Activity of XL647 in clinically selected NSCLC patients (pts) enriched for the presence of EGFR mutations: Results from Phase 2.

8053 Background: XL647 is a small molecule inhibitor of EGFR, HER2, and VEGFR2. Oral administration of XL647 results in dose-dependent, sustained inhibition of these target enzymes in preclinical studies. Increasing evidence of a close relationship between EGFR- and VEGFR2-mediated signaling pathways suggests that simultaneous inhibition of these pathways may provide improved efficacy.,XL647 is administered orally as a single dose of 350 mg on Days 1-5 of each 14 day cycle (intermittent cohort). A second cohort will receive 300 mg daily. The primary endpoint is tumor response by RECIST. Pts with previously untreated advanced NSCLC (Stage IIIB or Stage IV) with adenocarcinoma histology that meet at least one of the following demographic criteria: Asian, female, minimal (<15 pack-yrs) or no smoking history are eligible. The mutational status of EGFR and KRAS in tumor tissue is being analyzed when archived material is available.,Enrollment into the intermittent cohort is complete with 41 pts (median age 67 yrs, range 45-87; 30F/11M). A 28% partial response (PR) rate (10/36 evaluable pts) was observed. 7/10 patients with a PR had an EGFR mutation detected in tumor tissue (6 pts with exon 19 deletions and 1 pt with L858R mutation). 3/10 patients with PR did not have detectable EGFR mutations. One pt with EGFR L858R had modest tumor shrinkage (SD). Stable disease for ≥ 3 months was observed in a total of 36% of patients. Common adverse events reported to date are Grade 1/ 2 diarrhea, fatigue, rash, nausea and clinically asymptomatic QTc prolongation.,This study supports a clinical selection strategy to enrich a NSCLC population for EGFR mutations. XL647 has anti- tumor activity in selected NSCLC pts, demonstrating a 28% PR rate and 36% SD for ≥ 3 months, for an overall clinical benefit rate of 64%. All 8 pts with EGFR activating mutations experienced tumor shrinkage (7 with PRs and 1 SD). Three pts without an EGFR mutation experienced a PR. XL647 is well-tolerated in this patient population. Data from the daily dosing cohort will be presented. [Table: see text].