Exploring Immunotherapy Combinations for the Treatment of HCC

Josep M. Llovet, MD, PhD

Josep M. Llovet, MD, PhD

Novel immunotherapy combinations are currently under investigation for the treatment of patients with hepatocellular carcinoma (HCC), with several promising phase III trials incorporating checkpoint inhibitors now underway. Finding successful ways to combine these therapies is among the most significant trends emerging as part of the next wave of discovery in the field, according to experts.

The PD-1 inhibitor nivolumab (Opdivo) became the first immune checkpoint inhibitor to gain an accelerated approval from the FDA in September 2017 as second-line therapy following prior sorafenib (Nexavar). The agency is expected to make a decision on the PD-L1 inhibitor pembrolizumab (Keytruda) in a similar setting later this year.

The combination of atezolizumab (Tecentriq), a PD-L1 inhibitor, and bevacizumab (Avastin) is being developed through the FDA’s breakthrough therapy program as a first-line treatment for patients with advanced or metastatic HCC.

The potential for immunotherapy was a recurring topic of discussion during presentations at the 2018 International Liver Cancer Association (ILCA) Annual Conference. During the past 2 years, the toolkit of systemic therapies for unresectable HCC has grown beyond the frontline standard of care of sorafenib to include lenvatinib (Lenvima) as another first-line choice and several options for second-line agents.

Josep M. Llovet, MD, PhD, said he expects the focus of investigative efforts moving forward to be on developing frontline therapies that demonstrate superiority over the current options.

“I don’t see the field moving to third-line design,” said Llovet, who is founder and director of the Liver Cancer Program at Mount Sinai School of Medicine in New York and a professor at the University of Barcelona in Spain. “It has been estimated that only 40% of the patients who receive frontline [therapy] are suitable for second-line.” Even fewer patients then become eligible for third-line treatment, he said.

He noted that numerous combination regimens are under study, most of which involve immune checkpoint inhibitors.

“Immunotherapy using these checkpoint inhibitors may have a large impact,” Bruno Sangro, MD, PhD, said during a presentation. “We know that there is some activity in the second line after sorafenib. We have to wait and see what happens in the first-line setting. Everybody is taking for granted that these trials will be positive.”

Sangro, who is director of the liver unit at Clínica Universidad de Navarra in Pamplona, Spain, said HCC appears to be amenable to immunotherapy. “It’s been shown that the tumor microenvironment in liver cancer tumors has an accumulation of intratumoral immune cells that have an enhanced expression of exhaustion markers. These cells are activated but are exhausted and are not able to elicit tumor cell killing in an effective way. There’s an accumulation of these immunosuppressive T-regulatory cells and associated macrophages.”

Strategies for promoting an immune response through combination therapy are being explored. Sangro noted single agents and combinations are being evaluated or will be tested in less-advanced disease settings.

He cited 5 randomized phase III trials whose findings will help shape the landscape:

• KEYNOTE-240—Pembrolizumab plus best supportive care is being tested against placebo in an estimated 408 patients with advanced HCC previously treated with systemic therapy. The study is expected to be completed in early 2019 (NCT02702401).
• CheckMate-459—Nivolumab is being compared with sorafenib as first-line therapy in 726 patients with advanced disease. The study’s estimated completion date is next year (NCT02576509).
• HIMALAYA—Durvalumab (Imfinzi) with or without tremelimumab, a CTLA-4 inhibitor, is being evaluated against sorafenib as first-line therapy in 1200 patients with advanced disease (NCT03298451).
• IMbrave 150—Atezolizumab plus bevacizumab is being tested against sorafenib as first-line therapy in 480 patients (NCT03434379).
• CheckMate-9DX—Nivolumab is being compared with placebo as early-stage therapy in 530 patients with HCC who have a high risk of recurrence after curative resection or ablation, raising the potential for adjuvant immunotherapy in HCC (NCT03383458).

Additionally, Llovet said, a phase III trial is planned for the combination of lenvatinib and pembrolizumab, which has shown promise in an early study. He said that tyrosine kinase inhibitors are being paired with PD-1/PD-L1 agents in single-arm phase II trials, such as regorafenib (Stivarga) with pembrolizumab, cabozantinib (Cabometyx) with nivolumab, and ramucirumab (Cyramza) with durvalumab.

Richard Finn, MD, said findings from the KEYNOTE-240 and CheckMate-459 studies will be very influential. “Either of these studies will definitely determine whether PD-1 inhibition has a role in the future of liver cancer as a single agent,” said Finn, who is a professor of clinical medicine in the Division of Hematology and Oncology as well as director of the Signal Transduction and Therapeutics Program at the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California, Los Angeles. “These drugs are active. If you respond, you do very well.”

Going forward, Finn expects the focus to be on comparing active therapies. KEYNOTE-240 “is probably the last phase III placebo-controlled study in the second line [HCC] that we will see.”