Outcomes With Local Therapy and Tyrosine Kinase Inhibition in Patients With ALK/ROS1/RET-Rearranged Lung Cancers.

Purpose/Objective(s) Local therapy (LTX) prolongs progression-free and overall survival (OS) in patients with oligometastatic non-small cell lung cancer. We previously reported substantial LTX benefit in time to progression or next therapy (TTP/TTNT) in patients with EGFR-mutant lung adenocarcinoma treated with tyrosine kinase inhibitors (TKI). Here, we investigate the role of LTX in patients who progressed on TKI for ALK/ROS1/RET-rearranged stage IV lung adenocarcinoma. Materials/Methods This single-institution IRB-approved retrospective review included all patients with pathologically confirmed stage IV ALK/ROS1-rearranged or RET fusion-positive lung adenocarcinoma who underwent radiation therapy (RT), surgery, or percutaneous thermal ablation (PTA) from 2012 to 2020 for progressive disease (PD) while on an ALK, ROS1, or RET TKI and for whom TKI therapy was continued post LTX. Patients receiving consolidative LTX after initial response to TKI without PD were not included. PD was classified as solitary- (one site), oligo- (2-5 sites), or poly- (> 5 sites) PD. TTP and TTNT were measured from start of any LTX. OS was evaluated from start of first LTX and from diagnosis. Significance was assessed with the Kruskal-Wallis test and Cox Univariate Analysis. Results 61 eligible patients (37 ALK, 12 ROS1, 12 RET; 37 female, median age 62 at LTX) were identified. Most common TKIs were alectinib (34), selpercatinib (17), and crizotinib (11). 92% of patients underwent RT (82 RT courses: median dose 27 Gy, 72% ≤5 fractions), 13% and 8% underwent surgery and PTA, respectively, with 13% undergoing > 1 LTX modality. In 87% of interventions, LTX addressed all sites of PD. PD prior to LTX was predominantly oligoPD (94%). Most frequent LTX sites were brain (41%), bone (28%), and lung (27%). Subsequent PD after LTX was also mostly oligoPD (81%; 38% solitary). In-field local failure occurred in 19%. Median follow-up post LTX was 18 mo. Median TTP and TTNT from LTX were 5.1 and 7.8 mo, respectively. TTP and TTNT were not significantly different in the sub-cohort in which all sites of PD were treated with LTX. Median OS was 51 mo from diagnosis and 19.4 mo from first LTX. TTP was significantly shorter for ≥3rd LTX course v. Conclusion Local therapy for PD on ALK, ROS1 or RET TKIs was associated with clinically meaningful time on continued TKI therapy beyond progression.