FOLFIRI + pimasertib

FOLFIRI + pimasertib is a combination therapy that has been studied in clinical trials, particularly for KRAS-mutated metastatic colorectal cancer (mCRC). This combination pairs the standard chemotherapy regimen FOLFIRI with pimasertib, a MEK inhibitor that targets the MAPK pathway. ## Components and Mechanism of Action FOLFIRI is a chemotherapy combination that includes: - Folinic acid (leucovorin): Enhances the effectiveness of 5-FU - Fluorouracil (5-FU): An antimetabolite that disrupts DNA synthesis - Irinotecan: A topoisomerase I inhibitor that blocks DNA replication[5][6] Pimasertib is a MEK inhibitor that targets the mitogen-activated protein kinase (MAPK) pathway, which plays a central role in cell-cycle regulation, cell growth, signaling, and survival. This pathway is frequently dysregulated in human cancers, including colorectal cancer, making it a rational target for therapy[1][2]. ## Clinical Development A phase I study was conducted to investigate the safety and efficacy of adding pimasertib to FOLFIRI as second-line treatment for patients with KRAS-mutated metastatic colorectal cancer. The study had two parts: a safety run-in phase followed by a randomized phase II part[1]. The primary objective of the safety run-in phase was to determine the maximum-tolerated dose (MTD) and the recommended phase II dose of pimasertib combined with FOLFIRI[1][2]. ## Dosing and Administration In the phase I trial: - 16 patients were enrolled - 10 patients received pimasertib 45 mg per day plus FOLFIRI - 6 patients received pimasertib 60 mg per day plus FOLFIRI - The MTD was determined to be 45 mg per day of pimasertib[2] The FOLFIRI regimen was administered in 2-week cycles, with each cycle lasting 4 weeks in duration[1][5]. ## Efficacy Of the 15 patients in the efficacy analysis group: - 2 patients had partial response - 9 patients had stable disease - 3 patients had progressive disease - 1 patient could not be evaluated[2] ## Safety Profile Dose escalation of pimasertib in combination with FOLFIRI was limited by toxicity. At the MTD of 45 mg per day, pimasertib was adequately tolerated in patients with mCRC, and no unexpected or new safety signals or concerns were identified[1][2]. The most common treatment-emergent adverse events were: - Diarrhea - Nausea - Vomiting - Asthenia - Skin/rash events[2] The median time on trial treatment (FOLFIRI plus pimasertib) was 10.9 weeks (range 1–44 weeks), with the pimasertib 45 mg per day cohort having a median of 11.0 weeks (range 1–41 weeks) and the pimasertib 60 mg per day cohort having a median of 9.8 weeks (range 5–44 weeks)[1]. This combination represents an approach to target both the standard cytotoxic pathways (with FOLFIRI) and the MAPK pathway (with pimasertib) in KRAS-mutated colorectal cancer, which is often resistant to standard therapies.

Other names

pimasertib + FOLFIRI