Non-small Cell Lung Cancer Harboring EGFR Mutations Research Articles

First-line gefitinib for elderly patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations: A combined analysis of NEJ studies.

7563 Background: The first-line treatment with gefitinib has been established as a standard of care for advanced NSCLC patients with EGFR mutation by previous studies including NEJ002. Since the percentage of elderly population in those studies was lower than that of real situation, further validation of its usefulness for elderly patients with EGFR-mutated NSCLC is warranted. Methods: The efficacy and safety data of fit elderly patients (70 years or older with PS 0-2) with EGFR-mutated NSCLC who received the first-line gefitinib in NEJ001 (phase 2), NEJ002 (phase 3), and NEJ003 (phase 2) were combined. Same population treated with the first-line carboplatin plus paclitaxel in NEJ002 (n=34) were also examined their efficacy and safety for reference. Regarding the toxicity and quality of life (QOL), the comparison between elderly patients and younger patients (< 70 years old) both treated with first-line gefitinib in NEJ002 was also performed. Results: Data from 71 patients (7 from NEJ001, 33 from NEJ002, 31 from NEJ003) treated with first-line gefitinib were combined. Patients’ characteristics were as follows; mean age: 76.8 years (range 70-89), female: 73%, never smoker: 75%, PS 0-1: 92%. Overall response rate (73.2%) and median progression-free survival (14.3 months) in this group were significantly better than those in the reference group (26.5% and 5.7 months, respectively). Despite fewer patients received second-line chemotherapy in the first-line gefitinib group, its median overall survival (30.8 months) was not inferior to that of reference group (26.4 months). Regarding toxicities such as liver dysfunction, rash, diarrhea, and pneumonitis, and QOL examined by self questionnaires, there were no difference between the elderly patients and younger patients in NEJ002. Conclusions: First-line gefitinib still achieved high efficacy with acceptable toxicity in fit elderly patients with advanced NSCLC harboring EGFR mutation. Considering that elderly patients tend to receive fewer treatment lines compared with younger patients, first-line gefitinib would be strongly recommended for this population to avoid the risk of missing its administration.

Abstract 1800: Analysis of EGFR mutations before and after EGFR-TKIs treatment

Abstract Background: Gefitinib is the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that has the dramatically effects in selective patients with non-small cell lung cancer (NSCLC). EGFR mutations predict response and survival in patients treated with gefitinib. However, almost of these patients have a relapse within a year after the start of therapy. Although the mechanisms of acquired resistance to Gefitinib were MET amplification, L861Q and hepatocyte growth factor(HGF), main reason was a secondary EGFR mutation, threonine to methionine at codon 790 in exon 20 (T790M). Therefore, we analyzed EGFR mutations after gefitinib treatment in addition to before treatment in patients with NSCLC. Materials and methods: From December 2004 to September 2009, 37 patients with advanced NSCLC harboring EGFR mutations were treated with gefitinib in our hospital. When tumor was relapsed, we got written informed consent from patients, and re-examination of EGFR mutations was performed in 9 patients by present. EGFR mutations were examined by mutant-enriched polymerase chain reaction (PCR) method and/or peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp method. Samples were the paraffin-embedded specimens, transbronchial biopsied tissues, surgically resected tissues, bronchial washing liquids, and pleural effusion, and we used relapsed tumor samples at secondary analysis. In addition, we evaluated the response to treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) and progression free survival defined as the time from the date of beginning treatment to the date of disease progression or death. Results: 37 patients treated by gefitinib, response rate was 60%(22/37) and disease control rate was 78%(29/37). Within a year, most patients were relapse. In 9 patients, we could analyze EGFR mutations again. Secondary analysis of EGFR mutations was performed in safety. T790M, a resistant mutation of EGFR, was detected in 4 patients. Samples from lymph node biopsy were used in 2 patients, pleural effusion was in a patient, and transbronchial biopsied tissue was in a patient. 1 patient was adenosquamous cell carcinoma, and all of the rest were adenocarcinoma. Despite emergence of T790M, in a patient, readministration of gefitinib was effective (stable disease), furthermore, treatment of erlotinib after gefitinib was also effective (partial response). In 1 patient, secondary analysis is performing at present. Conclusion: These results suggested the importance of EGFR analysis after relapse in patients treated with gefitinib. We must consider why erlotinib was effective in patients with T790M, and screen appropriate subjects of readministration of EGFR-TKIs. The new therapeutic strategy according to the mechanism of resistance to EGFR-TKI is expected. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1800.

ITARGET: A phase II trial to assess the response to gefitinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) tumors

7504 Background: Somatic EGFR mutations correlate with increased response and survival in NSCLC patients (pts) treated with gefitinib. We conducted the 1st prospective US trial of 1st-line gefitinib in pts with advanced NSCLC harboring EGFR mutations. Methods: Chemotherapy-naïve pts with stage IIIB with effusion or IV NSCLC, measurable disease, and = 1 characteristic associated with mutations (female (F), adenocarcinoma (AC), never-smoking (NS), East Asian (EA)) underwent direct DNA sequencing of tumor tissue EGFR exons 18–24. Mutation-positive pts received gefitinib (250 mg/d) until progression or unacceptable toxicity. The primary outcome was response rate (RR) by RECIST criteria. Results: We sequenced 98 pts and detected EGFR mutations in 34 (35%); 3 were not assessable. Observed mutations were 18 (53%) exon 19 deletions (del), 9 (26%) L858R, 3 (9%) exon 20 insertions (ins), 2 T790M/L858R, 1 G719A, and 1 L861Q. Characteristics of the 98 screened pts were 69 F, 89 AC, 37 NS, and 5 EA; those of the 34 mutation pts were 20 (59%) F, 31 (91%) AC, 19 (56%) NS and 2 (6%) EA. The best predictor of EGFR mutation was NS. Of the 34 mutation pts, 31 (91%) received gefinitib. Reasons for non-treatment were pt preference (1 exon 19 del) and mutation associated with gefitinib-resistance (1 T790M/L858R, 1 exon 20 ins). Adverse events were mainly grade 1–2 rash and diarrhea; 1 case of grade 4 interstitial lung disease occurred after 2 weeks of therapy. The RR was 58% (95% confidence interval 39–75) and was 78% in L858R pts and 65% in del 19 pts. There were no responses among the G719A, L861Q, T790M/L858R and exon 20 ins pts treated. 12 pts have progressed, 18 remain on therapy. The median progression-free survival (PFS) is currently 11.8 mo and does not differ by mutation type, though follow-up is short (median 6.8 mo, range 1–24). 27 pts are still alive. Of the 31 pts treated, 22 (71%) had high EGFR gene copy number (amplification (3) or high polysomy (19)); RR and PFS did not vary by copy number. Conclusions: 1st-line gefitinib therapy in EGFR mutation-positive NSCLC pts is feasible in a multi-institutional study, well tolerated, and yields a substantial RR and PFS. This strategy should be compared to standard chemotherapy in a genotype-directed randomized trial. No significant financial relationships to disclose.