Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A randomized phase 2 study (GOAL, Spanish Lung Cancer Group).

Abstract

9012 Background: Low BRCA1 mRNA levels correlate with longer progression free survival (PFS) in erlotinib treated EGFR mutant NSCLC patients (p), while risk of shortened PFS was associated with intermediate/high BRCA1 levels (HR, 8.46; P<0.0001). We explored the combination of the poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib with gefitinib in EGFR mutant NSCLC p. In a previous phase 1 trial, the safety of the combination was confirmed. Recommended phase 2 dose (RP2D) is gefitinib, 250 mg daily, and olaparib, 200 mg thrice daily. Methods: Stage IV treatment naïve NSCLC p with centrally confirmed EGFR mutations and measurable disease were recruited in the study (NCT01513174). We randomly allocated p (1:1) to receive gefitinib 250 mg daily or the combination at the RP2D. The primary endpoint was PFS. PFS related to BRCA1 mRNA was a secondary endpoint, and 53BP1 and enhancer of zeste homolog 2 (EZH2) were analyzed as modulators of BRCA1, overall survival (OS), response rate (RR), safety and tolerability. Target accrual was 186 p. This sample provided 80% power to detect HR of 0.63 after 116 PFS events. The first PFS analysis, side effect profile and RR had a February 28th, 2018 cut-off, minimum follow-up of 18 months (mo). Results: Of the 182 p who underwent randomization, 91 received gefitinib and 91 received gefitinib+olaparib, with no differences in gender, age, never smoker, performance status, bone or brain metastases or EGFR mutation. Median PFS for exon 19 deletions and exon 21 L858R EGFR mutations was 10.4 mo for gefitinib group and 12.8 mo for gefitinib + olaparib group (HR for disease progression or death, 0.83; P=0.329). RR was 68% in gefitinib group and 78% in gefitinib + olaparib group. Conclusions: The gefitinib+olaparib combination did not provide significant benefit over gefitinib alone. Median PFS was 2.4 mo longer for the combination and risk of disease progression or death was 17% lower with gefitinib+olaparib than gefitinib alone. The pre-specified assessment of BRCA1, 53BP1 and EZH2 could determine if a subgroup of p might obtain major benefit from the combination. Clinical trial information: NCT01513174.