https://doi.org/10.55788/c2de28ca
Lunresertib, a first-in-class PKMYT1 inhibitor, targets CCNE1 amplification, FBXW7 alterations, and PPP2R1A alterations in solid tumours. The combination of lunresertib and FOLFIRI is under evaluation in several phase 1 and phase 2 trials. Dr Elisa Fontana (Sarah Cannon Research Institute, UK) presented the efficacy and tolerability data from the phase 1 MINOTAUR trial (NCT05147350) on the combination therapy, particularly for tumours with CCNE1 amplification and deleterious FBXW7 mutations, which are associated with poor prognosis and lack approved treatments [1].
The trial results demonstrated an ORR of 18.2% in heavily pretreated patients (n=33), including 4 confirmed and 2 unconfirmed partial responses (PR), regardless of prior irinotecan exposure. The prolonged clinical benefit rate among all tumour types was 51.5%, including 46.7% of the participants with recurrent colorectal cancer (CRC; n=15), suggesting prolonged duration of therapy for this particular group. Indeed, 40% of irinotecan-naïve CRC (2/5) patients remained on treatment for over 9 months, supporting the hypothesis of prolonged clinical benefit in CRC patients. The recommended phase 2 dose of lunresertib was established at 60 mg twice daily plus standard FOLFIRI.
The combination therapy was well tolerated, with a safety profile consistent with FOLFIRI alone, and no excess toxicity was observed. Neutropenia and leukopenia were the most common grade 3/4 treatment-related adverse events, reversible with FOLFIRI interruption.
In conclusion, this data is encouraging for early efficacy and tolerability, and suggests the need for further development in a randomised phase 2 study. The combination of lunresertib with FOLFIRI could potentially provide a new treatment option for gastrointestinal tumours with CCNE1 amplification and FBXW7 mutations.
- Fontana E, et al. Phase 1 Study of the PKMYT1 Inhibitor Lunresertib (Lunre) in Combination with FOLFIRI in Advanced Gastrointestinal (GI) Cancers (MINOTAUR Study). Abstract 504MO, ESMO Gastrointestinal Cancers Congress 2024, 26–29 June, Munich, Germany.
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