In this edition of his monthly column, Tiago Biachi, M.D. Advanced Fellow of Gastrointestinal Oncology at Memorial Sloan Kettering Cancer Center, discusses controversies in first-line treatment for the treatment of advanced hepatocellular carcinoma.
Few areas have made such a significant advance in gastrointestinal oncology in recent years as the treatment of advanced hepatocellular carcinoma (HCC). We evolved from the use of sorafenib as the only option to a scenario with multiple choices, where the process of choosing the most appropriate treatment for each patient has become a controversial topic.
In 2008, after the publication of the SHARP study, sorafenib became the treatment of choice for HCC not amenable to local or locoregional treatment, remaining the only option until 2018 – when the non-inferiority data on overall survival of lenvatinib vs. sorafenib (13.6 vs 12.3 months; HR 0.92) were published [1.2].
Considering the viral etiology in a large portion of the cases, which would lead to a high rate of neoantigens, immunological checkpoint inhibitors emerged as a promising strategy in HCC in preclinical studies. However, its first-line monotherapy use with nivolumab was compared to sorafenib in the phase III study CheckMate-459, and although it demonstrated a superior response rate (15 vs 7%), this did not translate into progression free survival (PFS) (3.7 vs 3.8 months) or OS (16.4 vs 14.7 months) [3].
Still using sorafenib as a control arm, the randomized, phase III study, IMBRAVE 150 evaluated the use of a combination of immunotherapy with atezolizumab and anti-angiogenic with bevacizumab. In this study, patients with hepatitis B or C, high-risk esophageal varices or active bleeding, in endoscopy performed in the last 6 months, were excluded. The combination demonstrated benefit in OS at 12 months (67 vs 54%), median PFS (6.8 vs 4.3 months) and response rate (33 vs 13%) compared to sorafenib, making it a new standard treatment option [4].
The controversy surrounding first-line treatment arose with the recent presentation at ASCO GI of data from the phase III HIMALAYA study. This study was designed with 3 treatment arms (durvalumab and tremelimumab, durvalumab or sorafenib), and reached its primary endpoint, the 3-year OS rate which was 30.7%, 24.7% and 20.2%, respectively for the combination of durvalumab and tremelimumab, durvalumab monotherapy or sorafenib monotherapy. Yet, despite higher response rates (20.1%, 17% and 5.1%), the PFS outcome was not achieved. Despite the close numbers between the combination and durvalumab monotherapy arms, the investigators point out that the study lacks statistical power for this comparison [5].
Comparisons between studies are discouraged and the choice between the most current regimens (IMbrave150 and HIMALAYA) should be based on their inclusion/exclusion criteria, as well as the expected toxicity profile. Analysis of response predictors that help in this decision making is expected in the future. Still, the isolated use of tyrosine kinase inhibitors remains an
option for those patients with contraindications to the use of immunotherapy, such as, for example, those who previously underwent liver transplantation.
References:
1. Llovet JM, Ricci S, Mazzaferro V et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90.
2. 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 Mar 24;391(10126):1163-1173.
3. Yau T, Park JW, Finn RS et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022 Jan;23(1):77-90.
4. Finn RS, Qin S, Ikeda M et al; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905.
5. Abou-Alfa GK, Chan SL, Kudo M et al. ,Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. 2022 ASCO Gastrointestinal Cancers Symposium, Oral Abstract Session, Abstract 379.
