Molecular profiling of patients with colorectal cancer and matched targeted therapy in Phase 1 clinical trials
Menée sur 254 patients atteints d'un cancer colorectal réfractaire à la chimiothérapie, cette étude évalue l'intérêt d'inclure ces patients dans des essais de phase I de thérapies ciblées associées à la présence de mutations spécifiques
Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in Phase 1 trials with targeted therapies will improve the outcomes of cancer patients. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered Phase 1 trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was performed in 254 patients: KRAS mutations (80/254, 31.5%), BRAF mutations (24/196, 12.2%), PIK3CA mutations (15/114, 13.2%), KRAS and PIK3CA mutations (9/114, 7.9%), low PTEN expression (97/183, 53.0%), and high pMET expression (38/64, 59.4%). In total, 68 patients received 82 different MTAs: PI3K pathway inhibitor (if PIK3CA mutation, n=10; or low PTEN, n=32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n=10; or BRAF mutation, n=1), second-generation anti-EGFR monoclonal antibodies (if wild-type KRAS, n=11), anti-HGF monoclonal antibody (if high pMET, n=10), mTOR inhibitor plus anti-IGF1R monoclonal antibody (if low PTEN, n=5) and BRAF inhibitor (if BRAF mutation, n=3). Median time to treatment failure on MTA was 7.9 weeks versus 16.3 weeks for their prior systemic antitumor therapy (p<0.001). Partial response was seen in one patient (1.2%, PI3K inhibitor with PIK3CA mutation) and stable disease > 16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory colorectal cancer patients with targeted agents in Phase 1 trials based on the current molecular profile does not confer a significant clinical benefit.
http://mct.aacrjournals.org/content/early/2012/06/20/1535-7163.MCT-12-0290.abstract