Identifying new and improved methods to treat patients in all stages of oncology care is integral to HOPA's mission. Two Houston, Texas based HOPA members and pharmacists share research on the efficacy of STRIDE versus sorafenib (an historical standard of care) as first-line therapy on unresectable Hepatocellular Carcinoma.


Godsfavour Umoru, PharmD, BCOP,  Houston Methodist Hospital and Joel Sunil, PharmD Candidate 2023 University of Houston College of Pharmacy.


Hepatocellular Carcinoma (HCC) is one of the most prevalent primary gastrointestinal malignancies, and accounts for more than 90% of patients with primary liver tumors.1 Given the lack of symptoms with early-stage disease, approximately 15 – 20% of patients present with metastatic disease at diagnosis. Prognosis of HCC is dependent on tumor size, differentiation, etiology, and metastases, with an average 5-year survival rate of 18%.1 Despite advances in treatment for unresectable HCC, more research is warranted as long-term benefit and survival are dismal with a median progression free survival (PFS) of 3 – 4 months.2 HCC can arise from several etiologies such as hepatitis B virus (HBV)/hepatitis C virus (HCV), alcoholic liver disease, and non-alcoholic fatty liver disease. Of these etiologies, alcoholic liver disease is the most common and exerts its pathogenesis through perpetual inflammation and fibrogenesis, causing the formation of dysplastic/malignant cells.3

The National Comprehensive Cancer Network (NCCN) recently highlighted the combination of tremelimumab-actl with durvalumab as a category 1 recommendation for unresectable HCC in the first-line setting based on the results from the HIMALAYA trial and subsequent FDA approval on October 21, 2022.4 Prior to this, atezolizumab with bevacizumab was the only category 1 recommendation in this setting based on the results from the IMbrave150 trial where the combination demonstrated superiority in overall survival (OS) compared to sorafenib (19.2 months vs 13.4 months; hazard ratio [HR], 0.66; 95% CI, 0.52 - 0.85; P=0.0009) and included special populations (i.e., patients with high risk disease and portal vein thrombosis).5 In addition, there was limited utility of dual immune checkpoint inhibitors (ICIs) for HCC outside of tumors with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) or high tumor mutational burden (TMB-H). However, the results of recent studies which demonstrated efficacy with dual ICIs in patients with metastatic malignancies, such as melanoma and non-small cell lung cancer (NSCLC), created the inspiration for their use in HCC.6,7


The open-label, sponsor-blind, multi-center, global, phase III HIMALAYA study was designed to evaluate the efficacy of STRIDE versus sorafenib (an historical standard of care) as first-line therapy in unresectable HCC.8 STRIDE consists of a single high dose of the CTLA-4 inhibitor tremelimumab-actl (300 mg) plus the PD-L1 inhibitor durvalumab (1500 mg every 4 weeks). From a mechanism of action standpoint, the combination provides synergistic anti-tumor activity as tremelimumab-actl increases the number of anti-tumor T cells while durvalumab works to prevent T-cell inactivation. Previous utilization within NSCLC showed that a single high dose of a CTLA-4 inhibitor primes anti-tumor T cells and prevents T cell attenuation during the priming phase, as observed by increased CD4 and CD8 T cell expansion after tremelimumab-actl administration.7,9 Anti-CTLA-4 adverse reactions are typically observed after repeat dosing, which brought about the question of whether a single high dose of tremelimumab-actl would maintain efficacy while minimizing adverse effects. The phase I/II sister study of HIMALAYA reported that patients treated with STRIDE had the highest CD8+ T cell counts compared to the other arms, including frequent dosing tremelimumab-actl plus durvalumab.9

Between October 2017 and June 2019, 1171 patients were randomized in a 1:1:1 fashion to receive STRIDE (n = 393), durvalumab 1500 mg every 4 weeks as monotherapy (n = 389), or oral sorafenib 400 mg twice daily (n = 389). Important inclusion criteria were no prior systemic therapy, Barcelona Clinic Liver Cancer (BCLC) stage B or C, Child-Pugh Score class A, ECOG performance score of 0 – 1, and at least 1 measurable lesion greater than 10 millimeters not previously irradiated.8 Of note, patients were excluded if they had main portal vein thrombosis, metastases to the central nervous system (CNS), or received an immunosuppressive medication within 14 days prior to the trial.9 The primary endpoint was OS of STRIDE compared to sorafenib and secondary endpoints included OS of durvalumab compared to sorafenib, PFS, time to progression (TTP), objective response rate (ORR), and disease control rate (DCR). Safety and patient-reported outcomes were also evaluated.8

