Patients with advanced, unresectable hepatocellular carcinoma may be gaining another first-line treatment option. In the global phase III HIMALAYA trial, a single priming dose of tremelimumab plus regular-interval durvalumab significantly improved overall survival, according to Ghassan K. Abou-Alfa, MD, MBA, Attending Physician at Memorial Sloan Kettering Cancer Center, New York, who presented the findings at the 2022 ASCO Gastrointestinal Cancers Symposium.1
The STRIDE regimen (T300+D) is a novel combination featuring a single “high-priming” 300-mg dose of the CTLA-4 monoclonal antibody tremelimumab and a regular schedule of the PD-L1 inhibitor durvalumab (1,500 mg every 4 weeks). According to Dr. Abou-Alfa, the priming dose of tremelimumab boosts the immune modulation process at the start of the immunogenicity pathway, and this enhances the immune response as treatment continues.
Ghassan K. Abou-Alfa, MD, MBA
“The STRIDE regimen statistically significantly improved overall survival vs sorafenib (hazard ratio [HR] = 0.78; P = .0035). STRIDE appeared to provide a long-term survival benefit, with a landmark 36-month overall survival of 30.7%,” Dr. Abou-Alfa reported.
The study also examined the benefit of first-line single-agent durvalumab and found it to be noninferior to sorafenib, with approximately 25% of patients alive at 3 years, compared with 20% with sorafenib. “T300+D and durvalumab monotherapy may represent new treatment options for patients with unresectable hepatocellular carcinoma,” Dr. Abou-Alfa commented.
When the HIMALAYA study launched in 2017, the only therapy approved for unresectable hepatocellular carcinoma was sorafenib. The subsequent approval of lenvatinib gave clinicians the option of two tyrosine kinase inhibitors, which are associated with a median overall survival of about 1 year and some worrisome toxicities. More recently, in IMbrave150, the PD-L1 inhibitor atezolizumab given with bevacizumab significantly improved overall survival vs sorafenib (median, 19.2 vs 13.4 months; HR = 0.66; P = .0009) and thus became a standard of care in 2020.2
About HIMALAYA
The HIMALAYA TRIAL was preceded by the phase I/II Study 22, which showed clinical activity and tolerability of T300+D, with a median overall survival of 18.7 months.3 Upon these findings, the U.S. Food and Drug Administration granted Orphan Drug designation to T300+D.
HIMALAYA was a global study with a heterogeneous population representative of patients with hepatocellular carcinoma. Investigators randomly assigned 1,171 patients to one of three different treatment regimens: T300+D; durvalumab monotherapy (1,500 mg every 4 weeks); or sorafenib (400 mg twice daily). A fourth arm, which involved a different schedule of tremelimumab plus durvalumab, closed early.
The primary endpoint was overall survival with T300+D vs sorafenib. Noninferiority for single-agent durvalumab was also tested (based on the primary endpoint being met).
Improvement in Overall Survival
At a median follow-up of 16 months, median overall survival was 16.4 months with T300+D vs 13.8 months with sorafenib (hazard ratio [HR] = 0.78; P = .0035). The Kaplan-Meier curves for survival began separating around 9 months. The hazard ratio for time up to 9 months was 0.87, improving to 0.70 for time after 9 months.
“T cells may already have been primed, thus suggesting the prompt and short time to response of 2.2 months. Further priming evolves over time, with continued separation of the Kaplan-Meier curves, and at the time of different landmark analyses. By 3 years, 30.7% of patients on T300+D were still alive, compared with 20.2% on sorafenib,” Dr. Abou-Alfa reported. With single-agent durvalumab, 24.7% of patients remained alive at 3 years.
For the secondary objective—the comparison of single-agent durvalumab to sorafenib—“durvalumab showed noninferiority to sorafenib,” he said. Median overall survival was 16.6 months with durvalumab and 13.8 months with sorafenib (HR = 0.86; 95% confidence interval = 0.73–1.03), with hazard ratios improving over time.
The STRIDE regimen statistically significantly improved overall survival vs sorafenib (HR = 0.78; P = .0035). STRIDE appeared to provide a long-term survival benefit, with a landmark 36-month overall survival of 30.7%.— Ghassan K. Abou-Alfa, MD, MBA
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The benefit achieved with T300+D was independent of sex, age, etiology, performance status, and extent of disease. Although the benefit appeared to be nil in females, that subset was small (< 100 patients) and “may not imply any significance,” he commented. Similarly, the regimen appeared to lack benefit in patients with hepatitis C viral etiology; however, when corrected for extrahepatic spread and albumin-bilirubin score imbalances were corrected, the hazard ratio became favorable and improved to 0.87.
In contrast to the overall survival benefit, progression-free survival was the same for the two arms: median, 3.8 months for T300+D and 4.1 months for sorafenib. “So what?” stated Dr. Abou-Alfa, deemphasizing the value of progression-free survival in the setting of dual checkpoint inhibition and restressing the critical value of overall survival.
Response rates were 20.1% with T300+D, 17.0% with durvalumab, and 5.1% with sorafenib, with complete response rates of 3.1%, 1.5%, and 0%, respectively. Of note, the time to response was quite rapid in the durvalumab arms—2.2 and 2.1 months—compared with 3.8 months with sorafenib. Dr. Abou-Alfa attributed these results to the priming effect of tremelimumab. Median duration of response was 22.3 months, with 65.8% of patients remaining in response at 12 months.
Both the STRIDE regimen and durvalumab monotherapy had manageable safety profiles, with lower rates of grade 3 or 4 treatment-related adverse events and adverse events leading to discontinuation of therapy than sorafenib. No increase in liver toxicity or bleeding risk was reported.
DISCLOSURE: Dr. Abou-Alfa reported financial relationships with Adicet Bio, Alnylam, AstraZeneca, Autem Medical, Bayer, BeiGene, Berry Genomics, Celgene, CytomX Therapeutics, Eisai, Exelixis, Flatiron Health, Genoscience Pharma, Helio Health, Incyte, Ipsen, Legend Biotech, Lilly, Center for Emerging & Neglected Diseases, Merck Serono, Nerviano Medical Sciences, QED Therapeutics, Rafael Pharmaceuticals, RedHill Biopharma, Roche/Genentech, Servier, Silenseed, SillaJen, Sobi, Surface Oncology, TheraBionic, TwoXAR, Vector Health, Yiviva, and Polaris.
REFERENCES
1. Abou-Alfa GK, Chan SL, Kudo M, et al: Phase 3 randomized, open-label, multicenter study of tremelimumab and durvalumab as first-line therapy in patients with unresectable hepatocellular carcinoma: HIMALAYA. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 379. Presented January 21, 2022.
2. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.
3. Kelley RK, Sangro B, Harris W, et al: Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: Randomized expansion of a phase I/II study. J Clin Oncol 39:2991-3001, 2021.
