Pembrolizumab for second line treatment of advanced hepatocellular carcinoma—who would benefit?
In the study “Pembrolizumab versus placebo as second-line therapy in patients from Asia with advanced hepatocellular carcinoma: a randomized, double-blind, phase III trial”, recently published in J Clin Oncol (1), Qin et al. reports on the final progression-free survival (PFS) and overall survival (OS) results of the KEYNOTE-394 trial. The trial included 453 Asian patients in Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 with preserved liver function and advanced hepatocellular carcinoma (HCC), progressing or being intolerable to first line treatment with sorafenib or (for 9%) oxaliplatin-based chemotherapy. Patients were randomized 2:1 to either treatment with programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab or placebo. Biomarker enrichment was not attempted. The primary endpoint was met with a modest but statistically significant improvement in median OS from 13.0 to 14.6 months [hazard ratio (HR) 0.79 (95% confidence interval: 0.63–0.99)]. In addition, PFS and objective response rate (ORR) were better with pembrolizumab than placebo.
This trial began inclusion of patients, while the similarly designed KEYNOTE-240 study was still recruiting world-wide. In that study, published in 2019 (2), a nominal improvement of outcome was observed, but statistically the primary endpoints of OS and PFS were not met and the trial was negative. However, a significant reduction in HR’s for PFS and OS was shown in a subgroup analysis of 176 patients included from Asia. Although the two studies are similar in size, randomization, treatment and major inclusion criteria, there are some differences apart from geography. Among others, KEYNOTE-240 was not placebo controlled and in KEYNOTE-394 statistics of long-term results are better as median follow-up is approximately 3 times longer (33.8 months).
As expected from demography (3), disease biology of the two study populations is different. Patients were on average 12 years younger in KEYNOTE-394 and 80% were infected with hepatitis B virus (HBV), while in KEYNOTE-240 only 40% were infected with hepatitis and 58% had a history of alcohol. Prognostic factors of patients in KEYNOTE-394 are less favorable with more patients being in PS 1 rather than 0, in Barcelona Clinic Liver Cancer (BCLC) stage C rather than B, and with more patients with high alpha-fetoprotein (AFP) and extrahepatic disease. Despite this, the median OS of patients in the placebo group is at least on par with multikinase inhibitor-treated patients in first line studies (4-6), suggesting selective inclusion.
The HR’s for OS are similar in the two KEYNOTE studies showing a 21–22% reduction in risk of death for the pembrolizumab-treated patients. The median PFS is short (≤3.0 months), but what is most striking is the effect on long-term survival that in KEYNOTE-394 is driven by a median duration of response of almost 2 years among the 13% who had an objective response. Hence, PFS was 16% at 12 months and 12% at 18 months, which compares favorably with currently approved second line treatments for unselected HCC populations (7,8). The effect on PFS resulted in a doubling of survivors at 3 years with pembrolizumab (23%) compared to placebo (11%), despite that 28% in the placebo group crossed over to treatment with an PD-L1 inhibitor.
Safety data were consistent with other studies demonstrating the tolerability of single-drug treatment with check point inhibitors in advanced HCC (9). Adverse effects (AEs) were frequent but often related to consequences of disease rather than treatment. AEs leading to treatment abortion were reported in only 4% in the KEYNOTE-394 study, and treatment-related death occurred in only 0.7% in the two KEYNOTE studies combined.
Within recent years, randomized studies have shown that antiangiogenic therapy and immunotherapy improve outcomes compared to sorafenib in the first-line setting, both in Asian populations (10,11) and in rest of the world (6), and these treatments have become standard of care for patients with advanced HCC in good PS without contraindications (12). The population of patients eligible for immunotherapy in second line is today therefore limited. The study by Qin et al. shows that in Asian HCC patients in PS 0–1 with preserved liver function and BCLC stage B and C disease, pembrolizumab is an active and tolerable second-line treatment after sorafenib, providing a modest, but statistically significant OS benefit. The long follow-up of patients in the KEYNOTE-349 allowed for disclosure of a striking long-term impact of pembrolizumab on PFS and OS in a minority of patients. These patients unfortunately cannot at present be identified a priori.
Other evidence-based, second-line options after progression on sorafenib or lenvatinib (5) are available, including cabozantinib (7), regorafenib (8), and ramucirumab (13). Antiangiogenic therapy combined with immunotherapy may also be considered for check-point inhibitor naïve patients, although side-effects may restrict its use in a fragile population (12). Both KEYNOTE studies of pembrolizumab in second line suffer from lack of assessments of predictive biomarkers (9). These are especially needed in the current context indicating a large benefit achieved by a minority, while the average impact is modest. In lack of predictive biomarkers for immunotherapy in HCC, close monitoring of treatment efficacy or resistance, e.g., using circulating tumor DNA (ctDNA) (14), could possibly facilitate a more personalized treatment approach and improve prognosis.
Funding: H.E. & N.C. Brogaards Legat til Kræftforskningens Fremme supported the preparation of this manuscript by an unrestricted grant.
Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article did not undergo external peer review.
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-17/coif). ML received a research grant from and participates in a Data Safety Monitoring Board at Scandion Oncology A/S, Denmark. ML also reports that H.E. & N.C. Brogaards Legat til Kræftforskningens Fremme supported the preparation of this manuscript by an unrestricted grant. The author has no other conflicts of interest to declare.
Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
- Qin S, Chen Z, Fang W, et al. Pembrolizumab versus placebo as second-line therapy in patients from Asia with advanced hepatocellular carcinoma: a randomized, double-blind, phase III trial. J Clin Oncol 2023;41:1434-43. [Crossref] [PubMed]
- Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2020;38:193-202. [Crossref] [PubMed]
- Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019;16:589-604. [Crossref] [PubMed]
- Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. [Crossref] [PubMed]
- 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;391:1163-73. [Crossref] [PubMed]
- Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. [Crossref] [PubMed]
- Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med 2018;379:54-63. [Crossref] [PubMed]
- Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389:56-66. [Crossref] [PubMed]
- Dyhl-Polk A, Mikkelsen MK, Ladekarl M, et al. Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. J Clin Med 2021;10:2662. [Crossref] [PubMed]
- Qin S, Ren Z, Feng YH, et al. Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study. Liver Cancer 2021;10:296-308. [Crossref] [PubMed]
- Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol 2021;22:977-90. [Crossref] [PubMed]
- Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol 2020;38:4317-45. [Crossref] [PubMed]
- Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:282-96. [Crossref] [PubMed]
- Matsumae T, Kodama T, Myojin Y, et al. Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy. Cancers (Basel) 2022;14:3367. [Crossref] [PubMed]