Early Signals Positive for Immunotherapy Plus Standard Therapy in HCC

Tim F. Greten, MD

Early evidence suggests that the combination of locoregional therapy with an immune checkpoint inhibitor is a safe and effective strategy to pursue for patients with advanced hepatocellular carcinoma (HCC), according to a leading liver immunology expert.

The concept was successfully tested in a phase I/II pilot study at the National Cancer Institute, Tim F. Greten, MD, a senior investigator at the NCI, told attendees at the 10th Annual Conference of the International Liver Cancer Association (ILCA).

The experimental regimen is among a broad range of immunotherapy strategies under investigation in HCC, Greten indicated. In addition to immune checkpoint inhibitors, these approaches include utilizing cytokine-activated killer cells, chimeric antigen receptor T cells, antibodies, oncolytic viruses, and vaccines.

For their combination study, NCI investigators sought to leverage the immunological effects of ablative therapies for patients with HCC. These effects include release of tumor-fighting cytokines, such as interleukins 1 and 6 and tumor necrosis factor alpha, said Greten, who also is head of the Gastrointestinal Malignancy Section in the NCI’s Thoracic and Gastrointestinal Oncology Branch.

Patients received tremelimumab, which targets the negative immune checkpoint CTLA-4, every 4 weeks and either radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) at 5 weeks into the study. Participants continued tremelimumab until disease progression.

Notably, Greten said the goal of the radiotherapy was to induce an immune response and, particularly with RFA, “it’s not done in an effort to completely eliminate every lesion within the liver.” He said the therapy was carefully applied to achieve these goals.

The study enrolled 32 patients with biopsy-confirmed HCC with Childs Pugh A/B7 scores and Barcelona Clinical Liver Cancer stage B or C scores. Most of the participants had already received prior sorafenib (Nexavar); other previous interventions included TACE (n = 11), surgery (n = 5), and ablation (n = 5). The group had a median age of 61 years (range, 36-76).

Among 23 patients treated with 10 mg/kg of tremelimumab, the combination therapy demonstrated a median time to progression of 7.4 months and median overall survival of 13.6 months, Greten said. The OS benefit was more pronounced among patients who received TACE (n = 11); the median OS was not reached, as opposed to a median OS of 10.1 months for participants who were given RFA (n = 12).

“The treatment is extremely well tolerated,” said Greten.

For all patients in the study, the most frequent grade ≥2 adverse events (AEs) were an increase in aspartate aminotransferase (AST) levels (n = 11), hyperbilirubinemia (n = 7), and an increase in alanine aminotransferase (ALT) levels (n = 6). There was a low incidence of grade 3-4 AEs; the most common were an AST increase for 7 patients, and hyperbilirubinemia and increased ALT in 3 patients each. Overall, 4 patients (13%) discontinued therapy due to toxicities.

Additionally, investigators concluded that the combination strategy resulted in an activation of tumor virus-specific responses and that anti-CTLA-4 therapy led to an infiltration of CD8-positive T cells in patients who responded to the therapy.

While this study serves as a proof of concept for combining standard therapies with an immunotherapy agent, other trials of checkpoint blockade agents also are registering positive signals, Greten indicated.

He noted tremelimumab demonstrated disease control rates of 76.4% as monotherapy in a 21-patient study and 84.2% in combination with ablation in a 32-patient cohort. In a larger trial among 206 patients, the PD-1 inhibitor nivolumab (Opdivo) resulted in a 9% overall response rate and a decline in tumor burden for 39% of 174 evaluable participants.

Some of the checkpoint strategies are already reaching phase III trials, Greten noted. Nivolumab is being compared with sorafenib as a primary treatment for advanced HCC (NCT02576509) and pembrolizumab (Keytruda) is being evaluated against best supportive care in patients who have previously received systemic therapy (NCT02702401).

Tim Greten. State-of-the-Art Lecture 1: Immunology and Immunotherapy of Hepatocellular Carcinoma. Presented at: 10th Annual Conference of the International Liver Cancer Association; Vancouver, Canada, September 9-11, 2016.

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