The treatment was generally well-tolerated in patients with ROS1-positive (ROS1+) non–small cell lung cancer (NSCLC).
Zidesamtinib (NVL-520; Nuvalent, Inc.) demonstrated clinically meaningful activity and durability in patients with ROS1-positive (ROS1+) non–small cell lung cancer (NSCLC) who had progressed on prior tyrosine kinase inhibitor (TKI) therapy. These results, which were presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC), are from the ongoing phase 1/2 clinical trial, ARROS-1 (NCT05118789).1,2
Trial Name: A Study of Zidesamtinib (NVL-520) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1)
ClinicalTrials.gov ID: NCT05118789
Sponsor: Nuvalent, Inc.
Completion Date (Estimated): October 31, 2026
Zidesamtinib is an investigational next-generation ROS1 TKI specifically designed to be highly selective, brain-penetrant, and TRK-sparing in patients with ROS1+ NSCLC. It has previously received a breakthrough therapy designation for this patient population who have been previously treated with 2 or more ROS1 TKIs and an orphan drug designation for ROS1+ NSCLC.1,3
“Zidesamtinib’s highly selective, brain-penetrant, TRK-sparing design allowed for meaningful disease control in patients who had exhausted available options,” Alexander Edward Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York City, said in a news release. “The promising preliminary results in TKI-naïve patients also support further development.”1
ARROS-1 is an ongoing global, single-arm dose escalation and expansion study that enrolled patients with advanced or metastatic ROS1+ NSCLC. The phase 1 segment of the trial will determine the recommended phase 2 dose (RP2D) and, if applicable, the maximum tolerated dose of zidesamtinib in patients with advanced ROS1+ solid tumors. Phase 2 will determine the objective response rate (ORR) assessed by a blinded independent central review (BICR) of zidesamtinib at the RP2D. Secondary objectives will include the duration of response (DOR), time to response, progression-free survival, overall survival, and clinical benefit rate of zidesamtinib in patients with advanced ROS1+ NSCLC as well as other solid tumors.1,2
The current analysis included patients with measurable disease who were previously treated with a TKI. They initiated 100 mg of zidesamtinib once per day by May 31, 2024, and the preliminary data were also collected from TKI-naïve patients treated by August 31, 2024. Along with ORR by BICR and DOR, key end points included intracranial ORR (IC-ORR) and safety. Data cutoff was on March 21, 2025.1,2
A total of 432 patients received treatment with zidesamtinib. Among the 117 efficacy-evaluable TKI-pretreated patients, the median prior therapies were 2, with about 50% having received 2 or more prior ROS1 TKIs and 93% exposed to lorlatinib (Lorbrena; Pfizer), repotrectinib (Augtyro; Bristol Myers Squibb), and/or taletrectinib (Ibtrozi; Nuvation Bio, Inc.). Central nervous system disease (CNS) was present in approximately 49% of patients.1
Durable responses were observed in TKI-pretreated patients, including in those with CNS involvement, ROS1 G2032R mutations, and patients with multiple prior ROS1 TKIs. ORR in patients previously treated with TKIs was approximately 44%, with a 12-month DOR rate of about 78%. Specifically, patients previously treated with prior crizotinib (Xalkori; Pfizer) or entrectinib (Rozlytrek; Genentech; n = 55) had an ORR of 51% with a 12-month DOR rate of 93%, and TKI-naïve patients (n = 35) had an ORR of 89% with a 12-month DOR rate of 96%.1
Further, an IC-ORR of approximately 83% was observed, and this included 4 complete responses. There were no CNS progression events at the time of data cutoff. Overall, zidesamtinib was generally well-tolerated, and the most common treatment-emergent adverse events (AEs; ≥15%) included peripheral edema (36%), constipation (17%), creatine phosphokinase increase (16%), fatigue (16%), and dyspnea (15%). Grade 3 and higher AEs were considered infrequent, and dose reductions and treatment discontinuations occurred in only 10% and 2% of patients, respectively.1
"There remains a clear need for new treatment options for patients with ROS1+ NSCLC, particularly those who are unable to tolerate the currently available TKIs, and those whose disease progresses with brain metastases or resistance mutations," Christopher Turner, MD, chief medical officer at Nuvalent, said in a news release. "We are encouraged by the data presented today, which we believe highlight the potential of zidesamtinib to deliver meaningful outcomes with a generally safe and well-tolerated safety profile. These data represent important progress toward our goal of offering a new standard of care for this patient community."3
