1. Fuerst, Mark L.

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First-line combination immunotherapy with durvalumab plus tremelimumab significantly improves overall survival (OS) in patients with advanced, unresectable hepatocellular carcinoma, the most common type of liver cancer, compared to patients who receive sorafenib.

Liver Cancer. Liver ... - Click to enlarge in new windowLiver Cancer. Liver Cancer

A single priming dose of the experimental anti-CTLA-4 agent tremelimumab added to the anti-PD-L1 agent durvalumab showed encouraging clinical activity and limited toxicity in a Phase II unresectable hepatocellular carcinoma trial, suggesting a single exposure to tremelimumab could improve durvalumab activity. The open-label, multicenter, Phase III HIMALAYA trial was designed to evaluate the efficacy and safety of these two immunotherapies or durvalumab alone versus sorafenib, the current standard of care in unresectable hepatocellular carcinoma.


Principal investigator Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center, presented the results of the HIMALAYA study at the 2022 ASCO Gastrointestinal Cancers Symposium (Abstract 379).


In January 2020, the FDA granted durvalumab plus tremelimumab orphan drug status for the treatment of hepatocellular carcinoma. "Pending FDA approval, this novel dual immunotherapy regimen could be readily available to all patients and would not require additional safety assessments prior to treatment," Abou-Alfa noted.


The overall liver cancer death rate has doubled since 1980. The most recent 5-year survival rates are 32.6 percent in patients diagnosed with localized liver cancer, 10.8 percent with regional disease, and 2.4 percent with distant disease.


About the Study

HIMALAYA enrolled patients with unresectable hepatocellular carcinoma and no prior systemic therapy. Patients were initially randomized to tremelimumab 300 mg plus durvalumab 1,500 mg every 4 weeks, durvalumab 1,500 mg every 4 weeks, sorafenib 400 mg twice daily, or tremelimumab 75 mg every 4 weeks (4 doses) plus durvalumab 1,500 mg every 4 weeks. Recruitment to the tremelimumab 75 mg plus durvalumab regimen was ceased after a planned analysis showed it did not meaningfully differ from durvalumab alone.


In total, 1,171 patients were randomly assigned to tremelimumab plus durvalumab (393 patients), durvalumab alone (389 patients), or sorafenib (389 patients). The primary objective of the study was OS for tremelimumab plus durvalumab versus sorafenib. Patients were followed for a median of about 16 months. Patients with known risk factors for the disease were represented in the trial, including those with viral hepatitis B, hepatitis C, and other non-viral origins. The trial was conducted in the U.S., Canada, and 14 other countries, including those in Europe, South America, and Asia.


While sorafenib was the only approved standard of care for liver cancer at the start of the trial, lenvatinib and atezolizumab plus bevacizumab are also now used as treatments for liver cancer.


Key Findings

The primary objective was met: OS was significantly improved for dual immunotherapy (16.4 months) versus sorafenib (13.8 months), which represents a 22 percent lower risk of death. The median 36-month OS rate was estimated at 30.7 percent for the combination treatment compared to 24.7 percent for those on durvalumab alone and 20.2 percent for sorafenib. The overall response rate for the combination of tremelimumab plus durvalumab was 20.1 percent compared to 17 percent for durvalumab and 5.1 percent for sorafenib.


Median progression-free survival (PFS) was not superior in the immunotherapy arms (3.8 months combination, 3.7 months durvalumab) as compared to sorafenib (4.1 months). No new safety signals were identified, Abou-Alfa noted. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 25.8 percent of patients on dual immunotherapy, 12.9 percent on durvalumab, and 36.9 percent on sorafenib. Grade 3/4 hepatic TRAEs occurred in 5.9 percent of patients on combination treatment, 5.2 percent on durvalumab, and 4.5 percent on sorafenib. No TRAE of esophageal varices hemorrhage occurred. Rates of TRAEs leading to discontinuation occurred in 8.2 percent of those on tremelimumab plus durvalumab, 4.1 percent on durvalumab, and 11 percent on sorafenib.


Next Steps

"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," Abou-Alfa stated.


The researchers will also explore the PFS results in more detail, as well as quality-of-life responses from patients in the trial to determine how best to administer and monitor the drugs to optimize patient care.


ASCO Expert in gastrointestinal cancers, Cathy Eng, MD, the David H. Johnson Chair in Surgical and Medical Oncology at Vanderbilt-Ingram Cancer Center, commented: "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. While the primary endpoint was met, based on the current data, the secondary endpoint of PFS was not superior in either investigational arm relative to the control arm, requiring further discussion," she concluded.


Mark L. Fuerst is a contributing writer.