Zidesamtinib, an investigational oral, highly selective ROS1 tyrosine kinase inhibitor designed to overcome common resistance mechanisms and improve brain penetration, has demonstrated activity in both pretreated and tyrosine kinase inhibitor–naive patients with ROS1-positive non–small cell lung cancer (NSCLC), according to data presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer.¹ Zidesamtinib has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration.

Results from the phase I/II ARROS-1 trial showed objective response rates of 44% in heavily pretreated patients, across all prior ROS1 tyrosine kinase inhibitor cohorts, and 51% in patients who received one prior tyrosine kinase inhibitor. Preliminary data in tyrosine kinase inhibitor–naive patients also revealed an 89% objective response rate, suggesting its potential use in the first-line setting.

“These findings highlight zidesamtinib’s potential to address significant unmet needs in this patient population, particularly in those with prior tyrosine kinase inhibitor exposure or central nervous system involvement,” said lead study author Alexander Drilon, MD, Professor and Chief of the Early Drug Development Service and Attending Physician of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, New York.

The promising preliminary data in tyrosine kinase inhibitor–naive patients further support [zidesamtinib’s] continued investigation as a potential front-line therapy....

— ALEXANDER DRILON, MD

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As Dr. Drilon explained, zidesamtinib was specifically engineered to be highly potent against ROS1 and ROS1 resistance mutations, penetrate the brain effectively, and avoid off-target tropomyosin receptor kinase (TRK) inhibition, which has caused side effects with some older ROS1 tyrosine kinase inhibitors.

ROS1 gene fusions occur in approximately 1% to 2% of patients with NSCLC and define a distinct molecular subset often seen in younger, never-smokers. Although early-generation ROS1 tyrosine kinase inhibitors such as crizotinib and entrectinib have provided significant benefit, said Dr. Drilon, challenges remain, including the emergence of resistance mutations (eg, ROS1 G2032R) and the high incidence of brain metastases. The development of newer tyrosine kinase inhibitors, such as repotrectinib and taletrectinib, aimed to address these limitations, but a need for options after these agents fail to benefit patients, better front-line therapies, and safer treatments persists.

Study Methods

The ARROS-1 study is a global phase I/II clinical trial that enrolled patients with any ROS1-positive cancer, with the presented data focusing specifically on NSCLC. A recommended phase II dose of 100 mg once daily was established. The safety population included 432 patients with ROS1-positive lung cancer treated at the recommended phase II dose. The tyrosine kinase inhibitor–pretreated efficacy population consisted of 117 patients with measurable disease and at least 6 months of follow-up. The primary endpoint was objective response rate by blinded independent central review.

According to Dr. Drilon, the baseline characteristics of the tyrosine kinase inhibitor–pretreated efficacy population were typical for ROS1-positive NSCLC; almost half of these patients (48%) had active central nervous system disease at baseline. More than one-third (36%) harbored secondary ROS1 mutations, with the common G2032R resistance mutation present in more than 20%. Regarding prior treatment, approximately half had received one ROS1 tyrosine kinase inhibitor (crizotinib or entrectinib), whereas the other half had received two or more (including lorlatinib, repotrectinib, and taletrectinib).

Intracranial Responses and Safety Profile

In tyrosine kinase inhibitor–pretreated patients, zidesamtinib demonstrated an objective response rate of 44% across all prior tyrosine kinase inhibitor lines (up to four). For those who had received one prior ROS1 tyrosine kinase inhibitor, the objective response rate was 51%.

The median duration of response and median progression-free survival in patients with any prior ROS1 tyrosine kinase inhibitor were 22 months and 9.7 months, respectively. For patients who had received one prior ROS1 tyrosine kinase inhibitor, the median duration of response was 22 months, and the median progression-free survival was 23.8 months.

Zidesamtinib also showed activity against specific resistance mutations. In patients with the ROS1 G2032R mutation, the objective response rate was 83% after one prior ROS1 tyrosine kinase inhibitor. The intracranial objective response rates were 85% in patients after crizotinib treatment and 48% in those who received up to four prior ROS1 tyrosine kinase inhibitors, including other brain-penetrant agents. Furthermore, zidesamtinib exhibited activity in patients who had received two or more prior tyrosine kinase inhibitors, including response rates of almost 50% after repotrectinib treatment and more than 40% after taletrectinib treatment.

Preliminary data in the tyrosine kinase inhibitor–naive population revealed an objective response rate of 89% in 35 response-evaluable patients, including three complete responses. All patients in this cohort experienced some degree of tumor regression. Of note, five of six patients with measurable intracranial lesions achieved an intracranial response, with four complete intracranial responses.

As for safety, use of zidesamtinib was generally well tolerated, according to the study authors. In the large safety population of 432 patients, common treatment-emergent adverse events occurring in at least 15% of patients included peripheral edema, constipation, creatine phosphokinase increase, and fatigue (most of which were grade 1 or 2). Of note, dizziness, a known tyrosine kinase inhibitor–related side effect, was not a common adverse event, perhaps because of zidesamtinib’s TRK-sparing design. Dose reduction and treatment discontinuation rates as a result of adverse events were 10% and 2%, respectively. No new safety signals were identified.

