First-Line NSCLC with Erlotinib: Effective, but not for Everybody
First-Line NSCLC with Erlotinib: Effective, but not for Everybody
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a multicenter randomized (not blinded) Phase 3 study of erlotinib vs chemotherapy for EGFR-mutation positive non-small cell lung cancer (NSCLC), progression-free survival was both significantly greater and toxicity less for patients treated with erlotinib. The findings suggest that erlotinib should be considered first-line therapy for patients with advanced EGFR mutation-positive NSCLC.
Source: Zhou C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncol 2011;12:735-742.
Non-small cell lung cancer (NSCLC) is the number one cause of cancer-related death worldwide.1 The majority of patients present with advanced disease and systemic chemotherapy remains only marginally effective at prolonging life. Recently, attention has focused on targeted therapies including the tyrosine kinase inhibitors (TKI) gefitinib (Iressa®) and erlotinib (Tarceva®). It is now understood that a subset of patients with NSCLC will have tumors with activating mutations in the EGFR gene (i.e., exon 19 deletions or exon 21 L858R point mutations) and such patients are more likely to achieve benefit from treatment with TKI therapy.2,3 Activating EGFR mutations are more commonly observed in tumors with adenocarcinoma histology, in non-smokers, in older patients, in females, and in Asians.4,5 However, using these clinical characteristics alone as selection criteria for demonstrating improved activity has not resulted in significant improvement in outcomes.3 Accordingly, there has been an increased emphasis on accurate EGFR testing in order to enrich the study population for demonstrating efficacy of TKI therapies. With this aim, a group of oncologists throughout China designed the OPTIMAL study which compared the efficacy and tolerability of erlotinib vs standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC.
For this, the investigators conducted an open-label, randomized, Phase 3 trial at 22 centers in which they enrolled adult patients with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation). Such patients were randomized to receive either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin, considered the standard doublet therapy for such patients throughout China. Gemcitabine was given at 1000 mg/m2 on days 1 and 8 and carboplatin at area under the curve of 5 on day 1 of each 3-week cycle. The randomization was conducted in such a way to balance for EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival and secondary outcomes included overall survival, objective response rate, time to progression, response duration, safety, and quality of life.
Of the 165 randomized patients, 83 patients were assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin. The median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 vs 4.6 months [P < 0.0001]). As expected, chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib). The most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Erlotinib appeared to demonstrate superiority over chemotherapy independent of patient age, sex, smoking history, tumor histology, or mutation type. Furthermore, patients who received erlotinib had a significant improvement in quality of life. The data from the trial were not mature enough to determine any treatment-associated improvement in overall survival.
Thus, compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with less toxicity and improved quality of life. The trial was the first Phase 3 study of erlotinib for mutation positive NSCLC and the results coupled with prior Phase 2 studies of both gefitinib and erlotinib and preliminary results from a Phase 3 trial of erlotinib vs. chemotherapy for mutation positive NSCLC should be sufficient for clinicians to take notice. It is clear now that clinicial parameters (non-smoker, female, adenocarcinoma histology) are not sufficiently reliable to support this alternative approach to chemotherapy and molecular testing is required. However, pathologists are now prepared to assess tissue for EGFR mutations and if present in the appropriate domains (e.g., exon 19 or 21) initial therapy should be with a tyrosine kinase inhibitior. The evidence is now in. Yet, the majority of NSCLC patients, even in China, are those without these mutations. Hopefully, new targets will be identified within larger subsets of NSCLC allowing for more widespread applicability of effective targeted therapy.
1. Ferlay J, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-2917.
2. Maemondo M, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-2388.
3. Mok TS, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957.
4. Rosell R, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958-967.
5. Shigematsu H, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-346.In a multicenter randomized (not blinded) Phase 3 study of erlotinib vs chemotherapy for EGFR-mutation positive non-small cell lung cancer (NSCLC), progression-free survival was both significantly greater and toxicity less for patients treated with erlotinib. The findings suggest that erlotinib should be considered first-line therapy for patients with advanced EGFR mutation-positive NSCLC.
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