Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations.

Abstract

459 Background: Therapeutic matching based on underlying molecular abnormalities showed promising results in patients with diverse advanced cancers in early phase clinical trials. PIK3CA mutations may predict response to therapies with PI3K/AKT/mTOR inhibitors. Methods: Tumors from patients with colorectal cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Results: Of 194 patients analyzed, 31 (16%) had PIK3CA mutations. Of 194 patients 175 (90%) were assessed for the presence of KRAS mutation. Patients with PIK3CA mutations had higher prevalence of simultaneous KRAS mutations than patients with wild-type (wt) PIK3CA (21/30, 70% vs. 63/145, 43%; p=0.009). Of the 31 patients with PIK3CA mutations, 17 (55%) were treated in clinical trials containing a PI3K/AKT/mTOR pathway inhibitor (median age, 57; median number of prior therapies, 4). Of these 17 patients, none achieved a partial or complete response (PR/CR) and only 1 (6%, 95% CI 0.01-0.27) patient had stable disease for more than 6 months (SD>6), which was not significantly different from the SD>6/PR/CR rate of 16% (11/67; 95% CI 0.09-0.27) in colorectal cancer patients without PIK3CA mutations treated on the same protocols targeting the PI3K/AKT/mTOR pathway (p=0.44). The median progression-free survival was only 1.9 months (95% CI 1.5-2.3). Conclusions: Heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer do not seem to benefit from protocols incorporating PI3K/AKT/mTOR inhibitors. PIK3CA mutations are associated with simultaneous KRAS mutations, which might account for therapeutic resistance.