Results from the randomized international phase III HIMALAYA trial showed that a combination of the anti–PD-L1 immunotherapy durvalumab plus the anti–CTLA-4 immunotherapy tremelimumab reduced the risk of death by 22% in patients with stage III or IV unresectable hepatocellular carcinoma compared to patients who received the kinase inhibitor sorafenib alone. The study’s findings will be presented by Ghassan K. Abou-Alfa, MD, MBA, and colleagues during the 2022 ASCO Gastrointestinal Cancer Symposium (Abstract 379).

Ghassan K. Abou-Alfa, MD, MBA

According to the American Cancer Society, primary liver cancer and intrahepatic bile duct cancer have more than tripled in incidence in the United States since 1980, and mortality rates have more than doubled in this time frame. This year, it is estimated that 41,260 people will be diagnosed and about 30,520 will die from the disease. Worldwide, liver cancer is diagnosed in more than 800,000 people each year and is the leading cause of cancer-related deaths, accounting for more than 700,000 deaths each year.

Study Methodology

In total, 1,171 patients with stage III or IV unresectable hepatocellular carcinoma who had received no prior systemic therapy were randomly assigned to one of three study arms: tremelimumab plus durvalumab as first-line therapy; durvalumab alone, or sorafenib alone. Patients with known risk factors for hepatocellular carcinoma were represented in the trial, including those with viral hepatitis B, hepatitis C, and other nonviral origins. The trial was conducted in the United States, Canada, and 14 other countries.

The primary endpoint of the study was overall survival. A key secondary endpoint was overall survival noninferiority of durvalumab to sorafenib. Other secondary endpoints included progression-free survival, objective response rate, duration of response, and safety.

Results

Patients were followed for a median of about 16 months.

The researchers found that there was a 22% lower risk of death for patients who received the combination of tremelimumab and durvalumab compared to sorafenib alone. At 3 years, approximately 30.7% of patients who had received the combination therapy were still alive, compared to 24.7% who received durvalumab alone and 20.2% who received sorafenib alone.

The overall response rate for the combination therapy was 20.1% vs 17% for durvalumab and 5.1% for sorafenib. Treatment-related grade 3 or 4 adverse events occurred in 25.8% of patients who received tremelimumab and durvalumab vs 12.9% for patients who received durvalumab and 36.9% for those who received sorafenib.

Clinical Significance

“Pending [U.S. Food and Drug Administration] approval, this novel dual immunotherapy regimen could be readily available to all patients and would not require additional safety assessments prior to treatment,” said principal investigator of the HIMALAYA trial Dr. Abou-Alfa, attending physician at Memorial Sloan Kettering Cancer Center, in a statement. “We plan on taking a deeper dive into outcomes based on causes for the disease, such as viral infection, as well as which regions of the liver are impacted.”

ASCO’s Perspective

Cathy Eng, MD, FACP, FASCO

“To date, the HIMALAYA study is one of the largest phase III studies conducted with long-term follow-up demonstrating the role of immunotherapy in surgically unresectable hepatocellular carcinoma. HIMALAYA chose a novel approach of priming with a single dose of combination immunotherapy followed by the single agent durvalumab,” said Cathy Eng, MD, FACP, FASCO, ASCO Expert in gastrointestinal cancers, in a statement. “While the primary endpoint was met, based on the current data, the secondary endpoint of progression-free survival was not superior in either investigational arm relative to the control arm, requiring further discussion.”

Disclosure: This study received funding from AstraZeneca. For full disclosures of the study authors, visit coi.asco.org.