A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors

Stephen Chan (1) , Martin Schuler (2) , Yoon-Koo Kang (3) , Chia-Jui Yen (4) , Julien Edeline (5, 6) , Su Pin Choo (7) , Chia-Chi Lin (8) , Takuji Okusaka (9) , Karl-Heinz Weiss , Teresa Macarulla (10) , Stéphane Cattan (11, 12) , Jean-Frederic Blanc (13) , Kyung-Hun Lee (14) , Michela Maur (15) , Shubham Pant (16) , Masatoshi Kudo (17) , Eric Assenat (18, 19) , Andrew Zhu (20) , Thomas Yau (1) , Ho Yeong Lim (21) , Jordi Bruix (22) , Andreas Geier (23) , Carmen Guillén-Ponce (24) , Angelica Fasolo (25) , Richard Finn (26) , Jia Fan (27) , Arndt Vogel (28) , Shukui Qin (29) , Markus Riester , Vasiliki Katsanou , Monica Chaudhari (30) , Tomoyuki Kakizume , Yi Gu , Diana Graus Porta , Andrea Myers (31) , Jean-Pierre Delord (32)

1 CUHK - The Chinese University of Hong Kong [Hong Kong]
2 Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen]
3 University of Ulsan
4 NCKU - National Cheng Kung University
5 OSS - Oncogenesis, Stress, Signaling
6 CRLCC - CRLCC Eugène Marquis
7 NCCS - National Cancer Centre Singapore
8 NTU - National Taiwan University [Taiwan]
9 National Cancer Center Research Institute [Tokyo]
10 Vall d'Hebron University Hospital [Barcelona]
11 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
12 Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille]
13 CHU Bordeaux
14 Seoul National University Hospital
15 UNIMORE - Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia
16 MD Anderson Cancer Center [Houston]
17 Kindai University
18 ICM - Institut régional de Cancérologie de Montpellier
19 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
20 Massachusetts General Hospital [Boston, MA, USA]
21 SKKU - Sungkyunkwan University [Suwon]
22 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
23 University Hospital of Würzburg
24 Hospital Universitario Ramón y Cajal [Madrid]
25 IRCCS San Raffaele Scientific Institute [Milan, Italie]
26 UC - University of California
27 Fudan University [Shanghai]
28 MHH - Medizinische Hochschule Hannover = Hannover Medical School
29 Chinese PLA General Hospital
30 IQVIA
31 Novartis Pharmaceuticals Corporation [East Hanover, NJ]
32 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole

Background Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab. Methods Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC. Results Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases ( n = 4) or blood bilirubin ( n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR. Conclusions At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted. Trial registration NCT02325739 .

Mots clés: Hepatocellular carcinoma; FGFR4; PD‑1; PD‑L1; Immune checkpoint inhibitors; Phase 1; KLB; FGF19

Domaines: Cancer

Stephen Chan, Martin Schuler, Yoon-Koo Kang, Chia-Jui Yen, Julien Edeline, et al.. A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors. Journal of experimental & clinical cancer research, 2022, 41 (1), pp.189. ⟨10.1186/s13046-022-02383-5⟩. ⟨hal-04510216⟩