Expert Point of View: Milind Javle, MD

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Immuno-oncology in [hepatocellular carcinoma] has come of age.
— Milind Javle, MD

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Milind Javle, MD, Professor of Gastrointestinal Oncology at The University of Texas MD Anderson Cancer Center, Houston, discussed the findings from the CheckMate 040 trial presented at the 2017 Gastrointestinal Cancers Symposium.

There is a strong rationale for investigating immunotherapy in liver cancer, he said. He cited, among a number of factors, the facts that immune tolerance is a hallmark of this disease and that chronic inflammation from viral infection results in profound immunosuppression.

Clinical trials of checkpoint inhibition are bearing this out. “CheckMate 040 is impressive in the sense that the response rate was 19%, the time to response was brisk (1.9 months), and the duration of response was not reached in the expansion cohort,” Dr. Javle said. Responses were unrelated to infection status and were similar whether in the first or second line.

“It’s impressive that 70% of patients survive 9 months with second-line treatment…. This indicates that even patients [with disease progression] do survive reasonably long,” he commented.

“However, in patients who did not respond, the result was more modest,” he continued. “Stable disease was seen in 46%, and their estimated median progression-free survival was only 4 months. From this study we can say that checkpoint inhibition may offer a major clinical benefit, but for a minority of patients—about 15% to 20%.”

Looking Ahead

Dr. Javle emphasized that predictive markers for immunotherapies are critically needed to identify patients likely to respond. Programmed cell death ligand 1 (PD-L1) may not be useful in this disease, since expression was low in general and not predictive of efficacy in this study. In some cancers, mutational burden may be predictive, but mutational burden is low in liver cancer. Other potential biomarkers have not proven useful yet.

“Where do we go next?” he asked. Phase III trials are evaluating nivolumab (Opdivo) vs sorafenib (Nexavar) in the first-line setting and pembrolizumab (Keytruda) vs best supportive care in the second-line setting. In the second line, “one could also conceive of” comparing anti–programmed cell death protein 1 (PD-1) agents to regorafenib (Stivarga), he suggested.

Anti–PD-1 agents may also prove more beneficial when combined with ipilimumab (Yervoy) and agents targeting LAG-3, TIM-3, TGFB-R2, as well as small-molecule inhibitors. The role of immunotherapy in the adjuvant setting is also of interest, he said.

What is clear already, he concluded, is that the “landscape is now changing” in hepatocellular carcinoma. “Immuno-oncology in this cancer has come of age.” ■

Disclosure: Dr. Javle reported no potential conflicts of interest.


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