“The promising preliminary data in tyrosine kinase inhibitor–naive patients further support zidesamtinib’s continued investigation as a potential front-line therapy, making it a significant addition to the therapeutic armamentarium for this challenging disease,” Dr. Drilon concluded.

DISCLOSURE: Dr. Drilon owns stock and has other ownership interests in Treeline Biosciences and mBrace Therapeutics; has received honoraria from Pfizer, Loxo/Bayer/Lilly, IASLC, Helsinn Therapeutics, BeOne Medicines (formerly BeiGene), Remedica, Turning Point Therapeutics, Verastem, Ignyta/Genentech/Roche, AstraZeneca, Liberum Bio, LUNGevity Foundation, NIH, PER, OncLive/MJH Life Sciences, Clinical Care Options/NCCN, Lung Cancer Research Foundation, AIOT, Chugai Pharma, Sirio Libanes Hospital, Answers in CME, and i3 Health; has served as a consultant or advisor to Ignyta, Loxo, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, BeOne Medicines, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Takeda/Ariad/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, Elevation Oncology (formerly 14ner), Monopteros Therapeutics, Novartis, EMD Serono/Merck, Repare Therapeutics, Melinta Therapeutics, ArcherDX, Nuvalent, Janssen, Amgen, Merus, AXIS, Medscape, Liberum Bio, Med Learning, PeerView, EPG Health, JNCCN, Ology Bioservices, Clinical Care Options, touchIME, Entos Pharmaceuticals, Prelude, Applied Pharmaceutical Science, Treeline Biosciences, MonteRosa, and EcoR1; has received research funding from Foundation Medicine; and has reported other relationships with Merck, GlaxoSmithKline, Teva Pharmaceuticals, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology, Merus, and Boehringer Ingelheim.

REFERENCE

1. Drilon AE, Cho BC, Lin JJ, et al: Pivotal ARROS-1 efficacy and safety data: Zidesamtinib in TKI pretreated patients with advanced/metastatic ROS1+ NSCLC. 2025 World Conference on Lung Cancer. Abstract PL02.15. Presented September 7, 2025.

Expert Point of View

The invited discussant of the ARROS-1 trial was pulmonologist Anne-Marie C. Dingemans, MD, PhD, Professor of Thoracic Oncology at Erasmus Medical Center in Rotterdam, the Netherlands. She provided a nuanced perspective on zidesamtinib’s place in the evolving landscape of ROS1-positive non–small cell lung cancer (NSCLC) treatment, focusing on the performance of this tyrosine kinase inhibitor in pretreated patients.

Anne-Marie C. Dingemans, MD, PhD

Dr. Dingemans acknowledged zidesamtinib’s design goals—high ROS1 selectivity, activity against resistance mutations, and brain efficacy—and contextualized its potential by outlining the current ROS1 tyrosine kinase inhibitor landscape. Several drugs are approved, with newer, potent inhibitors such as repotrectinib and taletrectinib likely becoming preferred first-line options.

While praising the activity of zidesamtinib, Dr. Dingemans noted that the overall response rates were “more or less comparable” to those of repotrectinib and taletrectinib. However, she highlighted that responses to zidesamtinib, when they occur, appear to be “very durable,” often exceeding 18 months. She also underscored the importance of zidesamtinib’s activity after newer tyrosine kinase inhibitors such as repotrectinib and taletrectinib, despite limited numbers in this highly pretreated setting.

Additional Clinical Considerations

A key point of discussion was the efficacy of zidesamtinib against the common G2032R resistance mutation. Dr. Dingemans observed that clinical responses varied based on the number of prior tyrosine kinase inhibitors received , an aspect that warrants further investigation into co-mutations or resistance mechanisms. In addition, she lauded the drug’s significant and durable intracranial efficacy, acknowledging the high prevalence of brain metastases in ROS1-positive NSCLC.

Regarding safety, Dr. Dingemans delved into the claim of TRK-sparing, a design goal aimed at avoiding TRK-related toxicities such as dizziness, ataxia, and weight gain. Although common treatment-emergent adverse events did not prominently feature neurologic symptoms, Dr. Dingemans pointed out that dose reductions occurred for peripheral neuropathy and paresthesia; in addition, weight gain, a known TRK-related effect, was observed in less than 50% of patients. She also cautioned about the potential for long-term weight gain with durable responses, suggesting TRK inhibition might not be fully absent.

Dr. Dingemans concluded with a “glass half full, half empty” assessment. Although zidesamtinib yielded durable responses in about half of pretreated patients, including those with G2032R mutations and brain metastases, the other half did not respond. Ultimately, she stressed the need for greater granularity on co-mutations and long-term toxicity data, particularly concerning TRK-related effects, to better select patients who may benefit from zidesamtinib.

DISCLOSURE: Dr. Dingemans reported financial relationships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Pfizer, Roche, AbbVie, Mirati Therapeutics, MSD, BeOne Medicines (formerly BeiGene), Eli Lilly, and Takeda Pharmaceuticals.

MORE INFORMATION

For more on the ARROS-1 trial of the investigational ROS1 tyrosine kinase inhibitor zidesamtinib in patients with ROS1 fusion–positive non–small cell lung cancer, see a video by Alexander Drilon, MD, on The ASCO Post Newsreels at ascopost.com/videos.