An ASCO guideline update offers new recommendations on systemic treatment for advanced hepatocellular carcinoma (HCC), based on promising findings from several recent randomized controlled trials as well as the approval of new first- and second-line immunotherapy combinations.1
John D. Gordan, MD, PhD
“This guideline integrates several important new therapeutic advances into the treatment of these kinds of cancers, and I think without some degree of information about that, there would be an open question about how to use them,” said Expert Panel Co-Chair John D. Gordan, MD, PhD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. “It also addresses the use of CTLA-4/PD-1 inhibitor combinations, which were previously not addressed [in the prior guideline].”2
Informing Treatment Decision-Making
In 2020, the phase III randomized IMbrave150 trial led to the approval of the atezolizumab/bevacizumab combination treatment for nonresectable HCC in the first-line setting.3 The advent of atezolizumab plus bevacizumab as a first-line treatment for most patients with late-stage disease helped expand the standard of care and was subsequently reflected in the 2020 ASCO guideline on systemic therapy for advanced HCC.2
Since then, new data have emerged from more recent trials on combination agents for patients with unresectable HCC. Of note, a phase II trial of the so-called STRIDE regimen, comprising the PD-1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab, found both clinical activity and tolerability of the dual immune checkpoint inhibitor combination.3 The phase III HIMALAYA trial then demonstrated the overall survival benefits of STRIDE vs sorafenib monotherapy and the noninferiority of durvalumab alone vs sorafenib alone in the front-line setting.4 Consequently, the U.S. Food and Drug Administration (FDA) approved the durvalumab/tremelimumab combination for nonresectable HCC in 2022.5
“I think that created a question for providers, though, because we now have two competing front-line regimens,” Dr. Gordan explained.
To help address choosing between treatments and to better reflect the maturation of data since the original guideline was published, an ASCO Expert Panel was convened to determine the preferred treatment options for first-, second-, and later-line therapies for patients with advanced HCC. Among the recommendations from the Panel was support for atezolizumab plus bevacizumab or durvalumab plus tremelimumab as first-line treatments for patients with advanced HCC, Child-Pugh class A, and an Eastern Cooperative Oncology Group performance status of 0 to 1.
The guideline also notes the combination of nivolumab plus ipilimumab may be considered after first-line treatment with atezolizumab plus bevacizumab, sorafenib, or lenvatinib. Nivolumab plus ipilimumab is a novel combination drug that received accelerated FDA approval in 2020 in the second-line setting following prior treatment with sorafenib.6 Approval was based on data from the phase I/II CheckMate 040 study, which showed manageable safety and promising durable objective responses.7
Michal G. Rose, MD
“I think most oncologists are already aware of many of the studies summarized in this guideline, but I hope this update helps them rapidly select the appropriate therapy for individual patients, based on their prior treatment, comorbidities, and preferences,” said Expert Panel Co-Chair Michal G. Rose, MD, of the Veterans Affairs Comprehensive Cancer Center at VA Connecticut Health Care System. “With the rapid expansion of data in all fields of cancer care, it is hard for the practicing oncologist to stay abreast of all these developments.”
Anticipating Additional Therapies
Although the guideline update will help clinicians keep pace with the recently approved combination treatments for advanced HCC, the Panel encountered many unanswered questions during their literature review that the guideline could not address. Fortunately, multiple phase II/III trials are underway or being planned to help close knowledge gaps in the field, such as trials to explore the role of dual immune checkpoint blockade and immune-based triplet therapies.8 Future research should also consider whether there are tumor-specific factors or specific clinical scenarios that would drive the selection among competing therapeutics, Dr. Gordan added.
“There are undoubtedly some patients who are more likely to respond to one regimen or the other, but we don’t have a way to stratify them right now, so the treatment selection is driven primarily by patient comorbidities or the ability to adhere to or obtain the different treatment regimens,” he explained. “But I think identifying tumor-specific biomarkers that could drive that selection would be a key next step.”
Dr. Rose concurred, noting that the field of advanced HCC therapy “lags behind many other fields of cancer in that it is not biomarker-driven, and treatment is not selected based on the underlying liver disease etiology.” Thus, she said, future research should focus on molecular predictors of response to therapy.
Another key area that could yield additional tools for improving survival in this population is the integration of locoregional therapy (ie, radiation and embolization procedures) with systemic treatment.9 For example, the EMERALD-1 study of transarterial chemoembolization (TACE) with or without systemic therapy was presented at the 2024 ASCO Gastrointestinal Cancers Symposium. It showed improved progression-free survival with TACE plus durvalumab plus bevacizumab vs TACE alone, although overall survival data are not yet mature.10
Dr. Gordan noted that these locoregional/systemic therapy studies “are classically hard to do because of the need to standardize procedures across sites.” Nonetheless, he said, locoregional/systemic therapy studies are an integral next step in ensuring patients with advanced HCC receive multidisciplinary care.
“I see this guideline update as an implementation tool to help ensure the appropriate uptake of the new data in the field of HCC,” Dr. Rose said. “The quicker we can get new therapies out to the field, the faster our patients will benefit.”
REFERENCES
1. Gordan JD, Kennedy EB, Abou-Alfa GK, et al: Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline update. J Clin Oncol. March 19, 2024 (early release online).
2. Gordan JD, Kennedy EB, Abou-Alfa GK, et al: Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol 38:4317-4345, 2020.
3. Zanuso V, Pirozzi A, Balsano R, et al: Safety and efficacy of atezolizumab and bevacizumab combination as a first line treatment of advanced hepatocellular carcinoma. J Hepatocell Carcinoma 10:1689-1708, 2023.
4. Abou-Alfa GK, Lau G, Kudo M, et al: Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid 1:EVIDoa2100070, 2022.
5. U.S. Food and Drug Administration: FDA approves tremelimumab in combination with durvalumab for unresectable hepatocellular carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-unresectable-hepatocellular-carcinoma. Accessed April 22, 2024.
6. Saung MT, Pelosof L, Casak S, et al: FDA approval summary: Nivolumab plus ipilimumab for the treatment of patients with hepatocellular carcinoma previously treated with sorafenib. Oncologist 26:797-806, 2021.
7. El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389:2492-2502, 2017.
8. Carloni R, Sabbioni S, Rizzo A, et al: Immune-based combination therapies for advanced hepatocellular carcinoma. J Hepatocell Carcinoma 10:1445-1463, 2023.
9. Farsad K, Nabavizadeh N, Kardosh A, et al: Combined locoregional and systemic therapy for advanced hepatocellular carcinoma: Finally, the future is obscure. Ann Transl Med 8:1700, 2020.
10. Lencioni R, Kudo M, Erinjeri J, et al: EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. J Clin Oncol 42(suppl 3):LBA432, 2024.
Originally published in ASCO Daily News. © American Society of Clinical Oncology. ASCO Daily News, March 20, 2024. All rights reserved.
