Radiation As a Local Ablative Therapy Option for Oligoprogressive EGFR-Mutant Non-Small Cell Lung Cancer after Treatment with Osimertinib

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved response rate and survival in patients with EGFR-mutant non-small cell lung cancer (NSCLC), but their efficacy is limited by acquired resistance and disease progression. Local ablative therapy (LAT) has shown a survival benefit in patients with oligometastatic disease in retrospective studies. At our institution, we are conducting a prospective single-arm Phase 2 study of EGFR-mutant NSCLC patients with oligoprogressive disease after treatment with osimertinib, a 3rd generation EGFR-TKI. Following LAT to the sites of progression with either radiation or surgery, patients are re-initiated on osimertinib. The primary endpoints are safety, tolerability, and efficacy of re-initiation of osimertinib, as assessed by progression-free survival (PFS). We hypothesize that osimertinib and radiation can be safely administered sequentially, and that LAT followed by re-initiation of osimertinib will result in improved PFS. Patients with no prior EGFR-TKI exposure (cohort 1) or progression after 1st/2nd generation EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with ≤5 progressing sites undergo LAT by either radiation therapy or surgery, then resume osimertinib until further disease progression. Patients previously treated with osimertinib with disease progression who qualify for LAT are also eligible (cohort 3). Prior to beginning radiation, patients must be off osimertinib for at least 2 wks, and total time off osimertinib must be less than 8 wks. Fifteen patients with a median age of 57 (range 36-71) were enrolled between 4/2016 and 1/2017 (cohorts 1/2/3: 9/3/3 patients). Overall, treatment has been well tolerated, with rash, diarrhea, thrombocytopenia, and alanine transaminase elevation the most common adverse events (AEs). Grade 3-4 AEs were observed in 4 (27%) patients. Objective response rates among evaluable patients prior to LAT in cohorts 1 and 2 were 71% (5/7) and 100% (2/2), respectively. Median PFS was 6.8 mo (95% CI: 3.4 mo-undefined) in cohort 1; there have been no progressions in cohort 2. To date, 2/5 patients receiving LAT have received radiation (both in cohort 3). One patient received 5 Gy x 5 to 2 lung lesions, while the other received 24 Gy and 18 Gy by stereotactic radiosurgery to 2 brain metastases. Additional endpoints include assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva; results from these analyses will also be presented. Oligoprogressive disease can be safely treated with LAT, including radiation therapy, in patients with limited metastatic EGFR-mutant NSCLC after EGFR-TKI therapy. This approach could potentially prevent premature switching to other, less-effective systemic therapies by maximizing the duration and efficacy of EGFR-TKI treatment in selected patients.