P0066 A randomised phase 3 study comparing first-line pemetrexed plus cisplatin followed by gefitinib as maintenance with gefitinib monotherapy in east Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer

Abstract

<h3>Background</h3> The IPASS study reported that gefitinib provided superior progression-free survival (PFS) compared with carboplatin and paclitaxel in a clinically selected lung cancer patient population; the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumours because patients with wild-type (WT) tumours had inferior outcomes. The current study compared PFS for pemetrexed plus cisplatin induction therapy followed by gefitinib as maintenance therapy versus gefitinib monotherapy as first-line treatments in patients with non-squamous non-small cell lung cancer. <h3>Methods</h3> Patients (<i>n</i>=236) with unknown EGFR mutation status were randomised 1:1 to pemetrexed plus cisplatin for six cycles or gefitinib. Patients without progressive disease after six cycles received gefitinib maintenance therapy. Primary endpoint analysis (Wilcoxon test after 169 PFS events) provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples were analysed for EGFR mutation status. <h3>Findings</h3> Baseline characteristics were balanced across treatment arms. 50 (68%) of 74 samples had mutations. Primary PFS analysis showed no significant difference between treatment arms (Wilcoxon <i>p</i>= 0.217). Unadjusted HR was 0.85 (95% confidence interval [CI] 0.63–1.13). During most of the study, the Kaplain Meier curve for pemetrexed plus cisplatin remained above the curve for gefitinib. In a prespecified subgroup analysis, EGFR-by-treatment interaction was statistically significant (<i>p</i>=0.008), showing treatment effect significantly differed by EGFR status. The PFS HR favoured pemetrexed plus cisplatin in EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients (EGFR-mutated: HR 0.83 [95% CI 0.42–1.62], <i>p</i>=0.585; EGFR-WT: HR 0.18 [95% CI 0.06–0.51], <i>p</i>=0.001). HRs for intention to treat (ITT) and EGFR-mutated patients were not constant and should be interpreted with caution. <h3>Interpretation</h3> In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, EGFR-WT patients did not benefit from front-line EGFR tyrosine kinase inhibitor treatment. Identification of EGFR mutational status is key for management of advanced non-squamous non-small cell lung cancer.