Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma

doi:10.1053/j.gastro.2022.09.005

Gastroenterology

Volume 164, Issue 1, January 2023, Pages 72-88.e18

https://doi.org/10.1053/j.gastro.2022.09.005 Get rights and content

Abstract

Background & Aims

Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1.

Methods

Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response.

Results

Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II–related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy.

Conclusion

Interferon signaling and major histocompatibility complex–related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Section snippets

Study Population and Endpoints

Under the umbrella of an international consortium comprising 13 centers in the United States and Europe (Supplementary Table 1), we retrospectively collected samples from 111 patients for this study. Eligible patients were ≥18 years with pathologically confirmed HCC at advanced stage (Barcelona Clinic Liver Cancer stage C) or intermediate stage (stage B) after confirmed progression to locoregional therapies and not amenable to a curative treatment approach. Response assessment was performed at

Baseline Characteristics and Clinical Courses

Among the 111 HCC samples collected for the study, 83 cases had enough tissue available for molecular analysis, met all inclusion criteria, and were thus included in the transcriptomic analysis (Figure 1A). The time difference between acquisition of the biological sample and initiation of systemic therapies is depicted in Supplementary Figure 1. Recruited patients were treated with nivolumab (n = 67; 80.7%), pembrolizumab (n = 14; 16.9%), or tislelizumab (n = 2; 2.4%) in either frontline (n =

Discussion

The present study represents a comprehensive characterization of the molecular patterns associated with response and resistance in patients with advanced HCC treated with anti-PD1. Herein, we identified IFN-signaling and antigen-presentation–related genes to be associated with OR, whereas presence of Tregs and pathways associated with immunosuppression are linked to resistance. We developed an 11-gene expression signature capable of predicting response to anti-PD1 in HCC and other solid cancer

CRediT Authorship Contributions

Order of Authors (with Contributor Roles):

Philipp K. Haber, MD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Writing – original draft: Lead).

Florian Castet, MD (Formal analysis: Supporting; Investigation: Supporting; Methodology: Supporting; Writing – original draft: Supporting).

Miguel Torres-Martín, PhD (Data curation: Equal; Formal analysis: Equal; Methodology: Supporting).

Carmen Andreu-Oller, MSc (Data curation: Supporting;

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: Conflicts of Interest These authors disclose the following: Jean-Francois Dufour has received consulting fees from AbbVie, Bayer Healthcare, Bristol-Myers Squibb, Falk, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Eli Lilly, Merck, Novartis, Roche. Jens U. Marquardt received honoraria from Roche, Bayer, Ipsen, Merz, AstraZeneca, MSD, and Leap-Tx, Eisai. Peter R. Galle is receiving honoraria from Adaptimmune, Bayer, BMS, AstraZeneca, Sirtex, MSD, Eisai, Ipsen, Roche, Lilly, and Guerbet. Arndt Vogel has received consulting fees and honoraria from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Janssen, Lilly, Merck, MSD, Novartis, Pierre Fabre, Roche, and Sanofi. Tim Meyer reports consulting fees from Ipsen, AstraZeneca, Roche, Bayer Healthcare, Adaptimmune, Boston Scientific, and Eisai. Lewis R. Roberts has received grant funding from Bayer, BTG International, Exact Sciences, Gilead Sciences, GlycoTest, Redhill, TARGET PharmaSolutions, and FUJIFILM Medical Systems, and has consulted for AstraZeneca, Bayer, Exact Sciences, Gilead Sciences, GRAIL, QED Therapeutics, and TAVEC. Beatriz Mínguez received consultancy fees from Bayer-Shering Pharma and Eisai-Merck, lectures/speaker fees from Eisai, MSD, and Roche, and a research grant from Laboratorios Viñas S.L. Moritz Schmelzle is receiving honoraria from ERBE, Amgen, Merck, and Bayer Healthcare. Max W. Sung is receiving consulting fees from Bayer, EISAI, and Exelixis. Richard S. Finn has received consulting fees from AstraZeneca, Bayer Healthcare, Eisai, CStone, Bristol-Myers Squibb, Eli Lilly, Pfizer, Merck, Roche/Genenetech, and Exelixis. Augusto Villanueva has received consulting fees from Guidepoint, Fujifilm, Boehringer Ingelheim, FirstWord, and MHLife. Josep M. Llovet is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha Ltd and AstraZeneca. The remaining authors disclose no conflicts.

: Funding This study was supported by a research grant from Bayer Pharmaceuticals to Josep M. Llovet. Philipp K. Haber is supported by the fellowship grant of the German Research Foundation (DFG, HA 8754/1–1). Florian Castet is supported by an AECC Clínico Junior grant, ID code (CLJUN20007CAST). Carmen Andreu-Oller is supported by a Fulbright fellowship. Marc Puigvehí received a "Juan Rodés" scholarship grant from Asociación Española para el Estudio del Hígado (AEEH). Jens U. Marquardt is supported by grants from the German Research Foundation (MA 4443/2–2; SFB1292) and the Volkswagen Foundation (Lichtenberg program). Arndt Vogel is funded by the DFG (SFB/TRR 209 - 314905040, and Vo959/9–1). Tim Meyer is funded by the NIHR UCH Biomedical Research Centre and Accelerator Award (HUNTER, Ref. C9380/A26813, partnership between the CRUK, AECC, and AIRC). Lewis R. Roberts and Mohamed A. Mohamed Ali are supported by the Mayo Clinic Hepatobiliary SPORE (P50 CA210964). Beatriz Mínguez is funded by Instituto de Salud Carlos III (ISCIII) (PI18/00961 and PI21/00714 co-funded by European Union). Moritz Schmelzle acknowledges a research grant from the DFG (SCHM2661/3–2). The work of Daniela Sia is supported by the Tisch Cancer Institute and the PhD Scientist Innovative Research Award. Josep M. Llovet is supported by National Cancer Institute (P30-CA196521), National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK128289), US Department of Defense (CA150272P3), European Commission/Horizon 2020 Program (HEPCAR, Ref. 667273–2), Accelerator Award (CRUK, AECC, AIRC) (HUNTER, Ref. C9380/A26813), Samuel Waxman Cancer Research Foundation, Centro de Investigación Biomédica en Red (CIBER) – ISCIII, Spanish National Health Institute (SAF2016–76390), Generalitat de Catalunya/AGAUR (SGR-1358), and the Acadèmia de Ciències Mèdiques i de la Salut de Catalunya i de Balears.

: Author names in bold designate shared co-first authorship.

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Original ResearchFull Report: GI CancerMolecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma

Abstract

Background & Aims

Methods

Results

Conclusion

Section snippets

Study Population and Endpoints

Baseline Characteristics and Clinical Courses

Discussion

CRediT Authorship Contributions

Lancet

Lancet Oncol

Gastroenterology

Lancet

Lancet Oncol

J Hepatol

Cancer Cell

Gastroenterology

Lancet

J Hepatol

J Hepatol

Cell

Cell

Hepatocellular carcinoma

Nat Rev Dis Primers

Sorafenib in advanced hepatocellular carcinoma

N Engl J Med

IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC)

J Clin Oncol

Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma

N Engl J Med

CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC)

Ann Oncol

Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial

J Clin Oncol

Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer

Clin Cancer Res

Original Research
Full Report: GI Cancer
Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma