Dual Immunotherapy Promising New Option for Liver Cancer

Roxanne Nelson, RN, BSN

January 24, 2022

SAN FRANCISCO ― A novel dual immunotherapy regimen significantly improved overall survival compared to a standard of care in patients with advanced, unresectable hepatocellular carcinoma (HCC) in the large phase 3 HIMALAYA trial.

The novel regimen, dubbed STRIDE (Single T Regular Interval D), comprised a single priming dose of the investigational agent tremelimumab followed by regular doses of durvalumab (Imfinzi).

Patients on this regimen experienced a 22% lower risk of death than patients treated with sorafenib (Nexavar), which at the time the trial began was the only approved frontline standard of care for patients with advanced HCC.

At 3 years, almost 31% of patients treated with combination therapy were still alive, vs 24.7% for durvalumab alone and 20.2% for sorafenib.

This novel regimen "may represent new treatment options for patients with untreated hepatocellular carcinoma," said lead author Ghassan Abou-Alfa, MD, MBA, an attending physician at Memorial Sloan Kettering Comprehensive Cancer Center in New York. "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."

He presented the new results here at the Gastrointestinal Cancers Symposium (GICS) 2022.

Discussing the abstract, Anthony B. El-Khoueiry, MD, from the University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, agreed that the STRIDE regimen, with the combination of one priming dose of tremelimumab and regular interval durvalumab, is a new first-line treatment option for advanced HCC patients.

"But there are some limitations to the study and topics that will require further additional investigation," he added.

Liver Cancer Increasing

Liver cancer is one of the few cancers for which deaths rates are increasing. In the United States. The overall rate of death due to liver cancer has doubled since 1980, Abou-Alfa told the audience. The most recent 5-year survival rates are 32.6% for localized disease, 10.8% with regional disease, and 2.4% with distant disease.

Until recently, first-line treatment for untreated HCC was limited to the multi- kinase inhibitors sorafenib and lenvatinib (Lenvima), which have been associated with median overall survival of approximately 1 year, but also with toxicities that impact the quality of life, he commented.

"More recently, the anti-PD-L1 agent atezolizumab plus bevacizumab showed significant survival benefit vs sorafenib and have become a standard of care following approval in 2020," he said

Tremelimumab is an experimental immunotherapy that targets the CTLA-4 receptor, and in 2020 it received orphan drug status for the treatment of HCC from the US Food and Drug Administration (FDA). The authors hypothesized that tremelimumab would boost the response to durvalumab, a PDL-1 inhibitor, as this had been observed in the phase 2 Study 22 trial, which had tested the STRIDE regimen..

Now in the phase 3 HIMALAYA trial, the STRIDE regimen was compared to durvalumab used alone and to sorafenib used alone.

The trial randomized 1171 patients to receive either the STRIDE regimen (single dose of 75 mg tremelimumab plus 1500 mg durvalumab every 4 weeks) or durvalumab alone (1500 mg every 4 weeks) or sorafenib alone (400 mg twice daily).

Initially, there was also a lower-dose tremelimumab-containing arm, but recruitment into this arm was halted after a planned analysis of Study 22 failed to show a meaningful efficacy difference between that arm and durvalumab alone.

At data cutoff, the study's primary objective was met. Overall survival was significantly improved for STRIDE vs sorafenib (hazard ratio; P = .0035). Median overall survival was 16.4 months for the STRIDE group vs 13.8 months for sorafenib and 16.6 months for durvalumab alone.

Median progression-free survival was 3.8 months, 3.7 months, and 41.1 month, respectively.

The overall response rate for the STRIDE arm was 20.1% compared to 17% for durvalumab and 5.1% for sorafenib, and the median duration of response was 22.3 months, 16.8 months, and 18.4 months, respectively.

Treatment-related grade 3 or 4 adverse events occurred in 25.8% of patients on the combination, compared to 12.9% for durvalumab and 36.9% for sorafenib.

Grade 5 events occurred in 2.3% of the STRIDE group, compared with 0% among those receiving durvalumab alone and 0.8% in the sorafenib group. Treatment discontinuation due to events occurred in 8.2%, 4.1% and 11.0% of patients, respectively.

New Option for First-Line Treatment

In his discussion of the abstract, El-Khoueiry raised a few issues with the HIMALAYA trial that he felt needed further investigation.

Due to the study design, no conclusions can be drawn regarding the STRIDE regimen vs durvalumab as a single agent — the study was not powered for that, he said.

Also, the trial excluded patients with main portal vein thrombosis (PVT), he noted, and he felt that the subgroup analysis of hepatitis C patients requires further study.

"Another point is that, compared with other studies, bleeding events were less common in the HIMALAYA trial, but it did exclude patients with main PVT who are at highest risk of bleeding," he pointed out.

STRIDE has a different toxicity profile from that seen with VEGF-containing combinations (eg, containing bevacizumab) and has a lower bleeding risk and a manageable rate of immune-mediated adverse events that require steroids. "But looking at non-VEGF regimens, is there an advantage to this, since most subsequent therapies target VEGF?" he questioned.

Another question is if there is a role for single agent PD-1/PD-L1 in first-line HCC. "This trial found that durvalumab was noninferior to sorafenib. This could be a first-line treatment option for select patients — maybe those who are poor candidates for combination therapy or have contraindications to VEGF," said El-Khoueiry.

Nevertheless, STRIDE represents an emerging treatment option for this population, especially for patients who have contraindications for bevacizumab and a high bleeding risk, he concluded.

"So for HCC, it is amazing that we now have multiple first-line treatment options available," he said. "The choice of therapy should be guided by toxicity profile and patient specific contraindications."

For the future, he emphasized that biomarker development is critical to enhance a personalized approach driven by tumor and host biology.

"Sorafenib is no longer an appropriate control arm for first-line trials," he said. "Timing of transition from liver-directed therapy to systemic therapy is critical given multiple available options."

HCC in the setting of compromised liver function continues to be an unmet need. "And finally, in the second line and beyond, therapy after first-line immunotherapy combinations is largely empiric," he said. "Research is needed to establish the efficacy of available and future therapeutic options post immunotherapy and the optimal sequence."

This study received funding from AstraZeneca, maker of durvalumab. Abou-Alfa reported relationships with Adicet Bio, Agios, Alnylam, Arcus Ventures,AstraZeneca, Autem Medica, Bayer, BeiGene, Berry Genomics, Bristol-Myers Squibb, Celgene, Center for Emerging & Neglected Diseases (CEND), CytomX Therapeutics, Eisai, Exelixis, Flatiron Health, Genoscience Pharma, Helio Health, Incyte, Ipsen, Legend Biotech, Lilly, Merck Serono, Nerviano Medical Sciences, QED Therapeutics, Polaris, Puma Biotechnology, Rafael Pharmaceuticals, RedHill Biopharma, Roche/Genentech, Servier, Silenseed, Sillajen, SOBI, Surface Oncology, TheraBionic, twoXAR, Vector Health, Yiviva, and Yiviva. El-Khoueiry reported relationships with ABL bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, CytomX Therapeutics, EISAI, EMD Serono, Exelixis, Fulgent Genetics, Gilead Sciences, Merck, Pieris Pharmaceuticals, QED Therapeutics, Roche/Genentech.mmune.

Gastrointestinal Cancers Symposium (GICS) 2022: Abstract 379. Presented January 21, 2022

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