Cabozantinib May Be 'New Treatment Option' for Liver Cancer

Roxanne Nelson, RN, BSN

January 24, 2018

SAN FRANCISCO — Treatment with cabozantinib (Cabometyx, Exelixis) significantly improved outcomes in patients with advanced hepatocellular carcinoma (HCC), leading researchers to suggest that it could offer a new treatment option for this patient population.

The new findings come from the phase 3 CELESTIAL trial and were presented at the Gastrointestinal Cancers Symposium (GICS) 2018.

This trial involved 707 patients with HCC who had experienced disease progression with sorafenib (Nexavar, Bayer) or other systemic therapies.

Median overall survival was 2.2 months longer for patients who received cabozantinib as compared to patients who received placebo. The study also met its secondary endpoint of progression-free survival — there was a 56% reduction in the risk for progression or death among patients who received active therapy.

"Cabozantinib represents a new treatment option for patients with advanced HCC after prior systemic anticancer therapy," said lead author Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"It significantly improves overall survival in advanced HCC patients," he said. "Progression-free survival and objective response rate were also significantly improved."

Cabozantinib is an oral inhibitor of multiple receptor tyrosine kinases, including RET, MET, and vascular endothelial growth factor 2 (VEGFR2), which are all involved in both normal cellular function and pathologic processes, such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

The drug has been marketed in the United States since 2012, when it was approved for use in the treatment of metastatic medullary thyroid cancer. In 2016, it was also approved for use in advanced renal cell carcinoma in patients who have received previous antiangiogenic therapy.

Details of the Study

Dr Abou-Alfa noted that cabozantinib showed preliminary clinical activity in patients with advanced HCC in a phase 2 trial (Ann Oncol. 2017;28:528-534). In that study, the median progression-free survival was 5.2 months, and the median overall survival was 11.5 months among patients who received cabozantinib.

The phase 3 trial now being reported was conducted in 707 HCC patients who were stratified according to disease etiology (hepatitis B, 38%; hepatitis C, 22%), geographic region (Asia, 25%), and the presence of extrahepatic spread (79%) and/or macrovascular invasion (27%).

The trial allowed for all patients to have previously received up to two lines of systemic therapy for HCC, one of which had to have been sorafenib. Dr Abou-Alfa explained that 100% of patients received sorafenib, owing to the fact that no other drugs had been approved at the time this trial was initiated.

Patients were randomly assigned in a 2:1 ratio to receive 60 mg of cabozantinib orally once daily or placebo. Treatment was continued until loss of clinical benefit or intolerable toxicity. No crossover was permitted.

The study met the primary endpoint at the second planned interim analysis. Results showed that the median overall survival was 10.2 months with cabozantinib vs 8.0 months with placebo; this extrapolated to a 24% reduction in the risk for death (hazard ratio [HR], 0.76; P = .0049).

Progression-free survival was also superior with cabozantinib in comparison with placebo (median: 5.2 months vs 1.9 months; HR, 0.44; P < .0001).

The overall response rate was limited, explained Dr Abou-Alfa; there was a 4% response in the cabozantinib group compared with a 0.4% response with placebo (P = .0086).

There was no complete response in either group. A partial response was seen in 4% of the cabozantinib group and in 0.4% of the placebo group; stable disease occurred in 60% with cabozanitnib vs 33% with placebo; and disease progression occurred in 21% with cabozantinib vs 55% with placebo. In addition, 15% of patients who received cabozantinib and 11% of patients who received placebo were not evaluable.

When stable disease was included, the disease control rate was 64% with cabozantinib vs with 33% with placebo.

In an analysis restricted to patients who had received only sorafenib prior to the study, the median overall survival was higher, at 11.3 months with cabozantinib vs 7.2 months with placebo (HR, 0.70). A small improvement was also seen for progression-free survival (5.5 months vs 1.9 months; HR, 0.40).

After the study, 25% of patients in the cabozantinib arm received subsequent therapy, compared to 30% who received placebo. "Understandably, more patients on placebo went on to other therapies because of early progression," Dr Abou-Alfa said.

The median time to subsequent systemic therapy was 6.6 months for the cabozantinib arm vs 3.3 months for patients who received placebo.

No new safety signals were observed with cabozantinib in this study. The most common grade 3/4 adverse events that occurred with higher frequency in the cabozantinib arm included hand-foot skin reaction (17% vs 0%), hypertension (16% vs 2%), increased aspartate aminotransferase (12% vs 7%), fatigue (10% vs 4%), diarrhea (10% vs 2%), asthenia (7% vs. 2%), and decreased appetite (6% vs <1%).

Problem With Drug Interruption?

In a discussion of the paper, Jordi Bruix, MD, PhD, of the University of Barcelona, in Spain, explained 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.

One point of concern was that the time to progression with cabozantinib was 3.8 months, whereas the median progression-free survival was 5.5 months. Thus, he wondered whether treatment was interrupted for many of the patients.

"This is something that I would like to see better explored when talking about adverse events and management, to understand to what extent the drug is safe and can be managed," Dr. Bruix said.

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."

Dr Abou-Alfa has participated in a consulting or advisory role with numerous pharmaceutical companies and has received travel expenses from Polaris. Dr Bruix has relationships with Argule, Bayer Schering, BristolMeyersSquibb, Kowa, Novartis, Onexo, Roche, BTG, and Sirtex Medical.

2018 Gastrointestinal Cancers Symposium. Abstract 207, presented January 19, 2018.

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