A phase Ib study to evaluate the PI3-kinase inhibitor GDC-0941 with paclitaxel (P) and carboplatin (C), with and without bevacizumab (BEV), in patients with advanced non-small cell lung cancer (NSCLC).

3044 Background: Genetic alterations affecting the PI3K pathway are frequently observed in NSCLC (eg. PTEN loss, PIK3CA gene amplification). In preclinical tumor models GDC-0941 is synergistic with chemotherapy and increases the efficacy of anti-VEGF when dosed concurrently. This study sought to determine whether GDC-0941 can be safely combined with P + C +/- BEV. Methods: In Arm A, BEV-ineligible patients (pts) with advanced NSCLC and 0 or 1 prior chemotherapy regimen received increasing GDC-0941 doses (3 + 3 design) with P (200 mg/m2) and C (AUC 6 mg/mL·min) every 3 weeks. BEV-eligible pts in Arm B received BEV (15 mg/kg) in addition to P and C. In both arms, GDC-0941 was given once daily on Days 1-14 of a 21-day cycle. P and C were given up to 6 cycles, while GDC-0941 (with or without BEV) was given to progression or toxicity. Study objectives were to evaluate safety and pharmacokinetics (PK), and to determine the maximum tolerated dose (MTD) of GDC-0941 in both arms. Results: As of 9 January 2011, 18 pts were enrolled in GDC-0941 cohorts of 60, 100, and 165 mg (Arm A) and GDC-0941 cohorts of 100, 165 and 250 mg (Arm B). Eleven of 18 pts were active. Treatment-related adverse events (AEs) in ≥20% of pts were alopecia, asthenia, nausea, stomatitis, neutropenia, decreased appetite, paresthesia, epistaxis, arthralgia, peripheral neuropathy and rash. All treatment-related AEs were Grade 1 and 2 except for neutropenia. Grade 3 (16%) and 4 (11%) neutropenia events were not dose-limiting. PK characteristics of GDC-0941, P, 6-OH-P and C were similar to historical single-agent profiles. Based on preclinical efficacy, target exposures were achieved in the 250 mg cohort. Dose escalation will continue to a maximum of 400 mg. Confirmed partial responses (PR) were seen in 8 of 18 (44%) patients, including 1 squamous NSCLC pt with a pathologic complete response upon resection of the primary lung lesion (Arm A, 165 mg GDC-0941). Median follow up at the time of data cut-off was 5.4 months (range 0.6-10.3 m). Conclusions: The combination of GDC-0941, P and C (+/- BEV) was well tolerated. The combination MTD has not yet been reached. Antitumor activity was observed.