Drug Update · Oncology

FDA Approves zidesamtinib for ROS1-positive NSCLC: 44% ORR in ARROS-1

September 12, 2026

ORR

44%

DOR ≥6 months (responders)

82%

DOR ≥12 months (responders)

69%

Dose

100 mg orally once daily

Approval date

2026-07-22

Trial

ARROS-1 (NCT05118789)

Efficacy population

117 patients

Clinical Perspective

This affects oncology clinicians treating adults with locally advanced or metastatic ROS1-positive NSCLC who have received prior ROS1 TKIs. The ARROS-1 data support using zidesamtinib 100 mg orally once daily for this previously treated ROS1 TKI population based on a 44% confirmed ORR and durable responses in responders. What remains to be defined is how zidesamtinib compares directly with other available ROS1-targeted agents in randomized trials and how sequencing will affect long-term clinical outcomes?

Dr. Rahul Verma, MBBS, MD (General Medicine), DM (Medical Oncology) · Oncology

The FDA approved zidesamtinib (Jideytro, Nuvalent, Inc.) on July 22, 2026 for adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who received at least one prior ROS1 tyrosine kinase inhibitor (TKI) ^[2]^[4]. Approval was based on ARROS-1, a multicenter, single-arm, open-label, multi-cohort trial in which zidesamtinib achieved a confirmed overall response rate (ORR) of 44% in the efficacy population of 117 patients; 82% of responders had a duration of response (DOR) ≥ 6 months ^[2]^[4].

Clinical Context

Zidesamtinib (Jideytro, NVL-520) is an oral, selective ROS1 tyrosine kinase inhibitor developed by Nuvalent, Inc., described in the literature as a brain-penetrant, tropomyosin receptor kinase (TRK)-sparing ROS1 inhibitor in preclinical and early clinical reports ^[3]. The FDA approval applies to adults with locally advanced or metastatic ROS1-positive NSCLC previously treated with a ROS1 TKI, addressing a population with prior targeted therapy exposure ^[2]^[4]. The approval was granted after review using oncology review programs noted by the FDA and zidesamtinib holds orphan drug designation ^[2]. The recommended and approved dosage is 100 mg orally once daily until disease progression or unacceptable toxicity ^[1]^[2]^[4]. Clinicians should consult current prescribing information for full dosing guidance.

Key Findings

Zidesamtinib (Jideytro) achieved a confirmed overall response rate (ORR) of 44% in the overall ARROS-1 efficacy population of 117 patients with previously treated locally advanced or metastatic ROS1-positive NSCLC; 82% of responders had a duration of response (DOR) ≥ 6 months and 69% had a DOR ≥ 12 months (ARROS-1, assessed by blinded independent central review) ^[2]^[4].
In the subgroup who received one prior ROS1 TKI (N=59), ORR was 49% (95% CI: 36, 63) and in those who received two or more prior ROS1 TKIs (N=58) ORR was 38% (95% CI: 26, 52) per BICR assessment in ARROS-1 ^[2]^[4].
Among 50 patients with measurable baseline CNS metastases (no recent brain radiation), intracranial responses were observed in 48% (95% CI: 34, 63) including 22% complete responses per modified RECIST v1.1 by BICR ^[4].
Responses were observed in patients with ROS1 resistance mutations, including responses in 54% (14/26) of patients with the solvent-front G2032R mutation in ARROS-1 ^[4].

Safety & Tolerability

Most common adverse reactions (≥15%) reported in the prescribing information were: edema, peripheral neuropathy, constipation, fatigue, and dyspnea ^[1].
Central nervous system adverse reactions occurred in 25% of patients in the pooled safety population; of these 2.5% were Grade 3 or 4. Dizziness occurred in 12% (0.2% Grade 3); psychiatric disorders occurred in 6% (0.7% Grade 3 or 4) ^[1].
QTc interval prolongation: among 435 patients with at least one post-baseline ECG assessment, 2% experienced a QTcF increase >60 msec from baseline and 0.2% had QTcF >500 msec; QTc prolongation led to dose interruption in 0.4% of patients ^[1].
Interstitial lung disease (ILD)/pneumonitis occurred in 1.8% of patients (Grade 3 or 4 in 0.4%) and led to dose interruption in 0.7%, dose reduction in 0.2%, and permanent discontinuation in 0.4% of patients ^[1].
Skeletal fractures were reported in 1.1% of patients; Grade 3 ankle fractures occurred in 0.4% ^[1].
Myalgia occurred in 13% of patients; concurrent myalgia with increased creatine phosphokinase (CPK) occurred in 2.1% of patients ^[1].
The label also includes warnings for pancreatic toxicity and embryo-fetal toxicity among other precautions detailed in the prescribing information ^[1]^[2].

Study Design

The FDA approval was based on ARROS-1 (NCT05118789), a multicenter, single-arm, open-label, multi-cohort clinical trial that evaluated zidesamtinib 100 mg orally once daily in 117 patients with previously treated locally advanced or metastatic ROS1-positive NSCLC; major efficacy outcome measures were confirmed ORR and DOR per RECIST v1.1 as assessed by blinded independent central review, with intracranial response assessed by modified RECIST v1.1 ^[2]^[4]. Clinicians should consult current prescribing information for full dosing guidance. Patient enrollment included individuals who had received one or two or more prior ROS1 TKIs; tumor assessments were performed every 8 weeks for the first 18 months and every 12 weeks thereafter in the trial ^[4].

FAQ

Q1 What is zidesamtinib (Jideytro) approved for?

Zidesamtinib (Jideytro) is approved for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who received at least one prior ROS1 tyrosine kinase inhibitor (TKI). The approval is based on response and duration outcomes from the ARROS-1 trial in a previously treated ROS1 TKI population.

Q2 How does zidesamtinib work?

Zidesamtinib is an inhibitor of the ROS1 tyrosine kinase, including ROS1 resistance mutations, and has been described in the literature as brain-penetrant and tropomyosin receptor kinase (TRK)-sparing in preclinical and early clinical reports; biochemical and in vitro data show inhibition of ROS1 and activity against multiple ROS1 resistance mutations. The prescribing information describes zidesamtinib as a ROS1 tyrosine kinase inhibitor with demonstrated antitumor activity in ROS1 fusion models and clinical activity in ARROS-1.

Q3 What is the recommended dose of zidesamtinib (Jideytro)?

The recommended dosage of JIDEYTRO is 100 mg taken orally once daily with or without food, continued until disease progression or unacceptable toxicity; the prescribing information provides detailed recommendations for dose reductions and monitoring for adverse reactions. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the most common side effects of zidesamtinib?

The most common adverse reactions (≥15%) listed in the prescribing information are edema, peripheral neuropathy, constipation, fatigue, and dyspnea. The label also includes warnings and precautions for central nervous system adverse reactions (including dizziness, ataxia, cognitive and psychiatric disorders), QTc interval prolongation, interstitial lung disease/pneumonitis, skeletal fractures, myalgia with creatine phosphokinase elevation, pancreatic toxicity, and embryo-fetal toxicity; specific incidence figures and monitoring recommendations are provided in the full prescribing information.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Approves zidesamtinib for ROS1-positive NSCLC: 44% ORR in ARROS-1

Direct Clinical Takeaway & Evidence Summary

FDA Approves zidesamtinib for ROS1-positive NSCLC: 44% ORR in ARROS-1

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

Cite & Reference This Monograph

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