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Cabozantinib improves OS for HCC

Cabozantinib significantly extended OS for patients with previously treated advanced hepatocellular carcinoma, according to results from the randomized, double-blind, placebo-controlled phase 3 Celestial trial.

Cabozantinib (Cabometyx, Exelixis) is a tyrosine kinase inhibitor that targets VEGF, AXL and MET.

“MET is very important because the liver has the receptor for MET, called the hepatocyte growth factor,” Ghassan K. Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “There are a lot of data that have shown the growth of liver tumors from hepatocellular carcinoma can be dependent on MET activity. We evaluated whether this TKI can prevent the growth of the tumors.”

The researchers randomly assigned 707 patients (median age, 64 years; 82% men) with advanced HCC from more than 100 sites across 19 countries 2:1 to receive 60 mg daily cabozantinib or matched placebo.

Researchers stratified patients by disease etiology, geographic region, and presence of extrahepatic spread or macrovascular invasion.

Patients had received up to two lines of prior systemic therapy for HCC (27% had received two prior lines) and progressed following at least one. Thirty-eight percent of patients had hepatitis B virus, 24% had hepatitis C virus, 78% had extrahepatic spread, 30% had macrovascular invasion and 25% were enrolled in Asia.

OS served as the study’s primary endpoint. Secondary endpoints included PFS and objective response rate.

Median OS was 10.2 months among patients who received cabozantinib and 8 months for those who received placebo (HR = 0.76; 95% CI, 0.63-0.92).

Median PFS was 5.2 months in the treatment group compared with 1.9 months in the placebo group (HR = 0.44; 95% CI, 0.36-0.52).

ORR per RECIST was 4% in the treatment group and 0.4% in the placebo group (P = .0086). A higher percentage of patients in the treatment group than placebo group achieved partial response or stable disease (64% vs. 33%).

In a subgroup analysis of patients whose sole treatment experience was sorafenib (Nexavar, Bayer), median OS was 11.3 months among patients who received cabozantinib compared with 7.2 months among those who received placebo (HR = 0.7; 95% CI, 0.55-0.88). Median PFS in the subgroup analysis was 5.5 months in the treatment group and 1.9 months in the placebo group (HR = 0.4; 95% CI, 0.32-0.5).

These results are important for several reasons, Abou-Alfa said.

“We really lack a second-line therapy at the moment,” he said. “Regorafenib [Stivarga, Bayer] also has been evaluated in randomized trials, but it requires that patients received prior sorafenib and progressed.

“Also, nivolumab [Opdivo, Bristol-Myers Squibb] was approved based on a phase 2 trial, but we’re still waiting on the phase 3 trial for the first-line therapy,” he added. “At least now we have some options, but I would say cabozantinib is a rather robust option that is available for our patients.”

Grade 3 or grade 4 adverse events that occurred more commonly in the treatment group included 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%).

Five patients experienced treatment-related grade 5 adverse events, including hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome. One patient in the placebo group experienced hepatic failure. The rate of discontinuation due to adverse events was 16% in the treatment group and 3% in the placebo group.

In a previous analysis, tivantinib (ARQ 197, Arqule) — a c-MET inhibitor — failed to show an improvement in this setting over placebo in a similar study design, Abou-Alfa said.

“However, the study limited accrual to patients with high c-MET expression,” he said. “We did not have this limitation, which brings into important perspective how much MET activity you need and whether it is important to limit to only the highest expression.” – by Talitha Bennett and Melinda Stevens

Reference:

Abou-Alfa GK, et al. Abstract 207.

Disclosures: Abou-Alfa reports consultant/advisory roles with and research funding from Bayer and Exelixis, among other pharmaceutical companies. Please see the abstract for a list of all authors’ relevant financial disclosures.

Cabozantinib significantly extended OS for patients with previously treated advanced hepatocellular carcinoma, according to results from the randomized, double-blind, placebo-controlled phase 3 Celestial trial.

Cabozantinib (Cabometyx, Exelixis) is a tyrosine kinase inhibitor that targets VEGF, AXL and MET.

“MET is very important because the liver has the receptor for MET, called the hepatocyte growth factor,” Ghassan K. Abou-Alfa, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “There are a lot of data that have shown the growth of liver tumors from hepatocellular carcinoma can be dependent on MET activity. We evaluated whether this TKI can prevent the growth of the tumors.”

The researchers randomly assigned 707 patients (median age, 64 years; 82% men) with advanced HCC from more than 100 sites across 19 countries 2:1 to receive 60 mg daily cabozantinib or matched placebo.

Researchers stratified patients by disease etiology, geographic region, and presence of extrahepatic spread or macrovascular invasion.

Patients had received up to two lines of prior systemic therapy for HCC (27% had received two prior lines) and progressed following at least one. Thirty-eight percent of patients had hepatitis B virus, 24% had hepatitis C virus, 78% had extrahepatic spread, 30% had macrovascular invasion and 25% were enrolled in Asia.

OS served as the study’s primary endpoint. Secondary endpoints included PFS and objective response rate.

Median OS was 10.2 months among patients who received cabozantinib and 8 months for those who received placebo (HR = 0.76; 95% CI, 0.63-0.92).

Median PFS was 5.2 months in the treatment group compared with 1.9 months in the placebo group (HR = 0.44; 95% CI, 0.36-0.52).

ORR per RECIST was 4% in the treatment group and 0.4% in the placebo group (P = .0086). A higher percentage of patients in the treatment group than placebo group achieved partial response or stable disease (64% vs. 33%).

In a subgroup analysis of patients whose sole treatment experience was sorafenib (Nexavar, Bayer), median OS was 11.3 months among patients who received cabozantinib compared with 7.2 months among those who received placebo (HR = 0.7; 95% CI, 0.55-0.88). Median PFS in the subgroup analysis was 5.5 months in the treatment group and 1.9 months in the placebo group (HR = 0.4; 95% CI, 0.32-0.5).

These results are important for several reasons, Abou-Alfa said.

“We really lack a second-line therapy at the moment,” he said. “Regorafenib [Stivarga, Bayer] also has been evaluated in randomized trials, but it requires that patients received prior sorafenib and progressed.

“Also, nivolumab [Opdivo, Bristol-Myers Squibb] was approved based on a phase 2 trial, but we’re still waiting on the phase 3 trial for the first-line therapy,” he added. “At least now we have some options, but I would say cabozantinib is a rather robust option that is available for our patients.”

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Grade 3 or grade 4 adverse events that occurred more commonly in the treatment group included 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%).

Five patients experienced treatment-related grade 5 adverse events, including hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome. One patient in the placebo group experienced hepatic failure. The rate of discontinuation due to adverse events was 16% in the treatment group and 3% in the placebo group.

In a previous analysis, tivantinib (ARQ 197, Arqule) — a c-MET inhibitor — failed to show an improvement in this setting over placebo in a similar study design, Abou-Alfa said.

“However, the study limited accrual to patients with high c-MET expression,” he said. “We did not have this limitation, which brings into important perspective how much MET activity you need and whether it is important to limit to only the highest expression.” – by Talitha Bennett and Melinda Stevens

Reference:

Abou-Alfa GK, et al. Abstract 207.

Disclosures: Abou-Alfa reports consultant/advisory roles with and research funding from Bayer and Exelixis, among other pharmaceutical companies. Please see the abstract for a list of all authors’ relevant financial disclosures.