ARROS-1 Trial: Zidesamtinib Demonstrates Activity in TKI-Pretreated ROS1-Positive NSCLC

Nuvalent announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for zidesamtinib for the treatment of adults with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC) who have received at least one prior ROS1 tyrosine kinase inhibitor (TKI).

The application is supported by data from the ARROS-1 phase 1/2 trial with a Prescription Drug User Fee Act (PDUFA) target action date of September 18, 2026.

Clinical Takeaway

Zidesamtinib demonstrated meaningful systemic and intracranial activity in ROS1-positive NSCLC following prior ROS1 TKI therapy, including in patients with the G2032R resistance mutation and active CNS metastases, with a tolerability profile designed to minimize off-target tropomyosin receptor kinase (TRK) inhibition.

If approved, zidesamtinib could emerge as an important post-TKI treatment option in a molecular subset where resistance and CNS progression remain persistent clinical challenges.

ARROS-1 Study Design (NCT05118789)

• This is a global phase 1/2, first-in-human study evaluating zidesamtinib, a ROS1-selective TKI designed to spare TRK inhibition, in patients with ROS1-positive NSCLC and other ROS1-driven solid tumors.
• The recommended phase 2 dose (RP2D) was established at 100 mg orally once daily.
• The pivotal phase 2 cohort included patients with ROS1-positive NSCLC previously treated with at least one ROS1 TKI.
• Key baseline characteristics included:
  • 117 TKI-pretreated patients
  • 49% with active CNS metastases at baseline
  • 36% with secondary ROS1 resistance mutations, including G2032R
• The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR).

Key Results

Overall Response:

• Among the 117 TKI-pretreated patients, zidesamtinib demonstrated:
  • ORR: 44%
  • Complete Response (CR): 1%
• Duration of Response (DOR):
  • 84% at 6 months
  • 70% at 12 months
  • 62% at 18 months
• Activity in ROS1 G2032R Resistance Mutation
  • Zidesamtinib demonstrated activity in patients harboring the ROS1 solvent-front resistance mutation G2032R.
    • ORR: 54% (14/26) overall
    • ORR: 83% (5/6) in patients with only one prior ROS1 TKI
  • This mutation has historically been difficult to target with earlier-generation ROS1 inhibitors.
• Intracranial Activity:
  • Among patients with measurable brain metastases (n = 56):
    • Intracranial ORR: 48%
    • Intracranial CR: 20%
  • In the prior crizotinib-only subgroup, intracranial responses were particularly notable:
    • Intracranial ORR: 85%
    • Intracranial CR: 54%

These findings highlight the drug’s CNS activity, an important feature in ROS1-positive NSCLC where brain metastases are common.

Safety

• The pivotal safety population included 432 ROS1-positive NSCLC patients treated with zidesamtinib 100 mg daily. The most common treatment-emergent adverse events (≥ 15%) included:
  • Peripheral edema
  • Constipation
  • Creatine phosphokinase (CPK) elevation
  • Fatigue
  • Dyspnea
• Treatment modifications were relatively infrequent:
  • Dose reductions: 10%
  • Treatment discontinuations: 2%
• Zidesamtinib’s ROS1-selective, TRK-sparing design may help reduce neurologic adverse effects associated with off-target TRK inhibition seen with some dual ROS1/TRK inhibitors.

Clinical Context and Where It Fits

ROS1 rearrangements occur in approximately 1–2% of NSCLC cases and are typically sensitive to targeted ROS1 inhibition. However, acquired resistance and CNS progression remain common mechanisms of treatment failure.

Several next-generation ROS1 inhibitors have recently expanded treatment options in this setting, including repotrectinib and taletrectinib.

Within this evolving treatment landscape, zidesamtinib may differentiate itself through:

• Activity in G2032R resistance mutations
• Meaningful intracranial response rates
• A ROS1-selective design intended to avoid TRK-related toxicities

If approved, zidesamtinib could provide an additional post-TKI targeted therapy option for patients with ROS1-positive NSCLC who develop resistance to earlier-generation inhibitors.

Sources:

• The ASCO Post. (2025, October 25). Zidesamtinib shows activity in pretreated and tyrosine kinase inhibitor–naive patients with ROS1-positive NSCLC. https://ascopost.com/issues/october-25-2025/zidesamtinib-shows-activity-in-pretreated-and-tyrosine-kinase-inhibitor-naive-patients-with-ros1-positive-nsclc/
• National Library of Medicine (U.S.). (n.d.). A study of NVL-520 in patients with advanced ROS1-positive NSCLC and other solid tumors (ARROS-1) (NCT05118789). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05118789
• Nuvalent. (2025, November 19). Nuvalent announces FDA acceptance of new drug application for zidesamtinib for the treatment of TKI-pretreated patients with advanced ROS1-positive non–small cell lung cancer. https://investors.nuvalent.com/2025-11-19-Nuvalent-Announces-FDA-Acceptance-of-New-Drug-Application-for-Zidesamtinib-for-the-Treatment-of-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC