Cabozantinib Improves Survival in Phase III HCC Trial

Gisela Schwab, MD

Cabozantinib (Cabometyx) improved overall survival (OS) versus placebo in patients with advanced hepatocellular carcinoma (HCC) who have previously received sorafenib (Nexavar), meeting the primary endpoint of the phase III CELESTIAL trial.

An independent monitoring committee has recommended stopping the study for efficacy following review of the second planned interim analysis, according to Exelixis and Ipsen, the co-developers of the multikinase inhibitor. The companies have not released data from CELESTIAL, announcing that detailed results will be presented at a future medical conference.

“We are excited that these positive results from the phase III CELESTIAL trial bring us one step closer to the potential of offering previously treated patients with this aggressive form of advanced liver cancer a much-needed new treatment option,” Gisela Schwab, MD, president, Product Development and Medical Affairs and chief medical officer, Exelixis, said in a press release. “This is an important milestone for the cabozantinib development program; we are committed to studying cabozantinib in a range of tumor types as part of our mission to deliver medicines that improve treatment outcomes and give patients hope for the future.”

The randomized, global phase III CELESTIAL trial examined cabozantinib versus placebo in patients with advanced HCC who received up to 2 prior systemic cancer therapies for HCC and had adequate liver function (n = 773).

Patients were randomly assigned 2:1 to placebo or 60 mg of cabozantinib once daily or placebo, and were stratified based on etiology of the disease (hepatitis C, hepatitis B, or other), geographic region (Asia versus other regions), and presence or absence of extrahepatic spread and/or macrovascular invasion. Crossover between the study arms was not allowed.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate (ORR), and progression-free survival (PFS). Exploratory endpoints include patient-reported outcomes, biomarkers, and safety.

Based on available clinical trial data from various published trials conducted in the second-line setting of advanced HCC, the CELESTIAL trial statistics for the primary endpoint of OS assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90% power to detect a 32% increase in median OS (hazard ratio = 0.76) at the final analysis. Two interim analyses were planned and conducted at 50% and 75% of the planned 621 events.

Previously, phase II results were published in the Annals of Oncology for 41 patients with HCC assigned to 100 mg daily of cabozantinib during a 12-week lead-in phase. At week 12, patients with stable disease were randomly assigned to cabozantinib or placebo, patients with a partial response could continue open-label cabozantinib treatment, and patients with progressive disease at or before week 12 discontinued treatment.

The primary endpoint of the lead-in phase was objective response rate (ORR) at week 12 and the primary endpoint for the randomized phase was PFS.

Among the 41 patients enrolled to receive open-label cabozantinib during the 12-week lead-in, 12 discontinued study treatment before week 12, 7 continued open-label cabozantinib after week 12, and 22 were randomized to receive cabozantinib (n = 10) or placebo (n = 12).

Median PFS after randomization favored the cabozantinib group (2.5 vs 1.4 months), but the difference was not statistically significant. From day 1, median PFS was 5.2 months and OS was 11.5 months in all patients.

ORR was 5% at week 12 and 2 patients had a confirmed partial response. The overall disease control rate was 66%, rising to 73% in the Asian subgroup.

Of 36 patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy.

The most common grade 3/4 adverse events were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Nearly 2 in 3 patients (59%) required dose reductions.

Kelley RK, Verslype C, Cohn AL, et al. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol. 2017;28(3):528-534. doi: 10.1093/annonc/mdw651.