Durvalumab-tremelimumab regimen significantly prolongs survival in advanced liver cancer
Durvalumab plus tremelimumab significantly extended OS compared with sorafenib among patients with advanced, unresectable hepatocellular carcinoma, according to research scheduled for presentation at ASCO Gastrointestinal Cancers Symposium.
The HIMALAYA trial represented the first large, phase 3 trial with a diverse HCC population and extensive long-term follow-up to assess mono- and combination immunotherapy, researchers wrote.
“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,” Ghassan K. Abou-Alfa, MD, MBA, medical oncologist at Memorial Sloan Kettering Cancer Center, said in a press release.
Background and methodology
Abou-Alfa and colleagues pursued the research after observing encouraging clinical activity and limited toxicity in a phase 2 study of patients with unresectable HCC who received a single priming dose of tremelimumab (MedImmune/AstraZeneca) plus durvalumab (Imfinzi, AstraZeneca). The results suggested single exposure to the former is sufficient to improve upon activity from the latter. Thus, they set out to evaluate efficacy and safety of STRIDE (single tremelimumab, regular interval durvalumab) or durvalumab alone vs. standard-of-care sorafenib (Nexavar, Bayer) among 1,171 patients with unresectable HCC and no prior systemic therapy.
Researchers randomly assigned the study participants to STRIDE, which consisted of 300 mg tremelimumab plus 1,500 mg durvalumab as a single dose, followed by 1,500 mg durvalumab every 4 weeks (n = 393); 1,500 mg durvalumab every 4 weeks (n = 389); or 400 mg twice-daily sorafenib (n = 389).
OS for STRIDE vs. sorafenib served as the primary objective, with OS noninferiority of durvalumab to sorafenib as a secondary objective. Secondary endpoints included PFS, objective response rate, duration of response and safety.
Key findings
Results showed STRIDE conferred significant improvement in OS vs. sorafenib (HR = 0.78; 96% CI, 0.65-0.92; median, 16.4 months vs. 13.8 months). After 3 years, approximately 30.7% of the STRIDE group remained alive compared with 24.7% of the durvalumab group and 20.2% of the sorafenib group.
Additionally, durvalumab met the objective of OS noninferiority to sorafenib (HR = 0.86; 96% CI, 0.73-1.03) and researchers observed higher ORRs for STRIDE (20.1%) and durvalumab (17%) compared with sorafenib (5.1%).
Abou-Alfa and colleagues identified no new safety signals and reported grade 3 or grade 4 treatment-related adverse events among 25.8% of the STRIDE group, 12.9% of the durvalumab group and 36.9% of the sorafenib group. Additional safety analyses revealed grade 3 or grade 4 hepatic treatment-related adverse effects among 5.9% of the STRIDE group, 5.2% with durvalumab and 4.5% with sorafenib, with the following rates of those events leading to discontinuation: 8.2% (STRIDE), 4.1% (durvalumab) and 11% (sorafenib).
Implications
The superior efficacy and favorable benefit-risk profile of the single priming dose of tremelimumab plus durvalumab, compared with sorafenib, suggest STRIDE should be a new first-line standard of care systemic therapy for unresectable HCC, according to Abou-Alfa and colleagues.
In future analyses, researchers will explore PFS results in more detail, in addition to quality-of-life responses from patients in the trial, to assess the best way to administer and monitor the drugs to optimize patient care.
“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 said.
References:
Abou-Alfa GK, et al. Abstract 379. Presented at: Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.
Durvalumab plus tremelimumab significantly improves survival for patients with advanced liver cancer compared to sorafenib. https://www.asco.org/about-asco/press-center/news-releases/durvalumab-plus-tremelimumab-significantly-improves-survival. Published Jan. 18, 2022. Accessed Jan. 18, 2022.
Perspective
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The randomized phase 3 HIMALAYA trial is the first study to show superior OS with an immunotherapy-only regimen compared with sorafenib in patients with advanced hepatocellular carcinoma naive to systemic therapy.
This practice-changing study should lead to FDA approval of the durvalumab-tremelimumab combination and perhaps durvalumab monotherapy, as both arms met their primary endpoints. Choosing between the combination regimen and the current standard of care — the PD-L1 inhibitor atezolizumab (Tecentriq, Genentech) combined with the VEGF inhibitor bevacizumab (Avastin, Genentech) — may prove more complex. Median PFS with durvalumab and tremelimumab was similar to sorafenib, whereas PFS was superior with atezolizumab and bevacizumab in the IMbrave150 study. Despite the lack of PFS benefit, the regimens conferred similar longer-term survival at 2 years. Information about subgroup outcomes, especially in those with nonviral liver diseases where immunotherapy has been suggested to be less effective, may also influence the choice between the regimens.
Many patients with advanced HCC — perhaps 20% to 25% in clinical practice — have either relative or absolute contraindications to antiangiogenic therapy, including untreated esophageal varices, recent bleeding, significant cardiovascular or peripheral vascular disease, uncontrolled hypertension or nonhealing wounds. The availability of immunotherapy-only regimens should prove valuable for such patients. Currently, nivolumab (Opdivo, Bristol Myers Squibb) is recommended per National Comprehensive Cancer Network guidelines for such patients based on the CheckMate-459 study, but FDA accelerated approval of nivolumab for HCC was withdrawn in 2021, leaving no FDA-approved standard.
Durvalumab and tremelimumab did result in a higher rate of serious toxicities compared with durvalumab alone, with 25.8% of patients experiencing grade 3 or grade 4 treatment-related adverse events compared with 12.9% in the durvalumab monotherapy group and a 2.3% rate of treatment-related deaths compared with 0%. Further details regarding these toxicities will be necessary to understand the risks of this regimen relative to other options, but these data make it clear that there are increased risks with the combination compared with durvalumab alone — a finding that contrasts with the prior phase 1/phase 2 results.
The positive results of the HIMALAYA study should lead to additional options for patients with advanced HCC, but further efficacy and safety data are needed to better predict whether this regimen will be widely used or reserved primarily for those who cannot receive bevacizumab. Anticipated results of other front-line phase 3 combination studies with lenvatinib (Lenvima, Eisai) plus pembrolizumab (Keytruda, Merck) and nivolumab plus ipilimumab (Yervoy, Bristol Myers Squibb) may further complicate initial therapy choice in the near future — a welcome problem that few might have predicted several years ago.
Reference:
Finn RS, et al. J Clin Oncol. 2021;doi:10.1200/JCO.2021.39.3_suppl.267.
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Abou-Alfa GK, et al. Abstract 379. Presented at: Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.