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.

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