SAN FRANCISCO — Pembrolizumab (Keytruda, Merck) has shown efficacy in the treatment of advanced hepatocellular carcinoma (HCC) in patients who have already been treated with sorafenib (Nexavar, Onyx/Bayer).
Another immunotherapy agent, nivolumab (Opdivo, Bristol-Myers Squibb) was recently granted accelerated approval by the US Food and Drug Administration for this indication.
Both immunotherapies are already approved for use in the treatment of several other cancers.
The new findings for pembrolizumab come from the Keynote 224 study, a phase 2 trial in 104 patients with advanced HCC who had radiographic progression after treatment with sorafenib. The findings were presented here at the Gastrointestinal Cancers Symposium (GICS) 2018.
Durable responses were seen, and there was promising progression-free survival (PFS) and overall survival (OS), reported lead author, Andrew X. Zhu, MD, PhD, professor of medicine, Harvard Medical School, and director, Liver Cancer Research, Massachusetts General Hospital Cancer Center, Boston.
The median PFS was 4.8 months, and the median OS has not been reached.
The 6-month PFS was 43.1% and 6-month OS was 77.9%.
“The safety profile was generally comparable to that established for pembrolizumab monotherapy in other indications, and no viral flares were seen,” said Dr Zhu.
Patients received 200 mg every 3 weeks for 2 years or until they experienced progressive disease, unacceptable toxicity, withdrawal of consent, or investigator decision. Their response to treatment was assessed every 9 weeks.
The median patient age was 68 years; 21.2% of patients were positive for hepatitis B (HBV), and 26.0% were positive for hepatitis C virus (HCV).
More than two thirds (79.8%) discontinued sorafenib because of disease progression and 20.2% for intolerance. Extrahepatic disease was present in 63.5% of the cohort.
Of 104 patients who received treatment, 23 continued therapy, with a median follow-up of 8.4 months (range, 0.4 to 13.6 months).
The overall response rate was 16.3%, and rates were similar across subgroups with different causes, including those with HBV and HCV infection. The median time to response was 2.1 months (range, 1.8 to 4.8 months), and 94% of responders were estimated to have a response duration of 6 months or longer.
A complete response was observed in 1 patient (1.0%), partial responses in 16 (15.4%), stable disease in 47 (45.2%), and progressive disease in 34 (32.7%).
Treatment-related adverse events occurred in 73.1% of patients, with the most common being fatigue (21.2%) and increased aspartate aminotransferase levels (12.5%). Grade 3 to 5 events were reported in 25% of patients, including 1 death from ulcerative esophagitis.
Dr Zhu noted that a phase 3 randomized trial is evaluating pembrolizumab vs placebo as second-line therapy in this population.
Replacing Sorafenib?
Approached by Medscape Medical News for an independent comment, Jeffrey A. Meyerhardt, MD, MPH, clinical director, Gastrointestinal Cancer Center, Dana-Farber Cancer Center, Boston, Massachusetts, noted that the activity observed with pembrolizumab is similar to that of nivolumab.
“The real question is if we should this move up to first line,” Dr Meyerhardt said. “Sorafneib’s approval was based on a very large study, but it has limited activity and intolerance is tough for some patients. Nivolumab is indicated for those who have progressed or are intolerant to sorafenib, but the way this field is moving, it may be time to combine therapies or move the newer ones to the first line.”
He cautioned that just because a therapy works in second or third line, that doesn’t mean it will be effective in first line, either in combination or alone. “It doesn’t always work, and we’ve seen that with other therapies,” Dr Meyerhardt said. “Moving it to first line isn’t always an improvement in the standard.”
However, sorafenib is not an ideal first-line therapy in HCC. “Its activity is limited and tolerance is tough, so we are looking at other options for disease control and quality of life,” he said. “In this case, sorafenib is not as good as a first-line treatment as we have for other cancers.”
Dr Meyerhardt pointed out that multiple options are available for HCC after sorafenib, “so the immunotherapy option does seem more attractive than some of the others.”
The study was funded by Merck & Co. Dr Zhu has disclosed a consulting or advisory role with Merck; several coauthors have disclosed relationships with industry.
Gastrointestinal Cancers Symposium (GICS) 2018. Abstract 209. Presented January 19, 2018.
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