504MO - Phase I study of the PKMYT1 inhibitor lunresertib (lunre) in combination with FOLFIRI in advanced gastrointestinal (GI) cancers (MINOTAUR study)

Background

Lunre, a first-in-class inhibitor of protein kinase membrane associated tyrosine/threonine 1 (PKMYT1), is synthetic lethal with CCNE1 amplification (amp) or FBXW7 mutations (mut), alterations present in w20% of GI cancers, and synergizes with irinotecan (iri) in tumor models harboring these alterations. Herein, we report the preliminary safety, tolerability, and efficacy of lunre and FOLFIRI from the MINOTAUR study (NCT05147350).

Methods

In this phase 1 study, iri naive or exposed patients (pts), candidates for FOLFIRI, with advanced CCNE1 ^amp or FBXW7 ^mut GI cancers received lunre daily (cont) or intermittently (int; 3d on /4d off) plus FOLFIRI (q2 wks). The primary endpoint was safety; dose/schedule finding followed BOIN design. Secondary endpoints included efficacy (overall response rate [ORR], molecular response rate [MRR; ≥50% decline in circulating tumor DNA]) and pharmacokinetics (PK).

Results

As of submission, 38 pts (median age: 55.5y; 12 CCNE1 ^amp ; 26 FBXW7 ^mut ) were treated; eighteen had colorectal cancer (CRC). Median prior lines of treatment (LoT) was 2 (range: 0-6); 47.4% had prior iri. Frequency of treatment-related adverse events (TRAEs) was similar to frequencies expected with FOLFIRI alone: grade (Gr) 3 to 4 in 44.7% of pts; TRAEs occurring in ≥10% of pts were neutropenia (31.6%) and leukopenia (13.2%). Rash (all low grade [Gr1 to 2]) occurred in 31.6% of pts. The preliminary RP2D of lunre was 60 mg BID cont. In efficacy evaluable pts (n=33) the ORR per RECIST was 18.2% (95% CI: 7-35.5); with 6 partial responses (CRC, anal, esophageal, gastric, jejunal [prior iri], and pancreatic [prior iri]). MRR was 60.9% (14/23). Eight pts (24.2%) were treated for >6 mo. Of 15 evaluable pts with CRC (median prior LoT, 3; prior iri n=10), 4 had DOT >6 mo, and 2 for >12 mo.

Conclusions

In the first evaluation of this novel combination, standard FOLFIRI and daily lunre 60 mg BID (RP2D) was well tolerated, with a safety profile consistent with FOLFIRI alone, and promising efficacy in a heavily pretreated CCNE1 ^amp and FBXW7 ^mut population, including prior iri exposure. Prolonged DOT in mCRC offers a valid therapeutic strategy and warrants confirmation in a randomized study.

Clinical trial identification

NCT05147350.

Editorial acknowledgement

Justin L. Eddy, Ph.D., an employee of Repare Therapeutics Inc., provided medical writing support.

Legal entity responsible for the study

Repare Therapeutics Inc.

Funding

Repare Therapeutics Inc.

Disclosure

Z.A. Wainberg: Financial Interests, Personal, Advisory Board, and honoraria: Amgen, Arcus, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Merck, Genentech, Gilead, Novartis, Seagen; Financial Interests, Personal, Other, Honoraria: Ipsen; Financial Interests, Institu- tional, Research Grant: Amgen, Arcus, Array/Pfizer, AstraZeneca, Bayer, Bristol Myers Squibb, Five Prime, Gilead, Ipsen, Molecular Templates, Roche/Genentech. A.H. Bent, V. Moreno Garcia, M. Pedregal Trujillo: Other, Personal, Other, Study Investigator: Repare Therapeutics. R. Mehta: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, AstraZeneca, Astellas, Eisai, Novartis, GSK, Boston Gene, Guardant Health, Natera; Financial Interests, Personal, Other, Consul- tant: Eli Lilly; Financial Interests, Personal, Member of Board of Directors: Arcus Biosciences. E.X. Chen: Other, Personal, Other, Study Investigator: Repare Therapeutics. J.L. Ramón Patino: Other, Personal, Other, Study Investigator: Repare Therapeutics. R.H. Moy: Financial Interests, Personal, Advisory Role: Puretech Health, Ideaya Biosciences, Nimbus Therapeutics; Financial Interests, Institutional, Funding: Nimbus Therapeutics, Repare Therapeutics. B. Madajewski, A. Petrone, P. Adesara-Patel, Y. Liu, X. Sun, E. Aguado-Fraile, P.A. Basciano, S. Sethuraman, N. Hawkey: Financial Interests, Personal, Full or part-time Employment, and stock and/or stock options: Repare Thera- peutics. E. Fontana: Financial Interests, Personal, Invited Speaker: BicycleTx Ltd., CARIS Life Science, Repare Therapeutics, Sapience Pharma, Seagen; Financial Interests, Institutional, Funding: Acerta Pharma, ADC Therapeutics, Amgen, Arcus Biosciences, Array BioPharma, Artios Pharma Ltd., Astellas Pharma Inc, Astex, AstraZeneca, Basilea, Bayer, BeiGene, BicycleTx Ltd., BioNTech, Blueprint Medi- cines, Boehringer Ingelheim, Calithera Biosciences, Inc, Carrick Therapeutics, Casi Pharmaceuticals, Clovis Oncology, Inc, Crescendo Biologics Ltd., CytomX Therapeutics, Daiichi Sankyo, Deciphera, Eli Lilly, Exelixis, F. Hoffmann-La Roche Ltd., Fore Biotherapeutics, G1 Therapeutics, Genentech, GSK, H3 Biomedicine Inc, Hutchinson MediPharma, Ignyta/Roche, Immunocore, Immunomedics Inc, Incyte, Instil Bio, Iovance, Janssen, Jiangsu Hengrui, Kronos Bio, Lupin Limited, MacroGenics, Menarini, Merck KGaA, Mereo BioPharma, Merus, Millennium Pharmaceuticals, MSD, Nerviano Medical Sci- ences, Nurix Therapeutics Inc, Oncologie, Oxford Vacmedix, Pfizer, Plexxikon Inc, QED Therapeutics Inc, Relay Therapeutics, Repare Therapeutics Inc, Ribon Therapeutics, Roche, Sapience, Seagen, Servier, Stemline, Synthon Biopharmaceuticals, Taiho, Tesaro, Turning Point Therapeutics Inc.