STRIDE as a novel, first-line standard of care regimen for unresectable hepatocellular carcinoma
HIMALAYA was the first large phase III trial with a diverse, representative unresectable hepatocellular carcinoma population and extensive long-term follow-up to assess both mono- and combination immunotherapy. In this study, the combination of a single priming dose of tremelimumab plus regular interval durvalumab (STRIDE) displayed superior efficacy and a favourable benefit-risk profile as compared to sorafenib.
Until recently, first-line treatment options for unresectable hepatocellular carcinoma (uHCC) were limited to the multi-kinase inhibitors sorafenib and lenvatinib, which have been associated with a median overall survival (OS) of approximately one year and toxicities that impact quality of life. Atezolizumab plus bevacizumab showed significant survival benefit vs. sorafenib and has become the standard of care. The STRIDE (Single Tremelimumab Regular Interval Durvalumab; T300+D) regimen showed encouraging clinical activity and was well tolerated in a phase II trial in uHCC. At ASCO GI 2022, results from the final analysis of the HIMALAYA trial were presented.
HIMALAYA is an open-label, multicentre, phase III study, in which patients with uHCC and no prior systemic therapy were initially randomised to STRIDE (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose] plus durvalumab 1,500 mg every 4 weeks [Q4W]), durvalumab monotherapy (1,500 mg Q4W), sorafenib (400 mg twice daily), or tremelimumab 75 mg Q4W (4 doses) plus durvalumab 1,500 mg Q4W (T75+D). Recruitment to T75+D ceased after a planned analysis of Study 22 showed T75+D did not meaningfully differ from durvalumab alone. The primary objective was overall survival (OS) superiority for STRIDE vs. sorafenib. The secondary objective was OS non-inferiority of durvalumab to sorafenib.
In total, 1,171 patients were randomised to STRIDE (N=393), durvalumab (N=389), or sorafenib (N=389). At data cut-off, 11.3% of patients in the STRIDE arm were still on study treatment, as compared to only 5.6% in the sorafenib arm. The main reason for discontinuation was progressive disease among all three arms. Baseline patient characteristics were well balanced between all study arms. Approximately 40% of patients were from Asia (excluding Japan) and roughly 60% had viral aetiology (hepatitis B or C). All patients were Child-Pugh A. Almost 40% of patients were PD-L1 positive, defined as tumour area positivity score ≥1%.
At data cut-off, the primary objective was met and OS was significantly improved for STRIDE vs. sorafenib (HR[96.02%CI]: 0.78[0.65–0.92]; p= 0.0035). Median overall survival was 16.4 months for STRIDE and 13.8 months for sorafenib, with 36-month OS rates of 30.7% and 20.2%, respectively. Furthermore, durvalumab met the objective of OS non-inferiority to sorafenib (HR[95.67%CI]: 0.86[0.73–1.03]). Median overall survival was 16.6 months for durvalumab and 13.8 months for sorafenib, with a 36-month OS rate of 24.7% for durvalumab monotherapy. Median progression-free survival was 3.78 months, 3.65 months and 4.07 months for STRIDE, durvalumab and sorafenib, respectively. Furthermore, respectively 46.9%, 48.5% and 34.4% of patients were treated with at least one cycle of therapy beyond progression. ORRs were higher for both STRIDE (20.1%) and durvalumab (17.0%) than for sorafenib (5.1%). The median time to response was only 2.17 months for patients in the STRIDE arm (vs. 3.78 months with sorafenib).
No new safety signals were identified. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 25.8% (STRIDE), 12.9% (durvalumab), and 36.9% (sorafenib) of patients. Grade 3-4 hepatic TRAEs occurred in 7.0% (STRIDE), 5.2% (durvalumab), and 4.8% (sorafenib) of patients. No TRAE of oesophageal varices haemorrhage occurred. Rates of TRAEs leading to discontinuation were 8.2% (STRIDE), 4.1% (durvalumab), and 11.0% (sorafenib).
A single priming dose of tremelimumab plus regular interval durvalumab with the STRIDE regimen significantly improved overall survival versus sorafenib. In addition, the overall survival upon durvalumab monotherapy was non-inferior to sorafenib, with a favourable benefit-risk profile. Both STRIDE and durvalumab monotherapy had manageable safety profiles, with lower rates of grade 3-4 TRAEs and TRAEs leading to discontinuation than sorafenib, and no increase in liver toxicity or bleeding risk. Therefore, the STRIDE regimen and durvalumab monotherapy may represent new treatment options for patients with uHCC.
Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. Presented at ASCO GI 2022; Abstract 379.