FDA Accepts NDA for Zidesamtinib in Previously Treated ROS1+ NSCLC

The U.S. Food and Drug Administration (FDA) accepted a new drug application (NDA) for zidesamtinib, an investigational ROS1-selective inhibitor intended for adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who previously received at least one ROS1 tyrosine kinase inhibitor (TKI), according to a news release from Nuvalent, Inc.

The regulatory agency set a prescription drug user fee act (PDUFA) target action date of Sept. 18, 2026.

According to the FDA’s website, an NDA is a request a company sends to the FDA asking for approval to make a new medication available to patients in the United States, supported by all the research showing it is safe and effective. Moreover, the website explains that a PDUFA target action date is the deadline by which the FDA must decide whether to approve a company’s NDA.

The NDA relies on findings from TKI pre-treated patients enrolled in the global phase 1/2 ARROS-1 clinical trial. Nuvalent also reported preliminary data from the ongoing TKI-naïve cohort, with both data sets presented during the Presidential Symposium at the IASLC 2025 World Conference on Lung Cancer.

Zidesamtinib was created to address limitations seen with currently available ROS1 inhibitors, particularly resistance that can occur through treatment-emergent mutations such as G2032R. The therapy is designed for brain penetrance to support patients who develop central nervous system (CNS) metastases, and to avoid inhibiting the tropomyosin receptor kinase (TRK) family, which may limit TRK-related side effects.

The investigational therapy has received breakthrough therapy designation for patients with metastatic ROS1-positive NSCLC previously treated with two or more ROS1 TKIs, as well as orphan drug designation for ROS1-positive NSCLC.

Phase 1/2 ARROS-1 Trial Data Highlight Notable Response Rates in Patients with Lung Cancer

Data from ARROS-1 demonstrated that patients with advanced ROS1-positive NSCLC who previously received one to four lines of ROS1 TKI therapy, with or without chemotherapy, achieved an objective response rate (ORR) of 44% and a complete response (CR) rate of 1% with zidesamtinib, CURE shared in a recent article.

Among patients previously treated with either Xalkori (crizotinib) or Rozlytrek (entrectinib), the ORR reached 51% with a CR rate of 2%. Patients who had only received Xalkori achieved an ORR of 68%, whereas those who previously received only Rozlytrek had an ORR of 33%.

Responses occurred even in individuals treated with at least two prior ROS1 TKIs, achieving an ORR of 38%. Patients exposed to Augtyro (repotrectinib) experienced an ORR of 47%, with duration of response (DOR) ranging from approximately 3.5 months to 17.2 months. Those who had received Ibtrozi (taletrectinib) demonstrated an ORR of 43%, with DOR ranging from approximately 5.2 months to more than seven months.

The ARROS-1 trial, a global first-in-human study, evaluated zidesamtinib across multiple dose levels in the phase 1 portion. The phase 2 portion uses a 100-mg once-daily recommended dose for both TKI-naïve and TKI pre-treated patients.

“In the pivotal dataset for TKI pretreated patients with advanced ROS1-positive NSCLC, zidesamtinib demonstrated a clinical profile consistent with its preclinical design goals,” Dr. Alexander E. Drilon said during the presentation of data at the IASLC 2025 World Conference on Lung Cancer. “[We saw] durable activity, including in heavily pretreated patients who have exhausted available options, including prior [Augtyro] and [Ibtrozi], and patients with the ROS1 G2032R resistance mutation.”

Drilon is chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York.

References

1. “Nuvalent Announces FDA Acceptance of New Drug Application for Zidesamtinib for the Treatment of TKI Pre-treated Patients with Advanced ROS1-positive NSCLC,” by Nuvalent, Inc. News release; Nov. 19, 2025.
2. “New Drug Application (NDA),” by the U.S. FDA. News release; Jan. 21, 2022.
3. “Zidesamtinib Elicits Responses in ROS1-Positive NSCLC,” by Caroline Seymour. CURE; Sept. 9, 2025. https://www.curetoday.com/view/zidesamtinib-elicits-responses-in-ros1-positive-nsclc

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