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Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer.

Price KA, Azzoli CG, Krug LM, Pietanza MC, Rizvi NA, Pao W, Kris MG, Riely GJ, Heelan RT, Arcila ME, Miller VA
J Thorac Oncol. 2010 5 (10): 1623-9

PMID: 20871262 · PMCID: PMC4020424 · DOI:10.1097/JTO.0b013e3181ec1531

INTRODUCTION - Concurrent signal transduction inhibition with the epidermal growth factor receptor (EGFR) inhibitor gefitinib and the mammalian target-of-rapamycin inhibitor everolimus has been hypothesized to result in enhanced antitumor activity in patients with non-small cell lung cancer (NSCLC). This phase II trial assessed the efficacy of the combination of gefitinib and everolimus in patients with advanced NSCLC.

METHODS - Two cohorts of 31 patients with measurable stage IIIB/IV NSCLC were enrolled: (1) no prior chemotherapy and (2) previously treated with cisplatin or carboplatin and docetaxel or pemetrexed. All patients received daily everolimus 5 mg and gefitinib 250 mg. Response was assessed after 1 month and then every 2 months. Pretreatment tumor specimens were collected for mutation testing.

RESULTS - Sixty-two patients were enrolled (median age: 66 years, 50% women, 98% stage IV, all current/former smokers, and 85% adenocarcinoma). Partial responses were seen in 8 of 62 patients (response rate: 13%; 95% confidence interval: 5-21%); five responders had received no prior chemotherapy. Three partial responders had an EGFR mutation. Both patients with a KRAS (G12F) mutation responded. The median time to progression was 4 months. Median overall survival was 12 months, 27 months for no prior chemotherapy patients, and 11 months for patients previously treated with chemotherapy.

CONCLUSIONS - The 13% partial response rate observed did not meet the prespecified response threshold to pursue further study of the combination of gefitinib and everolimus. The response rate in patients with non-EGFR mutant tumors was 8%, likely reflecting activity of everolimus. Further investigation of mammalian target-of-rapamycin inhibitors in patients with NSCLC with KRAS G12F-mutated tumors is warranted.

MeSH Terms (27)

Adenocarcinoma Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell Clinical Trials, Phase I as Topic Cohort Studies ErbB Receptors Everolimus Female Gefitinib Humans Lung Neoplasms Male Middle Aged Mutation Neoplasm Staging Proto-Oncogene Proteins Proto-Oncogene Proteins p21(ras) Quinazolines ras Proteins Salvage Therapy Sirolimus Survival Rate Treatment Outcome

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