First-SIGNAL: First-Line Single-Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung
Abstract
PURPOSE: Gefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy. PATIENTS AND METHODS: In this randomized phase III trial, a total of 313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ function were randomly assigned to receive either gefitinib (250 mg daily) or GP chemotherapy (gemcitabine 1,250 mg/m(2) on days 1 and 8; cisplatin 80 mg/m(2) on day 1 every 3 weeks, for up to nine courses). The primary objective was to demonstrate better overall survival (OS) for gefitinib compared with GP in chemotherapy-naive NSLAs. RESULTS: Three hundred nine patients were analyzed per protocol (gefitinib arm, n = 159; GP arm, n = 150). Gefitinib did not show better OS compared with GP (hazard ratio [HR], 0.932; 95% CI, 0.716 to 1.213; P = .604; median OS, 22.3 v 22.9 months, respectively). The 1-year PFS rates were 16.7% with gefitinib and 2.8% with GP (HR, 1.198; 95% CI, 0.944 to 1.520). Response rates were 55% with gefitinib and 46% with GP (P = .101). Myelosuppression, renal insufficiency, and fatigue were more common in the GP arm, but skin toxicities and liver dysfunction were more common in the gefitinib arm. Two patients (1.3%) in the gefitinib arm developed interstitial lung disease and died. CONCLUSION: Gefitinib failed to demonstrate superior OS compared with GP as first-line therapy for NSLAs.
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Third-generation EGFR-TKIs (WZ4002, CO-1686, AZD9291 and HM61713) irreversibly block T790M mutant EGFR and have demonstrated tumour responses in >50% of patients with the EGFR T790M mutation.
“The third-generation EGFR-TKIs include the WZ4002, CO-1686, AZD9291 and HM61713 inhibitors, which have demonstrated tumour responses in >50% of patients with the EGFR T790M mutation.8–12”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [8]
Eight randomised controlled phase III trials have demonstrated that first-generation or second-generation EGFR-TKIs represent the best first-line treatment option in patients with advanced NSCLC whose tumours harbour EGFR mutations, when compared with chemotherapy, because they significantly improved the RR and PFS.
“Eight randomised controlled phase III trials (table 1) have demonstrated that first-generation or second-generation EGFR-TKIs represent the best first-line treatment option in patients with advanced NSCLC whose tumours harbour EGFR mutations, when compared with chemotherapy, because they significantly improved the RR and progression-free survival (PFS).4–11”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [8]
Several other trials conducted in Asia confirmed the superiority of Gefitinib over chemotherapy in EGFR-mutated patients.
“Several other trials conducted in Asia confirmed the superiority of Gefitinib over chemotherapy in EGFR-mutated patients [16, 44, 64].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [64]
Several studies have consistently shown that EGFR TKIs (gefitinib, erlotinib, afatinib) produce higher response rates, longer PFS and improved quality of life compared with platinum-based doublet chemotherapy in PS 0-2 patients whose tumours have an activating EGFR mutation.
“Several studies have consistently demonstrated that the EGFR TKIs (gefitinib, erlotinib and afatinib) produce higher RRs, longer PFS and improve QoL compared with standard platinum-based doublet chemotherapy in patients with good PS (PS 0-2), whose tumour harbours an activating (sensitising) EGFR mutation [105-112].”
From Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2016) · cites this paper as [106]
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- Authors
- Han, J.-Y., Park, K., Kim, S.-W., Lee, D. H., Kim, H. Y., Kim, H. T., Ahn, M. J., Yun, T., Ahn, J. S., Suh, C., Lee, J.-S., Yoon, S. J., Han, J. H., Lee, J. W., Jo, S. J., & Lee, J. S.
- Affiliations
- Korea University (KR)
- Ji-Youn Han, Hyae Young Kim, Heung Tae Kim, Tak Yun, Sung Jin Yoon, Jong Hee Han, Sook Jung Jo, and Jin Soo Lee, National Cancer Center, Goyang; Keunchil Park, Myung Ju Ahn, and Jin Seok Ahn, Samsung Medical Center; Sang-We Kim, Dae Ho Lee, Cheolwon Suh, and Jung-Shin Lee, Asan Medical Center; Jae Won Lee and Sook Jung Jo, Korea University, Seoul, Republic of Korea.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2012-04-01
- Volume
- 30
- Issue
- 10
- Pages
- 1122-1128
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2154662831
- Cited by
- 736
- References
- 3
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 14 · 2023: 19 · 2022: 25 · 2021: 40 · 2020: 48 · 2019: 59 · 2018: 63 · 2017: 87 · 2016: 67 · 2015: 98 · 2014: 88 · 2013: 86 · 2012: 29
- FWCI
- 77.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- gefitinib, gemcitabine, cisplatin, lung adenocarcinoma, never smokers, first-line therapy, EGFR tyrosine kinase inhibitors, overall survival, progression-free survival, interstitial lung disease, adverse events
- MeSH terms
- Gefitinib, Gemcitabine, Adenocarcinoma, Adult, Aged, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Cisplatin, Deoxycytidine, Drug Administration Schedule, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Quality of Life, Quinazolines, Odds Ratio, Treatment Failure, Genes, erbB-1, Asian People, Protein Kinase Inhibitors, Kaplan-Meier Estimate
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