522P - Impact of age and single heterozygous UGT1A1 on the safety and efficacy of first-line FOLFIRI or FOLFOXIRI in combination with ramucirumab (RAM) for metastatic colorectal cancer (mCRC): Subgroup analyses of WJOG9216G (RECAST)

Background

In the WJOG9216G randomized phase II study for patients with previously untreated mCRC, confirmed objective response rate (ORR) and progression-free survival (PFS) of FOLFOXIRI plus RAM were similar to those of FOLFIRI plus RAM (Kito et al. ESMO 2022). Previous studies of FOLFOXIRI plus bevacizumab suggested that age and UGT1A1 status might be associated with increased toxicity (Marmorino et al. Ann Oncol 2019, Oki et al. Clin Colorectal Cancer 2018). We conducted an exploratory post-hoc analysis to assess the impact of age and UGT1A1 status on the safety and efficacy.

Methods

Patients (aged ≤70 years with ECOG PS 0-1 or 71-75 years with PS 0, and wild-type [WT] UGT1A1 or single heterozygous [SH] UGT1A1 *28 or *6) were randomly assigned to arm A (FOLFIRI plus RAM) or arm B (8 cycles of FOLFOXIRI plus RAM followed by 5-FU/l-leucovorin plus RAM). ORR, PFS, overall survival (OS), and safety were assessed according to age and UGT1A1 status.

Results

Of the enrolled 122 patients (59/63 in arm A/B), 50/49 were <70 years and 9/14 were ≥70 years; 28/34 were WT UGT1A1 and 31/29 were SH UGT1A1. ORR and PFS were similar between arm A/B, regardless of age and UGT1A1 status (Table). At a median follow-up of 42.1/40.4 months [m] in arm A/B, OS was tended to be better in arm A (median, 32.6/28.2m, hazard ratio [HR] 1.58, p=0.033), especially in <70 years (HR 1.67, p=0.034) or WT UGT1A1 subgroup (HR 1.71, p=0.078). The incidence of grade (G) ≥3 neutropenia (44/71% in arm A/B), febrile neutropenia (FN) (3/11%), and anorexia (3/14%) were numerically higher in arm B than those in arm A. This trend was particularly marked among the elderly and SH UGT1A1 patients. Table: 522P

Conclusions

Compared with FOLFIRI plus RAM, FOLFOXIRI plus RAM did not improve ORR, PFS, and OS and might increase incidences of some adverse events, regardless of age and UGT1A1 status.

Clinical trial identification

jRCTs041180166.

Editorial acknowledgement

Legal entity responsible for the study

West Japan Oncology Group (WJOG).

Funding

Eli Lilly Japan K.K.

Disclosure

Y. Kito: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical. H. Shoji: Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Zymeworks inc., Astellas; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Institutional, Local PI: Ono Pharmaceutical Co.,Ltd., MSD, Astellas, Amgen, Daiichi Sankyo, AbbVie, AstraZeneca, Taiho Phamaceutical, Elevation Oncology; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co.,Ltd,Takeda Pharmaceuticals. T. Yamada: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan, Bristol Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo. T. Tsushima: Financial Interests, Personal, Invited Speaker: Taiho Pharma, Ono Pharmaceutical, MSD, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Taiho Pharma, MSD, Ono Pharmaceutical. S. Mitani: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Chugai Pharmaceutical Co.; Financial Interests, Personal, Research Grant: Caris Life Science. H. Yasui: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Daiichi-Sankyo, Terumo, Eli Lilly Japan, Merck Biopharma, Yakult Honsha, Bayer Yakuhin, Takeda Pharmaceutical; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical; Financial Interests, Institutional, Local PI: MSD, Daiichi-Sankyo, Ono Pharmaceutical, Astellas Pharma, Amgen, AstraZeneca. H. Hara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Lilly, Merck Biopharma, Taiho, Takeda, Yakult, Bristol-Myers Squibb, Miyarisan; Financial Interests, Institutional, Coordinating PI: Amgen, Astellas, AstraZeneca, Bayel, BeiGene, Chugai, Daiichi Sankyo, Janssen, Merck Biopharma, MSD, Ono, Taiho, ALX Oncology, Jazz Pharmaceuticals. T. Esaki: Financial Interests, Personal, Invited Speaker: Chugai, Taiho, MI force, Daiichi Sankyo, Eli Lilly, Ono, Bristol; Financial Interests, Institutional, Local PI: MSD, Ono, Nihon Kayaku, IQVIA, Daiichi Sankyo, Chugai, Syneos Health Clinical, Quintiles, Astellas, Astellas Amgen Biopharma, Asahikasei Pharma, Amgen, ALX Oncology, Seagen, Taiho, Jazz Pharmaceuticals Ireland, Bristl. N. Izawa: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical . H. Kawakami: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd., Bayer Yakuhin Ltd, Eli Lilly Japan K.K., MSD K.K., Chugai Pharmaceutical Co. Ltd., Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co. Ltd., Yakult Pharmaceutical Industry, Teijin Pharma Ltd., Taiho Pharmaceutical Co. Ltd.; Financial Interests, Personal, Advisory Board: Daiichi Sankyo Co. Ltd., astellas; Financial Interests, Personal, Other, Lecture: GSK K.K, Otsuka Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant, Investigator-Initiated Trial: Bristol-Myers Squibb Co. Ltd.; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical Co. Ltd, Eisai Co., Ltd., Kobayashi Pharmaceutical Co. Ltd., Parexel International Corp., Pra Healthsciences, EPS Corporation., Kissei Pharmaceutical Co., Ltd., EPS International Co.,Ltd,., MSD K.K., Ono Pharmaceutical Co.,Ltd., PPD-SNBL K.K, SymBio Pharmaceuticals Limited., IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co.,Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Covance Japan Inc., Japan Clinical Research Operations, Chugai Pharmaceutical Co.,Ltd., Takeda Pharmaceutical Co.,Ltd., GSK K.K., Sanofi K.K., Nippon Boehringer Ingelheim Co.,Ltd., Sysmex Corporation, Novartis Pharma K.K., Otsukaa Pharmaceutical Co., Ltd., SRL, Inc., Daiichi Sankyo Co., Ltd., Amgen Inc., Medical Research Support, Eli Lilly Japan K.K. S. Hironaka: Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Other, lecture: Ono Pharm, BMS, Eli Lilly, Taiho, Daiichi Sankyo, MSD, Chugai, Merck Biopharma, Takeda, Yakult Honsha, Bayer, Novartis, Nihon Servier. K. Yamazaki: Financial Interests, Personal, Invited Speaker: Chugai Pharma, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Lilly, Sanofi, Ono Pharmaceutical, MSD, Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. K. Muro: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Ono, Chugai, Astellas; Financial Interests, Personal, Invited Speaker: Eli Lilly, Ono, Daiichi Sankyo, Taiho, Bristol-Myers Squibb, Takeda, MSD; Financial Interests, Institutional, Research Grant, Including local PI as role: Astellas, Amgen, Sanofi, Daiichi Sankyo, Taiho, MSD, Pfizer, Merck Biopharma, Eisai, Ono, Novartis, PRA Health Sciences Inc., Parexel International Inc.; Financial Interests, Personal, Steering Committee Member: Chugai, AstraZeneca, Amgen; Non-Financial Interests, Principal Investigator: Takeda. All other authors have declared no conflicts of interest.