line setting. Numerous other trials exploring the agent remain ongoing.

Reference

1. Meyer T, Baron A, Gordan J, et al. Outcomes in patients (pts) with hepatitis B virus (HBV) in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC). Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16; London, England. Abstract O-012. ilca2018.org/wp-content/uploads/2018/08/ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf.
2. Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi: 10.1056/NEJMoa171700
3. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2

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Meyer said that HBV infection accounts for at least 50% of primary liver tumors diagnosed globally. The virus is a main risk factor associated with HCC in eastern Asia and sub-Saharan Africa, where 80% of cases occur, according to an overview of the disease recently published in Lancet.³ By contrast, hepatitis C and excessive alcohol consumption are the main risk factors in the United States, Europe, and Japan.³