A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE

Tan, L; Brown, C; Mersiades, A; Lee, CK; John, T; Kao, S; Newnham, G; O&#39;Byrne, K; Parakh, S; Bray, V; Jasas, K; Yip, S; Wong, SQ; Ftouni, S; Guinto, J; Chandrashekar, S; Clarke, S; Pavlakis, N; Stockler, MR; Dawson, SJ; Solomon, BJ

Author(s): Tan, L; Brown, C; Mersiades, A; Lee, CK; John, T; Kao, S; Newnham, G; O'Byrne, K; Parakh, S; Bray, V; Jasas, K; Yip, S; Wong, SQ; Ftouni, S; Guinto, J; Chandrashekar, S; Clarke, S; Pavlakis, N; Stockler, MR; Dawson, SJ; Solomon, BJ;
Details: Publication Year 2024-02-28,Volume 15,Issue #1,Page 1823
Journal Title: Nature Communications
Publication Type: Research article
Abstract: In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.
Publisher: Springer Nature
Keywords: Humans; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology; Gefitinib/therapeutic use; *Lung Neoplasms/drug therapy/genetics/pathology; ErbB Receptors/genetics; Mutation; Protein Kinase Inhibitors/adverse effects; Aniline Compounds/therapeutic use; *Acrylamides; *Indoles; *Pyrimidines
Department(s): Medical Oncology; Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41467-024-46008-1
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-024-46008-1
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-05-07 04:32:35

Last Modified: 2024-05-07 04:39:44