Abstract PR008: MYTHIC: First-in-human (FIH) biomarker-driven phase I trial of PKMYT1 inhibitor lunresertib (lunre) alone and with ATR inhibitor camonsertib (cam) in solid tumors with CCNE1 amplification or deleterious alterations in FBXW7 or PPP2R1A

作者：Timothy A. Yap, Alison M. Schram, Elizabeth K. Lee, Fiona Simpkins, Mia C. Weiss, Patricia LoRusso, Martin Højgaard, Benedito A. Carneiro, Ryan H. Moy, Ignacio Garrido‐Laguna, María Koehler, Thaddeus J. Unger, Emeline Bacqué, Elia Aguado-Fraile, Sunantha Sethuraman, Snehal Dhake, Yajun Liu, Adrian J. Fretland, Xizi Sun, Yi Xu, Nathan Hawkey, Jen Truong, Stéphanie Lheureux · 发表于：Molecular Cancer Therapeutics · 年份：2023 · DOI：10.1158/1535-7163.targ-23-pr008 · 被引用次数：20 · 研究领域：Cancer Genomics and Diagnostics、Microtubule and mitosis dynamics、Advanced Breast Cancer Therapies

Abstract Background: Lunre (RP-6306), a first-in-class membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) inhibitor, disrupts G2/M checkpoint causing DNA damage in cells with synthetic lethal alterations. Lunre plus the ATR inhibitor cam (RP-3500) promotes premature mitosis via CHK1/Cdc25 regulation and tumor regression. The FIH phase 1 MYTHIC trial assessed lunre alone or in combo with cam (lunre + cam) (NCT04855656). Methods: Pts >12yrs with advanced solid tumors and CCNE1 amplification, or deleterious FBXW7 or PPP2R1A mutations received oral lunre alone (QD or BID) or lunre (QD or BID) + cam (QD) continuously or intermittently using BOIN design. Endpoints: safety, tolerability, RP2D, preliminary efficacy (RECIST v1.1, GCIG CA-125), clinical benefit rate (CBR; RECIST/GCIG CA-125 or therapy duration ≥16w), ctDNA molecular response, PK and PD. Results: As of June 1, 2023, 108 pts were treated; n=66 lunre alone; n=42 lunre + cam. Tumors: uterine (31.5%), colorectal (20.4%), ovarian (16.7%), others (31.5%); median 3 prior therapies. 39.8% had CCNE1, 36.1% FBXW7, 19.4% PPP2R1A, and 4.6% had 2 or no alterations. Treatment-related AEs for lunre alone vs lunre + cam: nausea/vomiting (31.8% vs 64.3%; G3 1.5% vs 0%), anemia (21.2% vs 64.3%; G3 7.6% vs 38.1%), rash (34.8% vs 31%; G3 7.6% vs 2.4%), fatigue (22.7% vs 38.1%; G3 1.5% vs 0%). Lunre DLTs included G2/3 rash reversible with drug holds +/- supportive care. Preliminary RP2Ds: (1) lunre a...