Phase 1b study of futibatinib plus pembrolizumab in patients with esophageal carcinoma: Evaluating the immunological effects.
Authors: Kojima Takashi , Shinohara Hajime , Eguchi Susumu , Izawa Naoki , Chin Keisho , Tanaka Yoshihiro , Machida Nozomu , Iwatsuki Masaaki , Iijima Katsunori , Horita Yosuke , Satoh Taroh , Ojima Hitoshi , Mitani Seiichiro , Nishino Kazumi , Hirai Hiroshi , Mizutani Hiroya , Chisamore Michael Jon , Minashi Keiko 
Published: January 2025

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Background:
Combination therapy using FGFR inhibitors and Immune checkpoint inhibitors (ICIs) are being explored as a novel strategy for esophageal cancer (EC) patients (pts). We reported the tolerability and encouraging antitumor activity of futibatinib (futi) plus pembrolizumab (pem) in cohort (CO) A (≥2nd line, ICIs naïve) and COB (≥2nd line, ICIs refractory) and futi plus pem with chemotherapy in COD (1st line, ICIs naïve) with EC pts at Ooki et al ASCO 2024. The purpose of this Cohort E (COE) was to evaluate the effects of futi as a single agent or futi in combination with pem on tumor immune microenvironment by detecting immune cells and immune-related gene expression.
Methods:
In COE of the study, advanced or metastatic EC pts with at least one prior therapy with a fluorouracil and platinum-based drug received a single agent of futi the first 7 days, followed by futi 20 mg once daily (continuous dosing) plus pem 200 mg/every 3 weeks (up to a maximum of 35 cycles). Regardless of FGFR overexpression level and ICIs naïve or refractory pts were include on the study. Tumor samples were collected by biopsy during the screening period, 7 days after the administration of futi, and 21 days after the combination administration of futi and pem. Expression of 18 biomarkers including CD3, CD4, CD8 were analyzed by multiplex IHC (NeoGenomics). Gene expression related to immunity in tumor microenvironment were evaluated by nCounter system (NanoString).
Results:
As of March 10, 2024, 18 pts (ICIs naïve, 3 pts; ICIs refractory, 15 pts) were enrolled. As a result of multiplex IHC, an increase of CD3
+
CD8
+
T cells was observed in the samples 7 days after a single treatment of futi comparing with baseline samples and a trend towards greater increased CD3
+
CD8
+
cells was observed 21 days after combination treatment. An increasing CD8A gene expression was observed by nCounter analysis after a single treatment of futi comparing with baseline and a trend towards greater increase in CD8A gene expression was observed after combination treatment. Confirmed partial responses were observed in 3 pts (2 pts were ICIs naïve and 2 pts were FGFR positive). ORR was 16.7% (3/18; 1 pt had no target lesion, 95% CI: 3.6, 41.4). Most common TRAEs were hyperphosphatemia (77.8%), diarrhea (33.3%), ALT increased, and AST increased (22.2%).
Conclusions:
The preliminary multiplex IHC and nCounter results suggest that futi promoted CD8
+
T cells infiltration into EC tumor microenvironments by single treatment and following combination treatment with pem at tolerable dosage.

Summary of CD3
+
CD8
+
T cell and CD8A gene expression after futibatinib and combination treatment (% change relative to the baseline).

N
Mean (S.D)
95%CI

Cell:CD3
＋
CD8
＋
T cell

C1D7 (futi)
15
176.4 (88.8)
[127.2, 225.5]

C2D21 (Combination)
12
306.3 (229.8)
[160.3, 452.3]

Gene:CD8A

C1D7 (futi)
16
139.4 (54.0)
[110.6, 168.2]

C2D21 (Combination)
14
245.9 (190.8)
[135.8, 356.1]