Abstract CT106: Local ablative therapy for oligoprogressive, EGFR-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib
Authors: Kim Chul , Roper Nitin , Hoang Chuong , Wisch Laura , Connolly Maureen , Chou Hsien-Chao , Wei Jun , Tyagi Manoj , Cultraro Constance M. , Xi Liqiang , Waris Maryam , Nguyen Khoa Dang , Szabo Eva , Padiernos Emerson , Kesarwala Aparna , Gao Shaojian , Steinberg Seth M. , Raffeld Mark , Rajan Arun , Khan Javed , Guha Udayan 
Published: August 2018

Background: Osimertinib is effective in EGFR-mutant NSCLC in both first- and second-line settings. However, the efficacy of osimertinib is limited by the universal development of resistance. Retrospective studies have shown a survival benefit to local ablative therapy (LAT) in those who develop oligoprogressive disease (progression at a limited number of anatomic sites) on EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy.

Methods: We initiated a prospective study of LAT in patients with EGFR-mutant NSCLC and oligoprogression during treatment with osimertinib (NCT02759835). Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1st/2nd generation EGFR-TKI therapy and acquired T790M mutation (cohort 2) start osimertinib. Upon progression, eligible patients with &lt;= 5 progressing sites undergo LAT and resume osimertinib after LAT. Patients previously treated with osimertinib eligible for LAT upon development of oligoprogression are also enrolled (cohort 3). The primary objective is to evaluate the safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS2). Another goal is to assess mechanisms of resistance to osimertinib by multi-omics analyses of tumor tissue and liquid biopsies.

Results: Between 04/2016 and 01/2018, 24 patients were enrolled (cohort 1: 16, cohort 2: 5, cohort 3: 3). Median age was 59.8 (range 36-77). The most common adverse events (AEs) on osimertinib treatment were rash, diarrhea, thrombocytopenia, and QTc prolongation with most of the AEs being grade 1 or 2. Among evaluable patients, confirmed objective response rates prior to LAT in cohorts 1 and 2 were 66.7 % (8/12) and 75% (3/4), respectively, with 11.2 months median PFS (95% CI: 3.6 months-undefined) in cohort 1 and 10.9 months in cohort 2 (95% CI: 6.7-12.8 months). To date, 12 patients had progressive disease, 8 of which had oligoprogression and subsequently underwent LAT (cohort 1: 3; cohort 2: 2; cohort 3: 3). Two patients were treated with combination of surgery and radiotherapy (RT), 4 patients with surgery, and 2 patients with RT. Median PFS2 was 2.3 months (95% CI: 1.0-5.9 months). Whole exome sequencing (WES) was performed on tumor tissues obtained pre-treatment and upon progression on osimertinib. MET amplification, transformation to small cell lung cancer, and EGFR C797S mutation were identified as mechanisms of resistance to osimertinib. Results of molecular analyses of tumor tissue and blood ctDNA will be presented.

Conclusions: Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In select patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies.

Citation Format: Chul Kim, Nitin Roper, Chuong Hoang, Laura Wisch, Maureen Connolly, Hsien-Chao Chou, Jun Wei, Manoj Tyagi, Constance M. Cultraro, Liqiang Xi, Maryam Waris, Khoa Dang Nguyen, Eva Szabo, Emerson Padiernos, Aparna Kesarwala, Shaojian Gao, Seth M. Steinberg, Mark Raffeld, Arun Rajan, Javed Khan, Udayan Guha. Local ablative therapy for oligoprogressive, EGFR-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT106.