Four-year overall survival update from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma

In the primary analysis (data cut-off [DCO]: 27 August 2021) of the phase 3 HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) was superior to sorafenib, and durvalumab monotherapy was noninferior to sorafenib, for overall survival (OS; Abou-Alfa et al. NEJM Evid 2022). With a median duration of follow-up of approximately 33 months in the primary analysis, STRIDE demonstrated a significant and durable long-term survival benefit versus sorafenib with estimated 36-month OS rates of 30.7% and 20.2%, respectively (Abou-Alfa et al. NEJM Evid 2022). Here, we report an updated OS analysis of HIMALAYA with 4 years of follow-up.

Participants with uHCC and no previous systemic treatment were randomised to STRIDE (tremelimumab 300 mg for one dose plus durvalumab 1500 mg every 4 weeks [Q4W]), durvalumab monotherapy (1500 mg Q4W) or sorafenib (400 mg twice daily). The primary objective was to assess OS for STRIDE versus sorafenib. The DCO for this updated analysis was 23 January 2023 (78% OS data maturity for STRIDE). OS and serious treatment-related adverse events (TRAEs) were assessed. OS HRs and CIs were calculated using a Cox proportional hazards model. In addition, baseline demographics and disease characteristics were assessed in long-term survivors (LTS), defined as all participants surviving ≥36 months beyond randomisation.

In total, 1171 participants were randomised to STRIDE (n=393), durvalumab (n=389) or sorafenib (n=389); median (95% CI) duration of follow-up for the OS analysis in all participants was 49.12 (46.95–50.17), 48.46 (46.82–49.81) and 47.31 (45.08–49.15) months, respectively. The OS HR (95% CI) for STRIDE versus sorafenib was 0.78 (0.67–0.92) and consistent with the primary analysis. The OS rates at 36 months for STRIDE (30.7%) and sorafenib (19.8%) were consistent with the primary analysis. The 48-month OS rate remained higher for STRIDE (25.2%) than for sorafenib (15.1%). Serious TRAEs (including death) occurred in 17.5% of participants treated with STRIDE and 9.6% of participants treated with sorafenib, with no new events occurring after the primary analysis for STRIDE (17.5%). Durvalumab OS noninferiority to sorafenib and safety was consistent with the primary analysis. Baseline demographics, clinical characteristics and subsequent therapies, including percentage of participants rechallenged with tremelimumab, for LTS in the STRIDE arm were generally consistent with the full analysis set, suggesting that long-term survival benefit was not driven by any particular subgroup of participants.

These data reinforce the sustained, long-term OS benefit of STRIDE versus sorafenib, demonstrating unprecedented 3- and 4-year OS rates and the longest follow-up to date in phase 3 studies in uHCC. The STRIDE regimen maintained a tolerable yet differentiated safety profile from other current uHCC therapies, with no new serious safety events. These results continue to support the benefits of STRIDE in a diverse population reflective of uHCC globally.

NCT03298451.

Medical writing support, under the direction of the authors, was provided by Claire Tinderholm, PhD, of CMC Connect, a division of IPG Health Medical Communications, funded by AstraZeneca, in accordance with Good Publication Practice (GPP 2022) guidelines.

AstraZeneca.

AstraZeneca.

B. Sangro: Advisory / Consultancy: AstraZeneca, BMS, BTG, Eisai, MSD, Roche, Sanofi, Sirtex, Terumo; Speaker Bureau / Expert testimony: Astra-Zeneca, Eisai, Incyte, Roche, Sirtex; Research grant / Funding (institution): BMS and Sirtex; Travel / Accommodation / Expenses: Astra-Zeneca, Roche. S. Chan: Honoraria (self): AstraZeneca, Roche, MSD; Advisory / Consultancy: Eisai, MSD, AstraZeneca. R. Kelley: Advisory / Consultancy: Astra Zeneca; Research grant / Funding (institution): Astra Zeneca; Travel / Accommodation / Expenses: Astra Zeneca. G. Lau: Advisory / Consultancy: Astra Zenica. M. Kudo: Honoraria (self): Eli Lilly, Bayer, Eisai, Chugai, Takeda, AstraZeneca; Advisory / Consultancy: Chugai, Roche, AstraZeneca, Eisai; Research grant / Funding (institution): Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, GE Healthcare. P. Galle: Honoraria (self): Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen.; Advisory / Consultancy: Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen.; Speaker Bureau / Expert testimony: Bayer, Boston Scientific, AstraZeneca, Adaptimmune, Eisai, Sirtex, Roche, Ipsen.; Research grant / Funding (self): Bayer, Roche; Travel / Accommodation / Expenses: Roche, AstraZeneca, Sirtex, Ipsen. L. Rimassa: Honoraria (self): Lecture fees: Bayer, Eisai, Gilead, Incyte, Ipsen, Merck Serono, Roche, Sanofi, Servier; Advisory / Consultancy: AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; Research grant / Funding (institution): Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks; Travel / Accommodation / Expenses: AstraZeneca. A. Heurgué: Honoraria (self): ASTRA-ZENECA, BAYER, IPSEN. V. Tam: Honoraria (self): Astra Zeneca, Eisai, Roche; Advisory / Consultancy: Astra Zeneca; Research grant / Funding (institution): Astra Zeneca, Eisai, Roche. T. Dao: Honoraria (self): AstraZeneca, Roche, MSD; Advisory / Consultancy: AstraZeneca, Roche, MSD; Travel / Accommodation / Expenses: Merck. V. Breder: Speaker Bureau / Expert testimony: AstraZeneca, Pfizer, EISAI. M. Reig: Advisory / Consultancy: Bayer ; BMS, Roche, Ipsen, Astrazeneca, Lilly, BTG, Universal DX, Geneos, Merck, Universal DX, Terumo; Speaker Bureau / Expert testimony: Bayer, BMS, Gilead, Lilly, Roche, AstraZeneca, Eisai; Research grant / Funding (institution): Bayer , Ipsen; Travel / Accommodation / Expenses: Terumo, AstraZeneca, Roche. M. Makowsky: Full / Part-time employment: AstraZeneca PLC. C. Gupta: Full / Part-time employment: Astrazeneca. A. Negro: Full / Part-time employment: AstraZeneca. G. Abou-Alfa: Advisory / Consultancy: Astellas, Astra Zeneca, Autem, Berry Genomics, BioNtech, Boehringer Ingelheim, BMS, Eisai, Exelixis, Fibriogen, Genentech/Roche, Helio, Incyte, Ipsen, Merck, Merus, Neogene, Newbridge, Novartis, QED, Servier, Tempus, Thetis, Vector, Yiviva; Research grant / Funding (self): Agenus, Arcus, Astra Zeneca, BioNtech, BMS, Elicio, Genentech/Roche, Helsinn, Parker Institute, Pertzye, Puma, QED, Yiviva. All other authors have declared no conflicts of interest.