Phase II Trial of Gefitinib and Everolimus in Advanced Non-small Cell Lung Cancer

• Published in: Journal of thoracic oncology Vol. 5; no. 10; pp. 1623 - 1629
• Main Authors: Price, Katharine A., Azzoli, Christopher G., Krug, Lee M., Pietanza, Maria C., Rizvi, Naiyer A., Pao, William, Kris, Mark G., Riely, Gregory J., Heelan, Robert T., Arcila, Maria E., Miller, Vincent A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2010; International Association for the Study of Lung Cancer
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Clinical Trials, Phase I as Topic; Cohort Studies; Everolimus; Female; Gefitinib; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Middle Aged; Mutation - genetics; Neoplasm Staging; Non-small cell lung cancer; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); Quinazolines - administration & dosage; ras Proteins - genetics; Receptor, Epidermal Growth Factor - genetics; Salvage Therapy; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Survival Rate; Treatment Outcome; Gefitinib; Everolimus; Non-small cell lung cancer
• ISSN: 1556-0864; 1556-1380; 1556-1380
• DOI: 10.1097/JTO.0b013e3181ec1531

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. 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. 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. 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.