With a follow-up of 36 months, the primary endpoint of OS was 16.43 months in the STRIDE arm (95% CI, 14.16 – 19.58) versus 13.77 months in the sorafenib arm (95% CI, 12.25 – 16.13), showing superiority. At data cutoff, 66.7% and 75.3% of patients died in the STRIDE and sorafenib arm, respectively (HR, 0.78; 96% CI, 0.65-0.93). The secondary endpoint of OS was 16.56 months in the durvalumab arm (95% CI, 14.06 – 19.12) vs 13.77 months in the sorafenib arm (95% CI, 12.25 – 16.13), inferring noninferiority. ORR was 20.1% with STRIDE, 17% with durvalumab, and 5.1% with sorafenib while complete response was 3.1% with STRIDE, 1.5% with durvalumab, and 0% with sorafenib. Median PFS was similar between all arms at 3.8 months with STRIDE (95% CI, 3.7 – 5.3), 3.7 months with durvalumab (95% CI, 3.2 - 3.8), and 4.1 months with sorafenib (95% CI, 3.8 - 5.5).8

STRIDE and durvalumab had manageable safety profiles, with 20.1% and 9.5% immune-related adverse effects (irAEs), and 12.6% and 6.4% grade 3 or 4 irAEs. The most common irAEs were hepatic events, diarrhea/colitis, and dermatitis/rash. Other common adverse events of interest were decreased appetite, fatigue, and insomnia.8


STRIDE presents an alternative first-line choice for patients with unresectable HCC with a manageable side effect profile and a 22% reduction in risk of death over sorafenib. The HIMALAYA trial is important because it demonstrates efficacy with PD-L1 and CTLA-4 combination blockade for HCC although longer follow-up is needed to see if this strategy will elicit durable disease control. Given the lack of a head-to-head comparison between the HIMALAYA and IMbrave150 trials, a critical look at the external validity of both is required to guide treatment decisions for the varied patient population encountered in clinical practice. Of note, the exclusion of patients with main portal vein thrombosis in the HIMALAYA trial may limit the utility of STRIDE as a first-line treatment for unresectable HCC since the IMbrave150 study showed that atezolizumab with bevacizumab reduced the risk of death and disease progression over sorafenib by 42% and 41%, respectively, in this high-risk population. However, there was a 7% risk of gastrointestinal bleeding due to bevacizumab. Consequently, STRIDE provides clinical utility for patients with esophageal varices unresponsive to banding, recent surgery, or cardiovascular disease who may not be eligible for an antiangiogenic agent like bevacizumab.

From a future direction’s perspective, studies evaluating the role of STRIDE as subsequent therapy after atezolizumab with bevacizumab failure would elucidate its viability for patients who may have absolute or relative contraindications to currently utilized tyrosine-kinase inhibitors. In addition, clinical practice would benefit from future studies aimed at highlighting the safety and efficacy of STRIDE in patients with moderately impaired liver function (Child Pugh class B).


  1. Asafo-Agyei KO, Samant H. Hepatocellular Carcinoma. [Updated 2023 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
  2. Paul SB, Chalamalasetty SB, Vishnubhatla S, et al. Clinical profile, etiology and therapeutic outcome in 324 hepatocellular carcinoma patients at a tertiary care center in India. Oncology. 2009;77(3-4):162-171.
  3. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene. 2003;22(33):5093-5107.
  4. National Comprehensive Cancer Network. Hepatocellular Carcinoma (version 1.2023). (Accessed April 4, 2023)
  5. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905.
  6. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23(35):8968-8977.
  7. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016;17(3):299-308.
  8. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evidence. 2022;1(8).
  9. Kelley RK, Sangro B, Harris W, et al. Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. J Clin Oncol. 2021;39:2991-3001.
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