KEY TAKEAWAYS
- The MINOTAUR phase 1 trial aimed to assess the safety, tolerability, and efficacy of lunre and FOLFIRI in pts with advanced GI cancers.
- The primary endpoints were safety; dose/schedule finding followed BOIN design.
- The FOLFIRI + lunre showed promising efficacy in heavily pretreated metastatic CRC, further validation is recommended.
Lunre is a first-in-class inhibitor of protein kinase membrane associated tyrosine/threonine 1 (PKMYT1), which is synthetic and lethal with CCNE1 amplification (amp) or FBXW7 mutations (mut), alterations present in w20% of gastrointestinal (GI) cancers, and synergizes with irinotecan (iri) in tumor models harboring these alterations.
Zev A. Wainberg and the team reported the preliminary safety, tolerability, and efficacy of lunre and FOLFIRI from the MINOTAUR study.
Researchers enrolled patients (pts) with advanced GI cancers (CCNEamp or FBXW7mut) received a daily or intermittent lunre in addition to FOLFIRI (every 2 weeks), whether irinotecan (iri)-naive or exposed. The study aimed to assess safety (primary endpoint), and followed a BOIN design for dose/schedule determination. Secondary endpoints were to evaluate efficacy (overall response rate (ORR) and molecular response rate (MRR)) and pharmacokinetics (PK).
Results showed that 38 pts (median age: 55.5 years; 12 with CCNE1 amplification and 26 with FBXW7 mutation), including additional eighteen with colorectal cancer (CRC), the median prior lines of treatment were 2 (range: 0-6), with 47.4% having prior exposure to irinotecan (iri).
Treatment-related adverse events (TRAEs) were consistent with expectations for FOLFIRI alone, with grades 3-4 observed in 44.7% pts. Neutropenia (31.6%) and leukopenia (13.2%) were the most common TRAEs occurring in ≥10% of pts, and rash (mostly grade 1 to 2) affected 31.6% of pts. The recommended phase 2 dose (RP2D) of continuous lunre was established at 60 mg twice daily.
In the subset of pts evaluable for efficacy (n=33), the ORR per RECIST was 18.2% (95% CI: 7-35.5), with partial responses observed in CRC, anal, esophageal, gastric, jejunal (prior iri), and pancreatic (prior iri) cancers. The MRR was 60.9% (14 out of 23 evaluable pts). About 24.2% pts continued treatment for more than 6 months. Among the 15 evaluable pts with CRC (median prior lines of treatment: 3; 10 with prior iri), 4 had treatment durations exceeding 6 months, including 2 pts with durations exceeding 12 months.
The study concluded that the combination of standard FOLFIRI with daily 60 mg BID lunre was well tolerated and demonstrated promising efficacy in heavily pretreated pts with CCNE1 amplification and FBXW7 mutation, including those previously exposed to iri. Further validation in randomized studies is warranted to confirm its potential as a therapeutic strategy for metastatic colorectal cancer.
The trial was sponsored by Repare Therapeutics.
Source: https://cslide.ctimeetingtech.com/esmogi24hybrid/attendee/confcal/show/session/39
Clinical Trial: https://www.clinicaltrials.gov/study/NCT05147350
Wainberg Z A, Bent A H, Garcia V M, et al. (2024). “Phase I study of the PKMYT1 inhibitor lunresertib (lunre) in combination with FOLFIRI in advanced gastrointestinal (GI) cancers (MINOTAUR study).” Presented at ESMO-GI 2024, (Abstract 504MO)
