Background: Progression-free survival (PFS) and response rate (RR) to EGFR tyrosine kinase inhibitors (TKIs) vary in P with NSCLC driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. High BRCA1 mRNA expression negatively influenced PFS among EGFR mutant P treated with erlotinib. We hypothesized that since olaparib can attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these P. Methods: This is a Phase IB dose escalation study (standard 3+3 design) to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK), and clinical activity of orally administered olaparib in combination with gefitinib in EGFR mutant advanced NSCLC. P were treated with gefitinib 250mg once daily plus olaparib at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: Twenty-two P were included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (6) and 250mg TDS (7). Most common toxicities were G1-2, including anemia, leucopenia, nausea, diarrhea, asthenia, rash and anorexia; G3 drug-related events included lymphopenia (1) and anemia (3). No DLT at dose levels 1 and 2; 1 DLT at dose level 3, and 2 at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Thirteen P harbored concomitant sensitizing mutation (exon 19 del or L858R mut) plus T790M (5 previously treated, and 7 untreated P). Twenty-one P were evaluated for response: for those not previously treated, complete responses (CR) were observed in 1 r75966P (7.1%) partial responses (PR) in 9 P (69.2%), stable disease (SD) in 3 P (23%) and no progressive disease (PD) (0%). In P previously with TKI, 3 (37.5%) had PR, 3 (37.5%) SD, and 2 (25.5%) PD. Durable PR and SD were observed in both EGFR TKI-naïve and previously treated P. Conclusions: This phase IB trial of gefitinib plus olaparib confirms tolerability of the combination and the activity seen warrants further exploration in treatment-naïve patients. MTD of olaparib was 200mg TDS. Clinical trial information: NCT01513174.