Durvalumab/Tremelimumab Sustains OS Benefit in Unresectable HCC

The combination of single tremelimumab (Imjudo) with a regular interval of durvalumab (Imfinzi; the STRIDE regimen) maintained an improvement in overall survival (OS) vs sorafenib (Nexavar) monotherapy in patients with unresectable hepatocellular carcinoma (uHCC), according to updated 5-year data from the phase 3 HIMALAYA study (NCT03298451) presented at the 2024 ESMO Congress.¹

With approximately 1 in 5 patients from the experimental arm alive at 5 years, presenting study author Lorenza Rimassa, MD, said these results set a new standard in uHCC.

“This 5-year updated analysis of the HIMALAYA study presents the longest follow-up to date in phase 3 studies for uHCC. STRIDE [single tremelimumab with regular interval durvalumab] sustained an OS benefit vs sorafenib [Nexavar] and demonstrated unprecedented long-term survival benefit at 5 years, with a 5-year survival rate of 19.6% for STRIDE vs 9.4% for sorafenib,” said Rimassa during the presentation.

Rimassa is an associate professor of medical oncology at Humanitas University and head of the Hepatopancreatobiliary Oncology Department at Istituto di Ricovero e Cura a Carattere Scientifico Maugeri Humanitas Research Hospital in Milan, Italy.

Results

In the study, STRIDE (n = 393) compared with sorafenib (n = 389), sustained an OS benefit in patients with uHCC. The median OS was 16.43 months (range, 14.16-19.58) in the STRIDE arm and 13.77 (range, 12.25-16.13) in the sorafenib arm, and the associated HR was 0.76 (95% CI, 2-sided P =.0008). The median follow-up duration was 62.49 vs 59.86 months, respectively.

For patients experiencing disease control per RECIST v1.1, the OS was enhanced, showing rates of 28.7% in the STRIDE arm and 12.7% in the sorafenib arm at 5 years and increasing over time. There were 12 patients (3.1%) in the STRIDE arm that achieved complete response vs 0 patients in the sorafenib arm, and 67 patients (17.0%) experienced partial response vs 20 patients (5.1%), respectively. Stable disease was achieved by 157 (39.9%) in the STRIDE arm and 216 patients (55.5%) in the sorafenib arm, and 141 patients (35.9%) vs 118 (30.3%), respectively, experienced disease progression.

“More patients treated with STRIDE vs sorafenib were still alive, still on study treatment, and fewer received a subsequent therapy at 5 years,” Rimassa noted.

Patients receiving STRIDE also experienced deeper tumor responses, including over 50% shrinkage in 34 patients, which was associated with longer overall survival, compared with 12 patients receiving sorafenib. In addition, 80 patients in the STRIDE arm vs 114 patients in the sorafenib arm experienced minor responses of less than 30% tumor shrinkage; however, this also led to a long-term survival benefit for those receiving STRIDE. In the STRIDE arm, there were 168 patients who had no shrinkage or growth vs 169 patients in the sorafenib arm.

Comparing 4-Year Results

In the 4-year results of the HIMALAYA study, the OS rates were 25.2% in the STRIDE arm vs 15.1% in the sorafenib arm, and the HR was 0.78 (95% CI, 0.67-0.92).2 The data cut-off was January 23, 2023, and of the 103 long-term survivors receiving STRIDE, 57.3% did not require any further anticancer treatment.

Study Design

Participants in the HIMALAYA study were required to have confirmed uHCC, a Child-Pugh score of A, and Barcelona Clinic Liver Cancer stage B or C.1 Patients had no prior systemic therapy for HCC, no main portal vein thrombosis, and had an ECOG performance status of 0 or 1. Stratification factors included the etiology of liver disease (hepatitis B virus, hepatitis C virus, or nonviral), macrovascular invasion (present or absent), and ECOG performance status (0 or 1).

A total of 1171 patients were randomly assigned to 3 arms. Patients in the STRIDE arm (n = 393) received 300 mg in 1 dose of tremelimumab plus 1500 mg of durvalumab every 4 weeks. Similarly, patients in the durvalumab monotherapy arm (n = 389) received 1500mg of durvalumab every 4 weeks, and patients in the sorafenib arm (n = 389) received a 400 mg dose of sorafenib twice daily.

The primary objective was determining the superiority of OS with STRIDE vs sorafenib. The secondary objectives included assessing noninferiority of OS with durvalumab compared with sorafenib, 36-month OS rate, safety, and investigator-assessed progression-free survival per RECIST 1.1, as well as objective response rate and disease control rate.

Multiple testing procedures included: OS superiority for STRIDE vs sorafenib, OS noninferiority for durvalumab vs sorafenib, OS superiority for durvalumab vs sorafenib, and 36-month OS rate for STRIDE vs sorafenib.

Safety

Rimassa stated that there were no new serious treatment-related adverse events (TRAEs) after the primary analysis with a data cut-off on August 27, 2023. At the 5-year data cut-off of March 1, 2024, 17.5% of patients in the STRIDE arm had experienced serious TRAEs, which was the same percentage reported at the primary analysis. Similarly, for the sorafenib arm, at the 5-year analysis data cut-off there were 9.9% of patients who experienced serious TRAEs vs 9.4% at the primary data cut-off.

In addition, there were 24.8% of patients in the STRIDE arm who had serious non-TRAEs at the 5-year data cut-off vs 23.0% at the primary data cut-off, and in the sorafenib arm there were 20.3% of patients experiencing serious non-TRAEs vs 20.3%, respectively.

“Overall survival benefit with STRIDE was enhanced in patients who achieved disease control. Any degree of tumor shrinkage was linked to long-term survival, with those experiencing deep responses showing the greatest benefit. These findings indicate that conventional response measures such as complete response or partial response, according to RECIST 1.1, may not fully capture the benefits of STRIDE,” Rimassa concluded.

References

1. Rimassa L, Chan S, Sangro B, et al. Five-year overall survival (OS) and OS by tumour response measures from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma (uHCC). Presented at the 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 947MO
2. B. Sangro, Chan SL, Kelley RK, et al. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann. Oncol. Published online February 1, 2024. doi:10.1016/j.annonc.2024.02.005