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Pembrolizumab induces durable responses in advanced liver cancer
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Pembrolizumab treatment led to durable OS and PFS among patients with advanced hepatocellular carcinoma who previously progressed on sorafenib, according to results of the phase 2 KEYNOTE-224 clinical trial presented at the Gastrointestinal Cancers Symposium.
“[The study] demonstrated the antitumor activity of pembrolizumab [Keytruda, Merck] with durable responses and manageable safety profiles,” Andrew X. Zhu, MD, PhD, director of liver cancer research at Massachusetts General Hospital, and professor of medicine at Harvard Medical School, told HemOnc Today. “It may potentially offer these patients a new treatment option pending a further confirmation trial.”
Studies have shown sorafenib (Nexavar, Bayer) — a synthetic compound targeting growth signaling and angiogenesis — improves survival among patients with HCC. Still, new treatment options are needed.
“[Although] it has shown improved survival benefits, the benefit is relatively modest, and its side effects need to be monitored closely and managed aggressively,” Zhu said.
Other studies have shown anti-PD-1 treatment with pembrolizumab had a manageable safety profile and antitumor activity in various cancers.
Researchers administered 200 mg pembrolizumab every 3 weeks to 104 patients (median age, 68 years; range, 43-87) with confirmed HCC for 2 years or until disease progression, unacceptable toxicities or withdrawal of consent.
Among the patients, 21.2% had hepatitis B virus infection, 26% had hepatitis C virus infection, 94.2% had a Child-Pugh A score, 79.8% had progressive disease on sorafenib and 63.5% had extrahepatic disease.
Overall response rate based on RECIST v1.1 by independent central review served as the primary endpoint. Secondary endpoints included duration of response, disease control response, PFS, OS, safety and tolerability.
Median follow-up was 8.4 months (range, 0.4-13.6). Twenty-three patients continued on therapy at the time of the analysis.
Researchers reported an ORR of 16.3% (95% CI, 9.8-24.9), which appeared similar between all subgroups of disease etiology. Median time to response was 2.1 months (range, 1.8-4.8).
One patient had a complete response, and 16 had partial responses to pembrolizumab. Among all responders, 94% had a response duration of at least 6 months.
Overall, 61.5% of patients experienced disease control.
Thirty-four patients had progressive disease.
Median PFS was 4.8 months (95% CI, 3.4-6.6) and median OS was not reached (95% CI, 9.4 to not reached).
In total, 43.1% of patients achieved 6-month PFS and 77.9% achieved 6-month OS.
Researchers observed treatment-related adverse events among 73.1% of patients, with more than 10% experiencing fatigue (22.2%) and increased serum aspartate aminotransferase (12.5%). Grade 3 to grade 5 treatment-related adverse events occurred among 25% of patients. One patient died of ulcerative esophagitis.
No hepatitis flare occurred, whereas 2.9% of patients experienced immune-mediated hepatitis.
Pembrolizumab can induce “significant antitumor activity with durable tumor shrinkage,” Zhu said. – by Melinda Stevens
Reference:
Zhu AX, et al. Abstract 209. Presented at: Gastrointestinal Cancers Symposium; Jan. 18-20, 2018; San Francisco.
Disclosures: Zhu reports a consultant/advisory role with Merck. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Ghassan K. Abou-Alfa, MD, MBA
Approval of sorafenib — which has been on the market for liver cancer for more than 10 years — was based on a phase 3 trial in which patients were randomly assigned to sorafenib or placebo. Sorafenib led to improved survival yet no responses. Patients will have stable disease but not necessarily shrinkage of the tumor. There has always been concern about the management of side effects.
In the phase 3 CELESTIAL trial, which looked at cabozantinib (Cabometyx, Exelixis) vs. placebo, positive results with cabozantinib were reported, with a clear improvement in survival in the second-line setting (10.2 months for cabozantinib vs. 8 months for placebo). This is an important study with a novel series of targets that differ from other predecessor tyrosine kinase inhibitors.
In the KEYNOTE 224 study, pembrolizumab — an anti-PD-1 therapy — has shown response rates of 60%, with a complete response noted in 1%. Understandably, because this was a phase 2 trial, we still lack survival data. KEYNOTE 224 is ongoing. A randomized phase 3 trial of pembrolizumab compared with placebo in the second-line setting of hepatocellular carcinoma also is underway.
There has been a similar experience with another checkpoint inhibitor — nivolumab (Opdivo, Bristol-Myers Squibb) — in a similar phase 2 trial that showed a response rate of 15% to 20%. The FDA since approved nivolumab for liver cancer in the second-line setting on the basis of pending results from a phase 3 trial of nivolumab compared with placebo in the first-line setting.
There are a lot of emerging data in the field for the agents mentioned, as well as others, such as lenvatinib (Lenvima, Eisai) and regorafenib (Stivarga, Bayer HealthCare).
Although we are waiting for further data — especially from phase 3 trials — it will take some time to help delineate the optimal sequence of those therapies.
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