Benjamin Leon Musher, MD
Until recently, sorafenib (Nexavar) was the only FDA-approved systemic therapy for the treatment of patients with unresectable hepatocellular carcinoma (HCC). Now, lenvatinib (Lenvima), regorafenib (Stivarga), cabozantinib (Cabometyx), nivolumab (Opdivo), pembrolizumab (Keytruda), and ramucirumab (Cyramza) have been added to the paradigm for patients across a multitude of settings, explained Benjamin Leon Musher, MD.
“A few years ago, we had 1 option to treat [patients with] unresectable HCC. Now, we have several,” said Musher. “I encourage clinicians to review the data. Until we have better data to guide us in terms of what to use for first-, second-, and third-line therapy, it’s going to be up to clinicians to determine what their patients can tolerate and what helps the best. Stay tuned because there will be data in the next few years.”
In an interview during the 2019 OncLive®
State of the Science Summit™ on Gastrointestinal Malignancies, Musher, associate professor of medicine–hematology and oncology at Baylor College of Medicine, reflected on the progress that has been made in HCC and highlighted promising combinations that are emerging in the space.OncLive: How has the field of newly diagnosed HCC changed in the last couple of years?Musher
: As of a few years ago, we only had 1 option for treating unresectable HCC, and that was sorafenib. In the last couple of years, several new drugs have been approved by the FDA, including targeted agents and a couple of immunotherapy agents. We still have a long way to go with this cancer, but we have some more options now than we did a few years ago. We also have to do a little bit more work to figure out what sequence to use them in.Could you discuss the CELESTIAL trial and the clinical implications of its findings?
The CELESTIAL trial randomized patients who had already received 1 or 2 lines of therapy to either cabozantinib or placebo. Cabozantinib is an oral agent, and it showed a survival benefit of a couple of months. Like other studies that have shown benefit in HCC, we’re not talking about a huge benefit; however, there was a statistically significant benefit that was better than what we have seen with chemotherapy in the past. This is an important study, as it gives patients another option once they have received sorafenib and possibly another line of therapy.What were some of the data to come from the RESORCE trial?
In the RESORCE trial, patients received either regorafenib or placebo after having progressed on sorafenib. Back then, sorafenib was the only drug that had been approved [by the FDA], so there was nothing else that it could compete against. The trial showed a 2- to 3-month overall survival (OS) benefit. Not surprisingly, toxicities were associated with regorafenib just like we’ve seen in colon cancer, including fatigue and hand–foot syndrome. These are events that we have to take very seriously in patients with liver cancer. Patients were all given the full dose of regorafenib which we, as clinicians, know is not necessarily the easiest to tolerate. Just like we do in colorectal cancer, we would start at a lower dose and titrate up. It is an FDA-approved and evidenced-based option for second-line therapy for patients with unresectable HCC.Would you like to highlight any other clinically impactful trials?
The CheckMate-040 trial tested nivolumab and the KEYNOTE- 224 trial looked at pembrolizumab. They both had fairly similar results, with a 20% response rate. Responses do appear to be durable, and the drug is very well tolerated as it is with other malignancies. Interestingly, PD-L1 expression did not appear to predict any response or lack of response, so it’s important that all patients who have received 1 line of therapy be considered for checkpoint inhibition.
A big caution area would be patients who have undergone liver transplantation, as there have been some reports of patients who are rejecting their transplanted liver. Patients who have hepatitis B virus should be treated for the infection for fear of reactivation or exacerbation of their liver disease. I would caution that a patient’s hepatitis B virus should be treated, and there’s a risk of more problems with coinfection of the hepatitis B and C viruses.