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S. Altug

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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.04 - A Randomized 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 Nonsquamous Non-Small Cell Lung Cancer (nSqNSCLC) (ID 1943)

      16:15 - 17:45  |  Author(s): S. Altug

      • Abstract
      • Presentation
      • Slides

      The IPASS study reported that in a clinically selected lung cancer patient population (East Asian, light ex-/nonsmokers with adenocarcinoma) gefitinib (G) provided superior progression-free survival (PFS) than chemotherapy with carboplatin/paclitaxel; however, the benefit was restricted to patients with epidermal growth factor receptor gene (EGFR)-mutant tumors whereas patients with wild-type (WT) tumors had inferior outcomes. Pemetrexed, in combination with cisplatin, (PC) has demonstrated improved efficacy in first-line treatment of nSqNSCLC and is a preferred chemotherapy choice. The primary objective was to compare PC induction therapy followed by G as maintenance therapy to G monotherapy, in terms of PFS, as first-line treatment in a similar “IPASS” patient population.

      Patients with unknown EGFR mutation status (N=236) were randomized 1:1 to PCG treatment for 6 cycles or G. Patients on Arm A without progressive disease after 6 cycles received G maintenance therapy. Stage IIIB/IV nSQ NSCLC, light ex-smokers or never-smokers, and ECOG PS 0-1 patients with no prior systemic therapy were eligible. Primary endpoint analysis was conducted using a Wilcoxon test after 169 PFS events. This assessment provided 80% power if the true hazard ratio (HR) was 0.65. Tissue samples from consenting patients were analyzed for EGFR mutation status.

      Baseline characteristics were balanced across treatment arms. One-hundred-forty-one patients provided tissue for EGFR mutation analysis (59.7%). Mutation status was determined for 74 samples (52.5%);50/74 samples (67.6%) had mutations (mutation type: EX19_DEL, n=25; L858R, n=23; other, n=2). The primary analysis of PFS showed no significant difference between treatment arms (Wilcoxon p=0.217). The unadjusted HR was 0.85 (95% CI: 0.63, 1.13). During most of the study period, the KM curve for PC remained above the G curve. In a prespecified subgroup analysis, EGFR-by-treatment interaction was statistically significant (p=0.008), showing treatment effect significantly differed by EGFR mutation status. The HR for PFS favored PC in both EGFR-mutated and EGFR-WT patients, but the magnitude of benefit was greater in EGFR-WT patients [EGFR-mutated patients HR=0.83 ([95% CI: 0.42, 1.62], p=0.585); EGFR-WT HR 0.18 ([95% CI: 0.06, 0.51], p=0.001)]. HRs for ITT and EGFR-mutated patients should be interpreted with caution as they were not constant. Arm A had more patients with ≥1 possibly drug-related CTCAE grade 3/4 TEAEs but similar rates of all-grade TEAEs during induction. Selected grade 3/4 or all-grade TEAEs which occurred significantly more included anemia, neutropenia, emesis, and neuropathy in Arm A and AST/ALT elevations, diarrhea, pruritus, and skin rash in Arm B. The toxicity profile was similar in both arms during the G maintenance period.

      In the ITT population, the PFS difference was not statistically significant. In the biomarker assessable population, results are consistent with the existing consensus that patients with WT EGFR do not benefit with front-line EGFR TKI treatment. Overall, the results show that identification of the EGFR mutational status is key in the management of advanced NSCLC. Even in the presence of clinically favorable predictors of EGFR mutation positivity (>60% in our population), “empirical” choice of EGFR TKIs as front-line therapy may be detrimental to NSCLC patients without EGFR mutations.

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