Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non-Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial

Universitair Ziekenhuis Leuven, Louvain, Flemish, Belgium
Journal of Clinical Oncology (Impact Factor: 18.43). 05/2007; 25(12):1545-52. DOI: 10.1200/JCO.2005.05.1474
Source: PubMed


Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non-small-cell lung cancer (NSCLC).
Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL).
A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild).
Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.

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Available from: Joachim von Pawel, Nov 09, 2015
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    • "The clinical development of EGFR inhibitors in NSCLC started before the discovery of EGFR mutations, therefore initial studies with Gefitinib and Erlotinib were conducted in unselected patients in both pretreated525354and in treatment-naïve patients in combination with standard chemotherapy55565758. In attempt to identify patients with improved outcome when treated with EGFR TKIs, several predictive biomarkers, such as EGFR overexpression/amplification[59]and HER2 overexpression/amplification[60], were studied before EGFR mutations emerged as the major predictive factor to these targeted agents. "
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    ABSTRACT: The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.
    Preview · Article · Jun 2015 · Oncotarget
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    • "During the past decade, some research demonstrated that EGFR TK inhibitor (EGFR-TKI) sensitivity was influenced by the presence of EGFR mutations and increased EGFR copy numbers.19–25 Some Phase III trials also revealed that, compared with those treated with erlotinib or gefitinib, the EGFR-mutated NSCLC patients who were treated with normal chemotherapy had poorer clinical outcomes.26,27 Currently, relevant research results suggest that the mutant status of EGFR can likely be a predicting factor for the response to cytotoxic chemotherapy and prognosis of advanced NSCLC patients; however, this issue remains debatable. "
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    Full-text · Article · Sep 2014 · Drug Design, Development and Therapy
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    • "Gefitinib and erlotinib, two EGFR tyrosine kinase inhibitors, demonstrated potent efficacy against advanced NSCLC as single treatment. However, when combined with chemotherapy, neither drug showed further benefits to patients with advanced NSCLC [16, 17]. Although therapeutic methods developed rapidly, platinum-based two-drug chemotherapy was still extensively used in the clinic. "
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    ABSTRACT: Introduction The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Material and methods In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m2 or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m2 (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. Results The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. Conclusions Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable.
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