The HIMALAYA study has met its primary end point of overall survival improvement in patients with unresectable hepatocellular carcinoma with tremelimumab plus durvalumab.
The frontline combination of tremelimumab and durvalumab (Imfinzi) achieved a statistically significant and clinically meaningful overall survival (OS) benefit compared with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) who had not received prior systemic therapy and were not eligible for localized treatment, meeting the primary end point of the phase 3 HIMALAYA trial.1
Tremelimumab plus durvalumab also demonstrated a tolerable safety profile with no increase in severe hepatic toxicity shown, and durvalumab administered as monotherapy was found to be non-inferior to sorafenib in terms of OS with better tolerability.
“HIMALAYA is the first phase 3 trial to add a novel single priming dose of an anti-CTLA4 antibody to another checkpoint inhibitor, durvalumab. This serves to boost the patient’s own immune system against their liver cancer, aiming to maximize long-term survival with minimal side effects. This is very exciting news for our patients,” said Ghassan Abou-Alfa, MD, MBA, attending physician at Memorial Sloan Kettering Cancer Center and principal investigator
of HIMALAYA, in a press release.
HIMALAYA (NCT03298451) was a randomized, open-label, multicenter, global phase 3 study in which durvalumab 1500 mg was given alone or in combination with tremelimumab 300 mg every 4 weeks and compared with sorafenib. A total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy were enrolled in 190 centers across 16 countries.
In addition to OS, the study evaluated time to progression, progression-free survival, objective response rate, duration of response, and disease control rate as secondary end points.
In an early analysis of the study, of tremelimumab plus durvalumab for the treatment of patients with advanced HCC, 433 patients were assessed, and data were available for 332 patients in parts 2 and 3 of the study, who were evaluated for safety and efficacy with a data cut-off of February 28, 2020. Seventy-five patients were treated with the 300 mg dose of tremelimumab in combination with durvalumab.2
The median OS observed with the combination was 18.73 months (95% CI, 10.78-27.27). The ORR observed with tremelimumab plus durvalumab was 24.0% (95% CI, 14.9%-35.3%) with the median DOR not reached.
In terms of safety assessed in 74 of the patients 35.1% experienced grade 3 or 4 treatment-related adverse events (TRAEs). Serious TRAEs were seen in 16.2% of patients and only 1.4% experienced grade 5 TRAEs.
“Inhibition of CTLA-4 has shown the ability to drive benefit particularly in the tail of the survival curve in several settings. This is the first time a dual immunotherapy regimen has improved overall survival as a 1st-line treatment for patients with unresectable liver cancer for whom treatment options are limited and long-term outcomes are poor,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca stated, in a press release.
The phase 3 study administered tremelimumab at the higher dose level in patients who had been diagnosed with HCC based on histopathological confirmation, did not receive prior systematic treatment for HCC, were Barcelona Clinic Liver Cancer (BCLC) stage B or stage C, were Child-Pugh Score class A, and had a ECOG performance status of 0 or 1 at the time of study enrollment.3
Patients who had hepatic encephalopathy within 12 weeks of the start of the study were ineligible to enroll as were those with clinically meaningful ascites, main portal vein tumor thrombosis, active or prior documented gastrointestinal bleeding within 12 months, and Hepatitis B or C virus co-infection or Hepatitis D virus co-infection.
Tremelimumab plus durvalumab was granted orphan drug designation by the FDA for the treatment of advanced HCC. Full results from the HIMALAYA study will be presented at an upcoming medical meeting.1
1. AstraZeneca News Release. Imfinzi plus tremelimumab significantly improved overall survival in HIMALAYA Phase III trial in 1st-line unresectable liver cancer. New release. October 15, 2021. Accessed October 15, 2021. https://bit.ly/3j6eCx6
2. AstraZeneca News Release. Imfinzi plus tremelimumab demonstrated promising clinical activity and tolerability in patients with advanced liver cancer. News release. May 29, 202. Accessed October 15, 2021. https://bit.ly/3DMoIeq
3. Clinicaltrials.gov. Study of durvalumab and tremelimumab as first-line treatment in patients with advanced hepatocellular carcinoma (HIMALAYA). Accessed October 15, 2021.