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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"A series of randomized trials have demonstrated that chemotherapy regimens provide a similar, modest level of efficacy in treating NSCLC (Azzoli et al., 2009; Bunn et al., 2002; D'Addario et al., 2009; Grossi et al., 2009; Scagliotti et al., 2008), while targeted therapeutic agents, such as Erlotinib and Gefitinib, improved the objective response rates in patients with EGFR mutation. However , the addition of chemotherapy to the targeted therapeutic agent regimen did not prolong the survival time (Gatzemeier et al., 2007; Giaccone et al., 2004; Herbst et al., 2004 Herbst et al., , 2005). Since it was first introduced by Eshhar et al., chimeric antigen receptor (CAR) redirected T cell therapy has emerged as a promising strategy for treating malignancies (Eshhar et al., 1993). "
[Show abstract][Hide abstract]ABSTRACT: The successes achieved by chimeric antigen receptor-modified T (CAR-T) cells in hematological malignancies raised the possibility of their use in non-small lung cancer (NSCLC). In this phase I clinical study (NCT01869166), patients with epidermal growth factor receptor (EGFR)-positive (>50% expression), relapsed/refractory NSCLC received escalating doses of EGFR-targeted CAR-T cell infusions. The EGFR-targeted CAR-T cells were generated from peripheral blood after a 10 to 13-day in vitro expansion. Serum cytokines in peripheral blood and copy numbers of CAR-EGFR transgene in peripheral blood and in tissue biopsy were monitored periodically. Clinical responses were evaluated with RECIST1.1 and immune- related response criteria, and adverse events were graded with CTCAE 4.0. The EGFR-targeted CAR-T cell infusions were well-tolerated without severe toxicity. Of 11 evaluable patients, two patients obtained partial response and five had stable disease for two to eight months. The median dose of transfused CAR+ T cells was 0.97×107 cells kg−1 (interquartile range (IQR), 0.45 to 1.09×107 cells kg−1). Pathological eradication of EGFR positive tumor cells after EGFR-targeted CAR-T cell treatment can be observed in tumor biopsies, along with the CAR-EGFR gene detected in tumor-infiltrating T cells in all four biopsied patients. The EGFR-targeted CAR-T cell therapy is safe and feasible for EGFR-positive advanced relapsed/refractory NSCLC.
Preview · Article · Mar 2016 · Science China. Life sciences
"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/amplificationand HER2 overexpression/amplification, were studied before EGFR mutations emerged as the major predictive factor to these targeted agents. "
[Show abstract][Hide abstract]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.
"In this population carrying 'bad' genetic alterations, concurrently with the classical EGFR-activating mutations, the employment of a combination strategy of chemotherapy and target agents may preserve a clinicobiological rationale. Although no benefit was demonstrated for adding TKIs to chemotherapy (INTACT-1 and 2 [32, 33], TRIBUTE  and TALENT trials ), intercalated erlotinib to cisplatin or carboplatin demonstrated a significant benefit in the context of an EGFR mutationpositive subgroup (FASTACT-1 and 2) [36, 37], although these evidences warrant to be replicate in the context of non-asian patients' populations. "
[Show abstract][Hide abstract]ABSTRACT: Cancer molecular heterogeneity might explain the variable response of EGFR mutant lung adenocarcinomas to tyrosine kinase inhibitors (TKIs). We assessed the mutational status of 22 cancer genes by next-generation sequencing (NGS) in poor, intermediate or good responders to first-line gefitinib. Clinical outcome was correlated with Additional Coexisting Mutations (ACMs) and the EGFR Proportion of Mutated Alleles (PMA). Thirteen ACMs were found in 10/17 patients: TP53 (n=6), KRAS (n=2), CTNNB1 (n=2), PIK3CA, SMAD4 and MET (n=1 each). TP53 mutations were exclusive of poor/intermediate responders (66.7% versus 0, p=0.009). Presence of ACMs significantly affected both PFS (median 3.0 versus 12.3 months, p=0.03) and survival (3.6 months versus not reached, p=0.03). TP53 mutation was the strongest negative modifier (median PFS 4.0 versus 14.0 months). Higher EGFR PMA was present in good versus poor/intermediate responders. Median PFS and survival were longer in patients with EGFR PMA ≥0.36 (12.0 versus 4.0 months, p=0.31; not reached versus 18.0 months, p=0.59). Patients with an EGFR PMA ≥0.36 and no ACMs fared significantly better (p=0.03), with a trend towards increased survival (p=0.06). Our exploratory data suggest that a quantitative (PMA) and qualitative (ACMs) molecular heterogeneity assessment using NGS might be useful for a better selection of patients.