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

Philipp K. Haber, Florian Castet, Miguel Torres-Martin, Carmen Andreu-Oller, Marc Puigvehí, Maeda Miho, Pompilia Radu, Jean Francois Dufour, Chris Verslype, Carolin Zimpel, Jens U. Marquardt, Peter R. Galle, Arndt Vogel, Melanie Bathon, Tim Meyer, Ismail Labgaa, Antonia Digklia, Lewis R. Roberts, Mohamed A. Mohamed Ali, Beatriz MínguezDavide Citterio, Vincenzo Mazzaferro, Fabian Finkelmeier, Jörg Trojan, Burcin Özdirik, Tobias Müller, Moritz Schmelzle, Anthony Bejjani, Max W. Sung, Myron E. Schwartz, Richard S. Finn, Swan Thung, Augusto Villanueva, Daniela Sia, Josep M. Llovet*

*Corresponding author for this work
9 Citations (Scopus)

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.

Original languageEnglish
JournalGastroenterology
Volume164
Issue number1
Pages (from-to)72-88.e18
ISSN0016-5085
DOIs
Publication statusPublished - 01.2023

Research Areas and Centers

  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)

Fingerprint

Dive into the research topics of 'Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma'. Together they form a unique fingerprint.

Cite this