ASCO Guideline Issues Updated Systemic Therapy Recommendations in HCC

Issuing evidence-based recommendations for systemic therapy regimens in this population involved a literature review that included 8 randomized phase 3 clinical trials from the 2020 version of the guideline that were maintained for the 2023 update. Additionally, the authors included 10 new randomized clinical trials in HCC as part of their evidence base for the latest guideline.

Systemic therapy options such as atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) may be appropriate for use among certain patients with hepatocellular carcinoma (HCC), according to an updated guideline published by the American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology.¹

According to the guideline authors, after sorafenib (Nexavar) demonstrated a survival benefit compared with placebo in this population across various clinical trials in 2008 and 2009, the treatment field had seen no other effective systemic therapy options for approximately a decade. However, the authors noted that the development of new systemic therapy options in recent years has yielded effective outcomes in the first- and second-line settings, which prompted the creation of a systemic therapy guideline for advanced HCC in 2020.²

For the updated guideline, the authors sought to address these clinical questions:

• What are the preferred treatment options for first-line systemic therapy for patients with advanced HCC?
• What are the preferred treatment options for second- or later-line therapy for patients with advanced HCC?

Issuing evidence-based recommendations for systemic therapy regimens in this population involved a literature review that included 8 randomized phase 3 clinical trials from the 2020 version of the guideline that were maintained for the 2023 update. Additionally, the authors included 10 new randomized clinical trials in HCC as part of their evidence base for the latest guideline.

First-line Systemic Therapy

Based on moderate-to-high-quality evidence, the authors issued a strong recommendation for administering atezolizumab/bevacizumab or durvalumab (Imfinzi) plus tremelimumab (Imjudo) as frontline therapy for those with advanced HCC, Child-Pugh class A disease, and an ECOG performance of 0 or 1.

If there is a contraindication to any of these treatments, lenalidomide (Revlimid) may be offered to the previously specified patient population.

In the phase 3 HIMALAYA trial (NCT03298451), durvalumab/tremelimumab yielded a significant improvement in overall survival (OS) compared with sorafenib monotherapy (HR, 0.78; 96.02% CI, 0.65-0.93).³ The durvalumab-based regimen, however, did not confer an improvement in progression-free survival (PFS; HR, 0.90; 95% CI, 0.77-1.05). The relative risk of having a grade 3/4 adverse effect (AE) was comparable between the durvalumab/tremelimumab and sorafenib arms (relative risk [RR], 0.96; 95% CI, 0.84-1.11).

In the HIMALAYA trial, treatment with durvalumab monotherapy demonstrated noninferiority vs sorafenib concerning OS (HR, 0.86; 95.67% CI, 0.73-1.03). Additionally, durvalumab alone resulted in fewer grade 3/4 AEs compared with sorafenib (RR, 0.71; 95% CI, 0.60-0.83).

Investigators of the phase 3 IMbrave150 trial (NCT03434379) reported a significant OS benefit with atezolizumab plus bevacizumab compared with sorafenib (HR, 0.66; 95% CI, 0.52-0.85).⁴ Additionally, the atezolizumab-based regimen yielded a significant PFS improvement (HR, 0.65; 95% CI, 0.53-0.81). The median time to deterioration of quality of life was 11.2 months in the atezolizumab arm vs 3.6 months in the sorafenib arm.

The authors also issued a strong recommendation backed by moderate evidence for administering sorafenib, lenvatinib (Lenvima), or durvalumab in the frontline setting for patients with Child-Pugh class A advanced HCC with an ECOG performance status of 0 or 1 who have contraindications to atezolizumab/bevacizumab or durvalumab/tremelimumab.

In a noninferiority phase 3 trial (NCT01761266), lenvatinib produced noninferior OS outcomes vs sorafenib (HR, 0.92; 95% CI, 0.79-1.06).⁵ Investigators also noted that lenvatinib elicited improvements in PFS (HR, 0.64; 95% CI, 0.55-0.76) and objective response rate (ORR; HR, 5.01; 95% CI, 3.59-7.01).

Treatment in Subsequent Lines

After frontline treatment with atezolizumab/bevacizumab, the guideline authors issued a weak recommendation based on low-quality evidence for the use of tyrosine kinase inhibitors (TKIs) or ramucirumab (Cyramza). Although authors noted that there are no currently published findings supporting the use of durvalumab/tremelimumab following frontline therapy, they nevertheless stated that this may be considered as a treatment option.

Following first-line therapy with durvalumab/tremelimumab, a weak recommendation was given for second-line treatment with a TKI based on low-quality evidence. The guideline authors noted that atezolizumab/bevacizumab may be considered after frontline treatment with the durvalumab combination, although no available data support the selection of patients for this regimen compared with a TKI.

Based on low-to-moderate quality evidence, a weak recommendation was issued for administering a TKI, ramucirumab, nivolumab (Opdivo) plus ipilimumab (Yervoy), or durvalumab following frontline treatment with sorafenib or lenvatinib. Guideline authors qualified this statement by writing that pembrolizumab (Keytruda) or nivolumab could serve as reasonable strategies following sorafenib or lenvatinib given in the first-line setting.

Regarding other recommendations in the guideline, a weak recommendation backed by low-quality evidence was issued for third-line treatment in patients with Child-Pugh A disease and good performance status. The authors noted that a small proportion of patients may have Child-Pugh A disease and a good performance status who could receive previously unused treatments in the third-line setting with a unique mechanism of action.

Additionally, very low quality evidence supported a weak recommendation for cautiously administering systemic therapy to patients with advanced HCC who have Child-Pugh class B disease with good performance status. Based on a modest clinical benefit that is anticipated with systemic therapy for those in this population, the authors recommended shared treatment decision-making between practices and patients.

“There is currently no head-to-head data to assist with discrimination between some of the recommended treatment options, for example…2 first-line combination therapy options are recommended because of their respective demonstrated benefit compared [with] sorafenib alone,” John D. Gordan, MD, PhD, an associate professor in residence in Hematology and Oncology at the University of California, San Francisco, and coauthors wrote.¹

“Biomarkers that could assist with treatment decision-making would be helpful in this context, and real-world and post hoc analyses have provided some information on genetic subtyping and biomarkers to guide the selection of patients for treatment…. This is an important future direction that we hope to update for the next iteration of this guideline,” they added.

References

1. Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline update. J Clin Oncol. Published online March 19, 2024. doi: 10.1200/JCO.23.02745
2. Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol. 2020;38(36):4317-4345. doi:10.1200/JCO.20.02672.
3. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022 Aug;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070.
4. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745.
5. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1.