Zedoresertib (WEE1) + Lunresertib (PKMYT1) Shows Early Tumor Shrinkage in CCNE1/FBXW7-Altered Solid Tumors (notably ovarian)

Zedoresertib is an oral, selective WEE1 inhibitor and lunresertib is an oral, selective PKMYT1 inhibitor; dual checkpoint abrogation is designed to force premature mitotic entry under replication stress, driving mitotic catastrophe in CCNE1 amp/FBXW7/PPP2R1A-altered tumors (synthetic lethal hypothesis). In this Phase 1 dose-escalation study (NCT04855656) in heavily pretreated advanced solid tumors (n=54; ovarian 35.2%, colorectal 31.5%; 1–9 prior lines), the most common ≥G3 TRAEs were anemia (9.3%), neutropenia (7.4%), and Palmar-Plantar Erythrodysesthesia (PPE) (7.4%), with no G5 events; DLTs occurred in 4/54 (9.3%). Among 44 RECIST-evaluable patients, 24 (55.5%) had tumor shrinkage (3 cCR, 5 uPR, 15 SD, 1 PD), and ctDNA molecular response rate (≥50% decline) was 39% (9/23); in the ovarian subset with CCNE1 amp/FBXW7 mut (n=16; 12 platinum-resistant), 81.3% had shrinkage with 3 cCR + 3 uPR and clinical benefit rate 93.8%—a signal that looks stronger than the ~10–20% ORR typically seen with single-agent non-platinum chemotherapy options used in platinum-resistant ovarian cancer (e.g., PLD/topotecan/weekly paclitaxel ranges).