Phase 1b study of futibatinib plus pembrolizumab with or without chemotherapy in patients with esophageal carcinoma: Updated results of antitumor activity.
Authors: Ooki Akira , Muro Kei , Nishino Kazumi , Kawakami Hisato , Ojima Hitoshi , Kojima Takashi , Tanaka Yoshihiro , Koyanagi Kazuo , Machida Nozomu , Eguchi Susumu , Suyama Koichi , Watanabe Yasutaka , Izawa Naoki , Iijima Katsunori , Hirai Hiroshi , Chisamore Michael Jon , Kato Ken 
Published: June 2024

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Background: Futibatinib (Futi) has been approved for the treatment of patients with advanced (adv) intrahepatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement based on the results of the pivotal phase 2 study (NCT02052778). Combination therapy using FGFR inhibitors and Immune checkpoint inhibitors (ICIs) are being explored as a novel strategy for cancer patients (pts). Previously, we reported the preliminary encouraging antitumor activity of Futi 20 mg once daily (QD) that is a highly selective and irreversible FGFR inhibitor plus pembrolizumab (Pem) with or without chemotherapy in pts with adv or metastatic esophageal carcinoma (EC). Here, updated results are being presented. Methods: In cohort D (COD), 1st line pts who were chemotherapy and ICI naïve for adv or metastatic EC received Futi 20mg QD plus Pem 200 mg/q3w, fluorouracil 800 mg/m2 on days 1-5 and cisplatin 80 mg/m2 every 3weeks. In cohort A (COA) and B (COB), adv or metastatic EC pts with at least one prior therapy with a fluorouracil and platinum-based drug received Futi 20mg QD plus Pem 200mg/q3w if ICI naïve or ICI refractory, respectively. Primary endpoint was dose-limiting toxicity (DLT) in COD, and overall response rate (ORR) in COA and B. Secondary endpoints included disease control rate (DCR), duration of response (DOR) and treatment-related adverse events (TRAEs). Results: As of October 31, 2023, 36 pts (COA), 50 pts (COB) and 21 pts (COD) were enrolled and the treatments are ongoing in 20 pts (COA: 12 pts and COD: 8 pts). In COD (n=19), confirmed partial responses (cPRs) were observed in 13 pts (12 pts were squamous cell carcinoma [scc]; 1 pt was adenocarcinoma [adeno]); ORR was 68.4% (95% CI: 43.4, 87.4) with DCR of 89.5% and median DOR (mDOR) was 5.6 months (median follow up [mfu]: 3.9 months). One pt became resectable due to tumor shrinkage. In COA (n=35), confirmed complete response and cPRs were observed in 1 and 14 pts (all pts were scc), respectively; ORR was 42.9% (95% CI: 26.3, 60.6) with DCR of 71.4% and mDOR was 16.0 months (mfu: 6.2 months). In COB (n=49), cPRs were observed in 3 pts (2 pts were scc; 1 pt was adeno); ORR was 6.1% (95% CI: 1.3, 16.9) with DCR of 51.0% and mDOR was 4.7 months (mfu: 4.7 months). In COD, common TRAEs (all grade, grade ≥3) were hyperphosphatemia (85.7%, 0%), Neutrophil count decreased (66.7%, 57.1%) and stomatitis (66.7%, 14.3%). One DLT was observed in COD (Grade 3, Stomatitis), In COA, common TRAEs were hyperphosphatemia (91.7%, 0%), diarrhea, stomatitis and nail disorder (22.2%, 0%) and in COB, hyperphosphatemia (80.0%, 0%), stomatitis (20.0%, 2.0%) and diarrhea (20.0%, 0%). Conclusions: Futi plus Pem with or without chemotherapy showed promising antitumor activity in adv or metastatic EC pts with both histology of scc and adeno. Futi plus Pem and chemotherapy was safe and manageable with no new safety signals observed in 1st line pts with adv or metastatic EC. Clinical trial information: jRCT2080224975 .