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Clinical Trial
. 2024 Aug;42(4):376-385.
doi: 10.1007/s10637-024-01433-3. Epub 2024 Jun 4.

A phase 1/1b, open-label, dose-escalation study of PD-1 inhibitor, cetrelimab alone and in combination with FGFR inhibitor, erdafitinib in Japanese patients with advanced solid tumors

Noboru Yamamoto  1 , Yasutoshi Kuboki  2 , Kenichi Harano  2 , Takafumi Koyama  1 , Shunsuke Kondo  1 , Akiko Hagiwara  3 , Noriko Suzuki  3 , Ei Fujikawa  3 , Kiichiro Toyoizumi  3 , Mayumi Mukai  3 , Toshihiko Doi  4
Affiliations
Clinical Trial

A phase 1/1b, open-label, dose-escalation study of PD-1 inhibitor, cetrelimab alone and in combination with FGFR inhibitor, erdafitinib in Japanese patients with advanced solid tumors

Noboru Yamamoto et al. Invest New Drugs. 2024 Aug.

Abstract

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.

Keywords: FGFR inhibitor; Immune checkpoint inhibitors; Monoclonal antibody; Small molecule inhibitor; Targeted cancer therapy.

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Conflict of interest statement

Noboru Yamamoto: Research grants as principal investigator (institution): AbbVie, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Carna Biosciences, Chiome Bioscience, Chugai, Cmic, Daiichi-Sankyo, Eisai, Eli Lilly, Genmab, GSK, InventisBio, Janssen, KAKEN, Kyowa Kirin, MERCK, MSD, Novartis, ONO, Otsuka, Pfizer, Rakuten Medical, Shionogi, Sumitomo Pharma, Taiho, Takeda, TORAY. Advisory role: Boehringer Ingelheim, Chugai, Cmic, Eisai, Healios, MERCK, Takeda. Honoraria as speaker: Chugai, Daiichi-Sankyo, Eisai, ONO. Yasutoshi Kuboki: Research grants as principal investigator (institution): Abbie, Amgen, AstraZeneca, Boehringer Ingelheim, Carna Biosciences, Chugai, Daiichi-Sankyo, Genmab, Hengrui, Incyte, Janssen, Lilly, Merk, Novartis, Taiho Astellas, and Takeda. Advisory role: Amgen, Abbie, Boehringer Ingelheim, Incyte, and Takeda. Honoraria as speaker: Lilly, Taiho, and Takeda. Kenichi Harano: Research grants as principal investigator (institution): Astra Zeneca, Daiichi-Sankyo, MERCK, MSD, Takeda. Advisory role: Astra Zeneca, Chugai, Taiho, Takeda. Honoraria as speaker: Astra Zeneca, Chugai, Eizai, MSD, Taiho, Takeda. Takafumi Koyama: Honoraria as speakers: AstraZeneca, Chugai, Novartis, and Sysmex. Research grants as principal investigator (institution): Chugai, Daiichi-Sankyo, Eli Lilly, Janssen, Novartis, PACT Pharma, Pfizer, Takeda and Zymeworks. Shunsuke Kondo: Research grants as principal investigator (institution): AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Chugai, Incyte, Eisai, Eli Lilly. Advisory role: Sanofi. Honoraria as speaker: Chugai, Eisai, Incyte, Takeda. Akiko Hagiwara, Noriko Suzuki, Ei Fujikawa, Kiichiro Toyoizumi, and Mayumi Mukai: Employees of Janssen Pharmaceutical K.K. and hold company stocks. Toshihiko Doi: Research grants as principal investigator (institution): Abbvie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Dainippon Sumitomo Pharma, Eisai, GSK, Janssen, MSD, Novartis, ONO PHARMACEUTICAL, Pfizer, PRA Health Science, SHIONOGI, and TAIHO PHARMACEUTICAL. Advisory role: A2 Health Care, Boehringer Ingelheim, Chugai Pharma, Janssen, KAKEN Pharma, KYOWA KIRIN, Mitsubishi Tanabe Pharma, Nano Carrier, Noil-Immube Biotech, Oncolys BioPharma, Otsuka Pharma, PRA Health Science, Rakuten Medical, SHIONOGI, Sumitomo Pharma, and Takeda Pharma. Honoraria as speaker: Daiichi-Sankyo.

Figures

Fig. 1
Fig. 1
Serum concentration (mean [SD]) versus time profiles of cetrelimab alone and combination therapy at all dosing levels (PK analysis set; cycle 1 day 1) IV, intravenous; PK, pharmacokinetics; Q2W, every 2 weeks; Q4W, every 4 weeks; QD, once daily; SD, standard deviation
See this image and copyright information in PMC

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