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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    • "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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    ABSTRACT: Non-small-cell lung cancer (NSCLC) has entered the age of individual treatment, and increasing point mutations of specific oncogenes and rearrangement of some chromosomes are biomarkers used to predict the therapeutic effect of targeted therapy. At present, there is a consensus among clinicians that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown favorable efficacy in NSCLC patients with EGFR mutation, and some relevant research has suggested that the presence of EGFR mutations is a favorable prognostic marker. However, the association of EGFR mutation status with the responsiveness to conventional chemotherapy agents and survival in NSCLC patients is still unclear. This review provides an overview of and assesses the role of EGFR as a prognostic marker for postoperative patients and as a predictive marker for response to cytotoxic chemotherapy. In addition, we review the comparison of response to chemotherapy between EGFR mutations in exon 19 and in exon 21 and the predictive role of p.T790M mutation.
    Drug Design, Development and Therapy 09/2014; 8:1595-1611. DOI:10.2147/DDDT.S69690 · 3.03 Impact Factor
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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.
    Archives of Medical Science 08/2014; 10(4):717-724. DOI:10.5114/aoms.2014.44862 · 2.03 Impact Factor
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    • "Therefore, to achieve a longer survival period, combination regimens of chemotherapy and EGFR-TKIs have been tried. Even though previous Phase III studies in unselected populations have shown that the concurrent combination of chemotherapy and erlotinib did not improve survival compared with chemotherapy alone,59,60 sequential intercalated combination regimens of chemotherapy and erlotinib (First-line Asian Sequential Tarceva And Chemotherapy Trial; FASTACT) have been shown to enable a significant improvement in responses and PFS, especially in patients with adenocarcinoma.61 One explanation for this lack of efficacy with a concurrent combination is that G1 cell cycle arrest caused by EGFR-TKIs might reduce the cell cycle phase-dependent activity of chemotherapy. "
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    ABSTRACT: Gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), has been approved in Japan for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) based on Phase II clinical trials since 2002. Erlotinib, another EGFR-TKI, was also approved a few years thereafter. In 2004, activating mutations in the EGFR gene were discovered to be a predictive biomarker for EGFR-TKI treatment, and gefitinib, which is not effective for patients with EGFR wild-type NSCLC, has since been used only in patients with EGFR-mutated NSCLC. In contrast, erlotinib is potentially effective for the treatment of EGFR wild-type NSCLC. Similar to gefitinib, erlotinib is also effective for EGFR-mutated NSCLC and has been used as an initial treatment for patients with advanced EGFR-mutated NSCLC. Both gefitinib and erlotinib can be used in a Japanese clinical setting. The approved daily dose of erlotinib (150 mg) is equal to the maximum tolerated dose of erlotinib. In contrast, the daily dose of gefitinib has been set at 250 mg, which is approximately one-third of the maximum tolerated dose of gefitinib. Accordingly, a higher serum concentration can be achieved using erlotinib, compared with gefitinib. This advantage can be applied to the treatment of central nervous system metastases (brain metastasis and carcinomatous meningitis), the treatment of which is complicated by the difficulty drugs have penetrating the blood-brain barrier. Although patients with EGFR-mutated NSCLC respond dramatically to EGFR-TKIs, some patients have a poor response and the majority eventually undergo disease progression. To overcome such resistance, several novel treatment strategies, such as combination therapy and next-generation EGFR-TKIs, have been attempted.
    Drug Design, Development and Therapy 07/2014; 8:1037-1046. DOI:10.2147/DDDT.S50358 · 3.03 Impact Factor
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