Microscopic, photorealistic image of liver tumor cells – Generated with Adobe Firefly
Extended follow-up from the HIMALAYA study (NCT03298451) demonstrates that the STRIDE (single tremelimumab [Imjudo], regular interval durvalumab [Imfinzi]) regimen continues to provide a significant overall survival (OS) advantage over sorafenib (Nexavar) in patients with unresectable hepatocellular carcinoma (HCC) at 5 years.1,2
This landmark analysis, the longest follow-up reported for a phase 3 HCC study, underscores the enduring efficacy and manageable safety profile of this dual immune checkpoint inhibitor (ICI) approach, setting a new benchmark for long-term survival in this challenging disease.
Historically, the prognosis for unresectable HCC has been poor, with 5-year survival rates typically below 10% with conventional therapies like sorafenib. The introduction of ICIs has significantly altered this landscape. The HIMALAYA study, which previously reported a sustained OS benefit at 4 years, now offers even more compelling long-term data on the STRIDE regimen.
Enduring Survival and Deepening Benefit
At a median follow-up of approximately 62.5 months for the STRIDE arm and 59.9 months for the sorafenib arm, the OS hazard ratio for STRIDE vs sorafenib was 0.76 (95% CI, 0.65–0.89). This translates to a remarkable 60-month OS rate of 19.6% for patients receiving the STRIDE regimen compared with 9.4% for those on sorafenib. The OS rate ratio, indicating the relative improvement, further widened over time, reaching 2.09 at 60 months in favor of STRIDE. This sustained and even improving relative benefit highlights the long-term impact of the dual ICI strategy.
The study also delved into the relationship between tumor response and OS. Patients achieving disease control (complete response, partial response, or stable disease) with the STRIDE regimen demonstrated even more pronounced long-term benefits, with a 60-month OS rate of 28.7% compared with 12.7% in the sorafenib arm. Notably, any degree of tumor shrinkage with STRIDE was associated with improved OS, indicating that conventional RECIST v1.1 criteria may not fully capture the nuanced benefits of this immunotherapy combination. For instance, patients with >25% to 100% tumor shrinkage experienced 60-month OS rates of 50.7% with STRIDE vs 26.3% with sorafenib.
“While these data support the clinical activity of durvalumab in uHCC, the continued improvement in OS with STRIDE over durvalumab, relative to sorafenib, highlights the added benefit of combining a single dose of tremelimumab with durvalumab within the STRIDE regimen,” authors wrote in the study published in the Journal of Hepatology.1
Understanding the Depth of Response
A key finding from this updated analysis is the emphasis on depth of response. While RECIST v1.1 defines partial response at 30% tumor shrinkage, the HIMALAYA data suggest that even lesser degrees of shrinkage with the STRIDE regimen can translate into meaningful long-term survival. For instance, patients with 25% to 30% tumor shrinkage, which would be categorized as stable disease by RECIST, showed improved OS with STRIDE compared to sorafenib. This observation suggests a need to reevaluate how response to ICI combinations is assessed, potentially incorporating a broader understanding of tumor dynamics beyond strict RECIST criteria.
More patients treated with STRIDE experienced tumor shrinkage, and to a greater extent, than those treated with sorafenib, demonstrating a greater depth of response. This was particularly evident in long-term survivors, where a higher proportion of STRIDE-treated patients achieved objective responses.
Interestingly, some patients in the STRIDE arm initially classified with progressive disease or stable disease later showed tumor shrinkage, a phenomenon more common with STRIDE than sorafenib. This delayed response pattern further supports the unique characteristics of ICI treatment.
Manageable Safety Profile Maintained
Crucially, the long-term follow-up reinforced the manageable safety profile of the STRIDE regimen. No new late-onset treatment-related serious adverse events were reported, and the proportion of serious treatment-related adverse events remained consistent with previous analyses. This sustained safety profile over 5 years is vital for clinicians considering long-term treatment strategies in this patient population. The study also found that the duration of treatment beyond RECIST v1.1 progression was relatively high across both arms, suggesting that continuing treatment may be beneficial in patients without clinical deterioration.
Implications for Clinical Practice
These 5-year data from the HIMALAYA study provide critical insights for the management of unresectable HCC. The sustained and deepening OS benefit, coupled with a consistent safety profile, solidifies the role of the STRIDE regimen as a robust first-line treatment option. The findings also prompt a reevaluation of how clinicians assess response to ICI therapy, encouraging a focus on the depth of tumor shrinkage as a potential predictor of long-term survival. The observation that 1 in 5 patients treated with STRIDE are alive at 5 years marks a significant advancement in the fight against unresectable HCC.