First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial.

Abstract

BACKGROUND:

In the Iressa Pan-ASia Study (IPASS), gefitinib claimed improved progression-free survival (PFS) versus carboplatin-paclitaxel in clinically selected lung cancer patients. The primary objective of this study was to assess the PFS of pemetrexed-cisplatin (PC) followed by gefitinib maintenance versus gefitinib monotherapy in an IPASS-like population.

METHODS:

In this open-label, randomised, phase 3 trial, eligible patients were ⩾18 years, chemonaïve, East Asian, light ex-smokers/never-smokers with advanced non-squamous non-small cell lung cancer, an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and unknown epidermal growth factor receptor (EGFR) mutation status who enrolled at 12 sites in Asia. Patients randomly received (1:1) pemetrexed (500 mg/m(2)) plus cisplatin (75mg/m(2)) for six 21-day cycles, followed by gefitinib maintenance or gefitinib monotherapy (250 mg/day). Patient tissue was retrospectively analysed for EGFR mutations. This study is registered with ClinicalTrials.gov, NCT01017874.

FINDINGS:

Between 23rd November 2009 and 27th April 2012, 253 patients entered, and 236 patients were randomly assigned to and treated with PC therapy (N=114) and gefitinib monotherapy (N=118). Between-arm baseline characteristics were balanced. PFS was not significantly different between treatment arms (p=0.217). The unadjusted hazard ratio (HR) was 0.85 (95% confidence interval (CI) 0.63-1.13). The HR should be cautiously interpreted as it was not constant. EGFR mutation status was determined for 74 tissue samples; 50 (67.6%) had mutations. In a pre-specified subgroup analysis, only the treatment-by-EGFR mutation interaction was significant (p=0.008) for PFS. For the entire treatment period, a higher proportion of patients in the PC/gefitinib arm versus gefitinib experienced possibly drug-related grade 3-4 treatment-emergent adverse events (39 of 114 [34%] versus 19 of 118 [16%]; p=0.002).

INTERPRETATION:

In the intention-to-treat (ITT) population, PFS was not significantly different. In the biomarker-assessable population, front-line EGFR tyrosine kinase inhibitor monotherapy was not efficacious in patients with wild-type EGFR. Identification of EGFR mutation status is key in the management of advanced non-squamous non-small cell lung cancer.

FUNDING:

Eli Lilly and Company.

• Authors: James Chih-Hsin Yang, Jin Hyoung Kang, Tony Mok, Myung-Ju Ahn, Vichien Srimuninnimit, Chia-Chi Lin, Dong-Wan Kim, Chun-Ming Tsai, Helen Barraclough, Sedat Altug, Mauro Orlando, Keunchil Park
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 50 Issue 13 Pg. 2219-30 (Sep 2014) ISSN: 1879-0852 [Electronic] England
• PMID: 24953333 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Glutamates
• Protein Kinase Inhibitors
• Quinazolines
• Pemetrexed
• Guanine
• Cisplatin
• Gefitinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Asian People (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cisplatin (administration & dosage)
• Disease-Free Survival
• Female
• Gefitinib
• Glutamates (administration & dosage)
• Guanine (administration & dosage, analogs & derivatives)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Male
• Middle Aged
• Pemetrexed
• Protein Kinase Inhibitors (administration & dosage, therapeutic use)
• Quinazolines (administration & dosage, therapeutic use)
• Young Adult