FDA OKs Zidesamtinib as New Option for Resistant ROS1+ NSCLC

Today, the FDA approved zidesamtinib (Jideytro; GSK) for adults with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC) who have previously received at least 1 ROS1 tyrosine kinase inhibitor (TKI).¹

The therapy was a part of the portfolio from GSK’s recently completed acquisition of Nuvalent, Inc, and makes it the manufacturer’s first approved medicine in lung cancer.

Overcoming Resistance in ROS1-Positive NSCLC

Zidesamtinib is a novel, brain-penetrant, ROS1-selective inhibitor designed to address limitations of currently available ROS1-targeted therapies.² It is engineered to remain active against tumors that have developed resistance to other ROS1 inhibitors, including those harboring treatment-emergent ROS1 resistance mutations such as G2032R.

The therapy was also designed to achieve central nervous system (CNS) penetration, with the goal of improving treatment options for patients with brain metastases. In addition, zidesamtinib avoids inhibition of the structurally related tropomyosin receptor kinase (TRK) family, potentially reducing the TRK-related CNS adverse events associated with dual TRK/ROS1 inhibitors. According to Nuvalent, these characteristics may support deep, durable responses across all lines of therapy.

"The ROS1-positive community is deeply invested in advancing care with treatments that are effective and tolerable,” Janet Freeman-Daily, cofounder and president of The ROS1ders, said in a news release. “Today's approval gives patients and their doctors an important new option and represents meaningful progress for our community."

ARROS-1 Trial Demonstrates Durable Responses in ROS1-Positive NSCLC

The decision was based on data from the ARROS-1 trial (NCT05118789), a phase 1/2 first-in-human trial for patients with advanced ROS1-positive NSCLC and other solid tumors.

The completed phase 1 portion enrolled patients with ROS1-positive NSCLC who previously received at least 1 ROS1 TKI, as well as those with other previously treated ROS1-positive solid tumors. The primary end point was to evaluate the overall safety and tolerability of zidesamtinib. Additional objectives included determining the recommended phase 2 dose (RP2D), preliminary anti-tumor activity, and pharmacokinetic characterization.

The ongoing phase 2 portion is a global, single-arm, open-label study with registrational intent in both TKI-naive and previously treated patients with advanced ROS1-positive NSCLC. In phase 1, the RP2D was established as zidesamtinib 100 mg once daily.

Nuvalent announced pivotal data from the phase 1/2 trial in June 2025, which supported its new drug application and demonstrated zidesamtinib’s meaningful activity in heavily pretreated patients with advanced ROS1-positive NSCLC.

Among 117 patients previously treated with ROS1 TKIs, the objective response rate (ORR) was 44%. Responses were durable, with 78% of responders remaining in response at 12 months and 62% at 18 months. Efficacy appeared higher in patients who had received only 1 prior ROS1 TKI, with an ORR of 51% and an initial estimated response durability of 93% at both 12 and 18 months.

Activity was also observed in patients with ROS1 G2032R resistance mutations (ORR, 54%) and in those with brain metastases, with an intracranial ORR of 48%, including 20% achieving complete intracranial responses. Nearly half of patients had active CNS disease, and 36% harbored resistance mutations. In addition, preliminary data in TKI-naive patients showed an ORR of 89%.

Regarding its safety profile, zidesamtinib was generally well tolerated, with dose reductions and discontinuations due to adverse events occurring in 10% and 2% of patients, respectively.

"These data demonstrate the potential for zidesamtinib to deliver meaningful clinical outcomes for TKI pre-treated patients, including those progressing with brain metastases or treatment-emergent resistance mutations, and to offer a favorable tolerability profile consistent with its goal of avoiding off-target side effects through ROS1-selectivity,” Alexander Drilon, MD, ARROS-1 trial investigator and chief of the early drug development service at Memorial Sloan Kettering Cancer Center, said in a news release.

References

1. Jideytro (zidesamtinib) approved in the US for previously treated ROS1-positive non-small cell lung cancer. News release. GSK. July 22, 2026. Accessed July 22, 2026. https://www.gsk.com/en-gb/media/press-releases/jideytro-zidesamtinib-approved-in-the-us-for-previously-treated-ros1-positive-non-small-cell-lung-cancer
2. Nuvalent announces FDA acceptance of new drug application for zidesamtinib for the treatment of TKI pre-treated patients with advanced ROS1-positive NSCLC. News release. Nuvalent. November 19, 2025. Accessed July 22, 2026. 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
3. Nuvalent announces positive pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC. News release. Nuvalent. June 24, 2025. Accessed July 22, 2026. https://investors.nuvalent.com/2025-06-24-Nuvalent-Announces-Positive-Pivotal-Data-from-ARROS-1-Clinical-Trial-of-Zidesamtinib-for-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC