The FDA has accepted for priority review a biologics license application seeking the approval of a single priming dose of tremelimumab added to regular interval durvalumab in the treatment of patients with unresectable hepatocellular carcinoma.
The FDA has accepted for priority review a biologics license application (BLA) seeking the approval of a single priming dose of tremelimumab added to regular interval durvalumab (Imfinzi; the STRIDE regimen) in the treatment of patients with unresectable hepatocellular carcinoma (HCC).1 A supplemental BLA has also been submitted for durvalumab in this indication.
Both applications are supported by final findings from the phase 3 HIMALAYA trial (NCT03298451), in which the regimen (n = 393) resulted in a 22% reduction in the risk of death compared with sorafenib (Nexavar; n = 389) in this patient population (hazard ratio [HR], 0.78; 96.02% CI, 0.65-0.93; P = .0035).2 The median overall survival (OS) in the investigative arm was 16.4 months (95% CI, 14.2-19.6) vs 13.8 months (95% CI, 12.3-16.1) in the control arm, meeting the primary end point of the research.
The Prescription Drug User Fee Act date is during the fourth quarter of 2022, following the use of a priority review voucher.
“The HIMALAYA phase 3 trial showed an unprecedented 3-year OS in this setting with a single priming dose of tremelimumab added to [durvalumab], highlighting the potential for this regimen to improve longer-term survival outcomes,” Susan Galbraith, executive vice president of Oncology Research & Development at AstraZeneca, stated in a press release. “Patients with advanced liver cancer are in great need of new treatment options, and we are working closely with the FDA to bring this novel approach to patients in the United States as soon as possible.”
The open-label, multicenter, global, phase 3 trial enrolled patients with confirmed unresectable HCC who had an ECOG performance status of 0 or 1 and Child-Pugh A disease. Patients could not have previously received systemic therapy, nor could they have main portal vein thrombosis.
A total of 1324 patients were randomized to receive the STRIDE regimen comprised of tremelimumab given at 300 mg for 1 dose and durvalumab given at 1500 mg every 4 weeks (n = 393), durvalumab monotherapy given at the same dose and schedule (n = 389), sorafenib given at a twice-daily dose of 400 mg (n = 389), or tremelimumab given at 75 mg every 4 weeks for 4 doses in combination with durvalumab given every 4 weeks (n = 153; T75+D). The T75+D arm has since closed.
Stratification factors included macrovascular invasion (yes vs no), etiology of liver disease (hepatitis B virus [HBV] vs hepatitis C virus [HCV] vs others), and ECOG performance status (0 vs 1).
The primary objective of the trial was OS for the STRIDE regimen vs sorafenib, and a key secondary objective was OS for durvalumab monotherapy vs sorafenib monotherapy. Additional secondary objectives included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per investigator assessment and RECIST v1.1 criteria, as well as safety.
HIMALAYA had multiple testing procedure which started with determining the superiority of the STRIDE regimen over sorafenib in terms of OS, followed by establishing OS noninferiority for single-agent durvalumab vs single-agent sorafenib with a margin of 1.08, followed by OS superiority for durvalumab monotherapy vs sorafenib monotherapy.
At a data cutoff of August 27, 2021, 99.0% of those on the STRIDE regimen arm received treatment, 31.8% were still on the study, and 11.3% were still receiving treatment on the study. Just under 90% of patients (88.7%) discontinued treatment because of objective disease progression (47.0%), subjective disease progression (15.7%), toxicity (13.4%), another unspecified reason (6.2%), patient decision (4.9%), met discontinuation criteria (1.3%), or loss to follow-up (0.3%).
In the STRIDE regimen arm, the median age was 65.0 years (range, 22-86), and 83.2% of patients were male. Moreover, 39.7% of patients resided in Asia, excluding Japan, and 60.3% resided in the rest of the world, including Japan. Regarding viral etiology, 41.0% of patients had nonviral status, 31.0% had HBV, and 28.0% had HCV. The majority of patients (62.1%) had an ECOG performance status of 0, and the remainder had a status of 1.
Of the 393 patients in the STRIDE regimen arm, 40.7% received subsequent second-line anticancer therapies; 36.4% of these patients received targeted therapy, 1.8% received immunotherapy, 1.8% had cytotoxic chemotherapy, 0.3% received antiangiogenic therapy, and 0.3% received another form of treatment.
Additional data presented during the 2022 Gastrointestinal Cancers Symposium showed that the HR for OS for the time up to 9 months for the STRIDE regimen vs sorafenib was 0.87 (95% CI, 0.68-1.11); the HR for time after 9 months was 0.70 (95% CI, 0.56-0.89).
The median PFS achieved with the STRIDE regimen was 3.78 months (95% CI, 3.68-5.32; HR, 0.90; 95% CI, 0.77-1.05) vs 4.07 months (95% CI, 3.75-5.49) with sorafenib and 3.65 months (95% CI, 3.19-3.75) with durvalumab monotherapy (HR, 1.02; 95% CI, 0.88-1.19).
The median time to progression with the STRIDE regimen was 5.42 months (95% CI, 3.81-5.62) vs 3.75 months (95% CI, 3.68-5.42) with durvalumab monotherapy and 5.55 months (95% CI, 5.13-5.75) with sorafenib monotherapy.
The STRIDE regimen elicited an ORR of 20.1% vs 17.0% with durvalumab monotherapy and 5.1% with sorafenib, with a median DOR of 22.34 months, 16.82 months, and 18.43 months, respectively. The disease control rate achieved with the STRIDE regimen was 60.1% vs 54.8% with single-agent durvalumab and 60.7% with sorafenib.
Regarding safety, the toxicity profiles of the STRIDE regimen and single-agent durvalumab proved to be consistent with what has been previously reported for each agent. No new safety signals were observed.
Moreover, 97.4% of those who received the STRIDE regimen experienced any-grade toxicities vs 88.9% of those who received single-agent durvalumab, and 95.5% of patients who received sorafenib. Treatment-related adverse effects (AEs) were experienced by 75.8%, 52.1%, and 84.8% of patients, respectively. Grade 3 or 4 toxicities were reported by 50.5%, 37.1%, and 52.4% of patients, respectively; 25.8%, 12.9%, and 36.9% of patients, respectively, experienced grade 3 or 4 toxicities linked with treatment.
Nine patients in the STRIDE arm experienced a TRAE that resulted in death vs 0 patients on the durvalumab arm and 3 patients on the sorafenib arm. TRAEs resulted in discontinuation in 8.2% of those in the STRIDE regimen arm, 4.1% of those in the durvalumab arm, and 11.0% of those in the sorafenib arm.
Previously, in January 2020, the FDA granted an orphan drug designation to durvalumab and tremelimumab for use in the treatment of patients with HCC.3