CABOZATINIB FOR LIVER CANCER

The targeted agent cabozantinib (Cabometyx, Exelixis) could be a new treatment option for previously treated patients with advanced hepatocellular carcinoma (HCC), suggest results from a phase 3 trial.

As compared with placebo, treatment with cabozantinib resulted in longer overall survival and progression-free survival.

Median overall survival was 2.2 months longer for patients who received cabozantinib, and treatment was associated with a 56% reduction in the risk for progression or death.

The results were initially presented at the Gastrointestinal Cancers Symposium (GICS) 2018 and were reported by Medscape Medical News at that time. They have now been published in the New England Journal of Medicine.

"The data show the efficacy and safety in this population," said lead author Ghassan K. Abou-Alfa, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City. "It has potential as a new treatment option for second- and third-line therapy."

Cabozantinib is a small-molecule inhibitor of the tyrosine kinases c-Met and vascular endothelial growth factor (VEGF)–receptor 2 (VEGFR2); it also inhibits AXL and RET. It has been available in the United States since 2012, when it received approvalby the US Food and Drug Administration for the treatment of medullary thyroid cancer. In 2016, it was approved for the treatment of advanced renal cell carcinoma in patients who have received previous antiangiogenic therapy.

Met Endpoints

A previous phase 2, randomized discontinuation trial demonstrated a median overall survival of 11.5 months and a median progression-free survival of 5.2 months in patients treated with cabozantinib. On the basis of these results, Abou-Alfa and his colleagues conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate cabozantinib vs placebo in previously treated patients with advanced HCC.

A total of 707 patients who had received previous treatment with sorafenib and had experienced disease progression after at least one systemic treatment for HCC were randomly allocated to receive either cabozantinib 60 mg once daily or placebo. The primary endpoint was overall survival; secondary endpoints were progression-free survival and the objective response rate.

The median overall survival was 10.2 months for patients in the cabozantinib group vs 8.0 months for patients in the placebo group (hazard ratio [HR] for death, 0.76; 95% confidence interval [CI], 0.63 - 0.92; P = .005). This met the criterion for statistical significance.

With regard to secondary endpoints, the median progression-free survival was 5.2 months with cabozantinib vs 1.9 months with placebo (HR for disease progression or death, 0.44; P < .001). The objective response rates were 4% and <1 em="" respectively="" style="max-width: 100%;">P

 = .009).

Adverse Events High but Well Tolerated

Adverse events of any grade were reported in 99% of the patients in the cabozantinib group and in 92% in the placebo group. Events of grade 3 or 4 occurred in 68% and 36% of patients, respectively. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs 0% with placebo), hypertension (16% vs 2%), increased aspartate aminotransferase level (12% vs 7%), fatigue (10% vs 4%), and diarrhea (10% vs 2%).

The safety results for cabozantinib were consistent with those from the earlier phase 2 study in HCC with the known safety profile of cabozantinib. The most common adverse events were similar to those observed with other VEGF-receptor tyrosine kinase inhibitors in this setting.

Abou-Alfa noted that the therapy was well tolerated and that adverse events were managed with dose reductions and supportive care.

Dose reductions occurred in 291 patients (62%) in the cabozantinib group and in 30 patients (13%) in the placebo group. The median average daily dose was 35.8 mg for cabozantinib.

Moving Beyond VEGF

During GICS, paper discussant Jordi Bruix, MD, PhD, of the University of Barcelona, in Spain, agreed that the study results demonstrate that cabozantinib provides a clinically meaningful survival benefit to patients with advanced HCC who have received previous therapy.

"An important aspect of the trial is that survival in the placebo arm is consistent with findings from other second-line trials with other therapies," Dr Bruix said, "and that is about 8 months."

That is now a benchmark of survival that can be expected without treatment and that can be used in future trials, he pointed out. He also noted that almost all of the new systemic therapies that have been approved for treatment of advanced HCC target the VEGF pathway. "So this leaves a proportion of patients who cannot benefit and are in need of treatment, and we need to look beyond VEGF," Dr Bruix said. "They are still in need of effective treatment."

The study was supported by Exelixis, the manufacturer of cabozantinib. Dr Abou-Alfa has received consulting fees and advisory board fees from Bayer and Bristol-Myers Squibb. Dr Meyer has received grant support and consulting fees from Bayer and BTG and consulting fees from Bristol-Myers Squibb, Merck, and Eisai. Dr Bruix has relationships with Argule, Bayer Schering, Bristol-Meyers Squibb, Kowa, Novartis, Onexo, Roche, BTG, and Sirtex Medical.

N Engl J Med. Published online July 5, 2018. Abstract