Frontline zidesamtinib produced a 94% response rate and 100% intracranial response rate in TKI-naive ROS1-positive advanced NSCLC.
Zidesamtinib (Jideytro) produced an objective response rate (ORR) of 94% in tyrosine kinase inhibitor (TKI)-naive patients with advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC), according to data from the phase 1/2 ARROS-1 trial (NCT05118789) presented at the
In the ROS1 TKI-naive efficacy population (n = 94), zidesamtinib elicited an ORR of 94% (n = 88 of 94; 95% CI, 87%-98%) by blinded independent central review (BICR) per RECIST v1.1, including a complete response (CR) rate of 15% (n = 14 of 94). Median duration of response (DOR) was not reached (95% CI, 20 months-not evaluable [NE]), with an estimated 86% (95% CI, 75%-92%) of responses ongoing at 12 months; median progression-free survival (PFS) was also not reached (95% CI, NE-NE), with a 12-month PFS rate of 90% (95% CI, 81%-95%).
“Zidesamtinib demonstrated clinically meaningful activity in TKI-naive patients with advanced ROS1-positive NSCLC,” lead study author, Alexander Drilon, MD, said during the presentation. “These data support continued investigation of zidesamtinib as frontline therapy for TKI-naive patients.” Drilon is the chief of the Early Drug Development Service and the Carol Bassok Lowenstein Chair at Memorial Sloan Kettering Cancer Center in New York, New York.
ARROS-1 is a global, first-in-human phase 1/2 trial of zidesamtinib, a highly selective, brain-penetrant ROS1 TKI designed to minimize tropomyosin receptor kinase inhibition, in patients with advanced ROS1-positive NSCLC and other ROS1-positive solid tumors. Phase 1 dose escalation (25-150 mg once daily) in TKI-pretreated patients established a recommended phase 2 dose of 100 mg once daily; the phase 2 primary end point is ORR by BICR, with DOR, PFS, overall survival, intracranial activity, safety, and pharmacokinetics as secondary end points.
As of the April 16, 2026, data cutoff, the trial had enrolled 629 patients, including 183 ROS1 TKI-naive patients with advanced NSCLC and a pooled safety population of 532 patients receiving zidesamtinib 100 mg once daily. The efficacy population reported here (n = 94) was drawn from the registrational-intent ROS1 TKI-naive cohort and included patients with measurable disease by BICR and no more than 1 prior line of platinum-based chemotherapy with or without immunotherapy; median follow-up was 15.2 months (range, 1.1-30.5).¹
Median age was 59 years (range, 26-87); 59% of patients were female and 59% were never-smokers. Most had stage IV disease (93%) and an ECOG performance status of 0 (60%), and 17% had baseline central nervous system (CNS) metastases; 27% (n = 25 of 94) had received prior platinum-based chemotherapy with or without immunotherapy, of whom 16 also received prior immunotherapy.
Among the 10 ROS1 TKI-naive patients with measurable (≥5 mm) CNS lesions at baseline who had not received brain radiation within 2 months of their first zidesamtinib dose, the intracranial ORR by BICR was 100% (95% CI, 69%-100%), including an intracranial CR rate of 70%. Intracranial DOR (IC-DOR) rates were 100% at both 6 and 9 months and 78% (95% CI, 36%-94%) at 12 months; median IC-DOR was not reached (95% CI, 9 months-NE). No CNS progression events were observed among the 78 ROS1 TKI-naive patients who entered the study without brain metastases at baseline, per BICR.
In the pooled safety population of ROS1-positive NSCLC patients treated with zidesamtinib 100 mg once daily, regardless of prior TKI exposure (n = 532), the most common treatment-emergent adverse effects (TEAEs) of any grade were peripheral edema (42%), blood creatine phosphokinase (CPK) increase (23%), constipation (23%), weight increase (22%), and aspartate aminotransferase (AST) level increase (19%); grade 3 or higher events occurred most often with weight increase (7%) and blood CPK increase (5%). Treatment-related adverse effects in at least 15% of patients included peripheral edema (34%), weight increase (18%), blood CPK increase (18%), dysgeusia (17%), and AST increase (15%). Dose reductions occurred in 12% of patients because of a TEAE (11% TRAE-related), and 4% discontinued treatment because of a TEAE (1% TRAE-related); pneumonia, pneumonitis (each n = 3), and weight increase (n = 2) were the only events leading to discontinuation in at least 2 patients.
Zidesamtinib is already FDA approved for adults with locally advanced or metastatic ROS1-positive NSCLC who received a prior ROS1 TKI, based on efficacy in the TKI-pretreated ARROS-1 population; it remains investigational in the TKI-naive setting.² Investigators concluded that the frontline safety profile was consistent with prior reports and that these data support continued investigation of zidesamtinib as a potential frontline therapy for TKI-naive ROS1-positive NSCLC.¹
Disclosures: Drilon reported honoraria, consulting, and advisory board roles with numerous companies including Nuvalent, Bristol Myers Squibb, Roche/Genentech, Pfizer, Novartis, and Bayer; institutional research funding from Foundation Medicine, Teva, Taiho, GlaxoSmithKline, and PharmaMar; equity in Treeline; and royalties from Wolters Kluwer/UpToDate. The study was sponsored by Nuvalent, Inc., now a wholly owned subsidiary of GSK.
