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Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer
T Macarulla1, A Cervantes2, J Tabernero1
1Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, P Vall d'Hebron 119-129, Barcelona 08035, Spain.
Background:
The mitogen-activated protein kinase (MAPK) pathway has been implicated in the molecular pathogenesis of human cancers, including metastatic colorectal cancer (mCRC). This provides a rationale for the development of MAPK-targeted agents such as pimasertib.
Methods:
Patients with KRAS mutant mCRC were treated in the second-line setting with FOLFIRI (5-fluorouracil/folinic acid/irinotecan) plus pimasertib. 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.
Results:
Sixteen patients were enrolled in the trial. Ten and six patients were treated daily with 45 and 60 mg of pimasertib plus FOLFIRI, respectively. The MTD was considered to be 45 mg per day. The most common treatment-emergent adverse events were diarrhoea, nausea, vomiting, asthenia and skin/rash event. Of the 15 patients in the efficacy analysis group, two patients had partial response, nine patients had stable disease, three patients had progressive disease as their best overall response and one patient could not be evaluated.
Conclusions:
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.
Insights
Pimasertib combined with FOLFIRI chemotherapy showed acceptable tolerability in metastatic colorectal cancer (mCRC) patients. The maximum tolerated dose (MTD) of pimasertib was determined to be 45 mg daily, with manageable side effects.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The MAPK pathway is crucial in metastatic colorectal cancer (mCRC) pathogenesis.
- Pimasertib is a targeted agent for the MAPK pathway.
Purpose of the Study:
- Determine the maximum tolerated dose (MTD) and recommended Phase II dose of pimasertib with FOLFIRI.
- Evaluate safety and preliminary efficacy in KRAS mutant mCRC patients.
Main Methods:
- Phase I safety run-in trial.
- Second-line treatment with FOLFIRI plus escalating doses of pimasertib.
- Patients with KRAS mutant mCRC.
Main Results:
- MTD established at 45 mg/day pimasertib.
- Common adverse events included diarrhea, nausea, and rash.
- Two partial responses and nine stable disease cases observed.
Conclusions:
- Pimasertib at 45 mg/day is tolerated with FOLFIRI in mCRC.
- No new safety concerns identified.
- Toxicity limited dose escalation.
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