FDA Accepts NDA for Zidesamtinib in Pretreated Advanced ROS1+ NSCLC

Zidesamtinib elicited positive activity in patients with advanced ROS1-positive NSCLC who previously received a ROS1 TKI in the phase 1/2 ARROS-1 trial.

The FDA has accepted a new drug application (NDA) for zidesamtinib, an investigational ROS1-selective inhibitor, for the treatment of patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC) who received at least 1 prior ROS1 tyrosine kinase inhibitor (TKI), according to a release from the developer, Nuvalent.1 A Prescription Drug User Fee Act target action date of September 18, 2026, has been set.

Zidesamtinib was evaluated in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors in the first-in-human phase 1/2 ARROS-1 trial (NCT05118789). The NDA submission was supported by results for TKI-pretreated patients with ROS1-positive NSCLC, and TKI-naïve patients from ARROS-1. Results from the trial were shared in the Presidential Symposium at the IASLC 2025 World Conference on Lung Cancer.2

Among patients who received any ROS1 TKI (range, 1-4) with or without chemotherapy, the overall response rate (ORR) was 44% (95% CI, 34%-53%), with a complete response (CR) rate of 1%. A duration of response (DOR) of at least 6 months, 12 months, and 18 months was observed in 84% (95% CI, 71%-92%), 78% (95% CI, 62%-88%), and 62% (95% CI, 28%-84%), respectively. The progression-free survival (PFS) rates at 6 or more months, 12 or more months, and 18 or more months were 57% (95% CI, 47%-66%), 48% (95% CI, 38%-57%), and 40% (95% CI, 24%-55%).

Among patients who received 1 prior ROS1 TKI of either crizotinib (Xalkori) or entrectinib (Rozlytrek), with or without chemotherapy, the ORR was 51% (95% CI, 37%-65%), with a CR rate of 2%. A DOR of at least 6 months, 12 months, and 18 months was observed in 93% (95% CI, 74%-98%), for all time points. The PFS rates at 6 or more months, 12 or more months, and 18 or more months were 70% (95% CI, 56%-81%), 68% (95% CI, 53%-79%), and 68% (95% CI, 53%-79%).

In patients with ROS1 G2032R resistance mutation who received any ROS1 TKI, the ORR was 54% (95% CI, 33%-73%), with a DOR of 6 or more months and 12 or more months in 79% (95% CI, 47%-93%) and 60% (95% CI, 28%-81%), respectively. The intracranial ORR (IC-ORR) was 48% (95% CI, 35%-62%), with an IC-CR rate of 20%. The IC-DOR at 6 or more months and 12 or more months was 79% (95% CI, 56%-91%) and 71% (95% CI, 46%-87%), respectively.

In patients with ROS1 G2032R resistance mutation who received 1 prior ROS1 TKI of either crizotinib or entrectinib, the ORR was 83% (95% CI, 36%-100%), with a DOR of 6 or more months and 12 or more months in 80% (95% CI, 20%-97%) at both timepoints. The IC-ORR in patients who only received prior crizotinib was 85% (95% CI, 55%-98%), with an IC-CR rate of 54%. The IC-DOR at 6 or more months and 12 or more months was 91% (95% CI, 51%-99%).

“In the pivotal dataset for TKI pre-treated patients with advanced ROS1-positive NSCLC, zidesamtinib demonstrated a clinical profile consistent with its preclinical design goals,” wrote lead study author Alexander E. Drilon, MD, chief of Early Drug Development Service and a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, in the presentation.2

A total of 514 patients with any ROS1-positive solid tumor were enrolled between phase 1 and phase 2 of the trial; of them, 432 had advanced ROS1-positive NSCLC and received zidesamtinib at 100 mg once daily, and 117 patients with TKI pre-treated ROS1-positive NSCLC were included in the pivotal efficacy population.

In the ROS1 TKI-pretreated population, the median age of patients was 57 years (range, 31-83), 56% were female, 68% were never smokers, and 62% had an ECOG performance status of 1, 49% had active central nervous system disease, and 22% had ROS1 G2032R mutation.

The median number of prior anticancer therapies was 2 (range, 1-11), with 53% having received chemotherapy. Of the 47% of patients who received 1 prior ROS1 TKI of crizotinib or entrectinib, 51% received crizotinib and 59% had entrectinib. Additionally, 3% of patients received 1 prior ROS1 TKI of repotrectinib (Augtyro) or taletrectinib (Ibtrozi). Of the 50% of patients who received at least 2 prior ROS1 TKIs, 93% received lorlatinib (Lorbrena), repotrectinib, or taletrectinib.

The primary end point of phase 2 was the ORR by blinded independent central review. Secondary end points included DOR, PFS, intracranial activity, and safety, among others.

Regarding safety, any-grade treatment-emergent adverse events (TEAEs) that occurred in at least 15% of all patients treated with zidesamtinib at 100 mg once daily included peripheral edema (36%), constipation (17%), blood creatine phosphokinase increased (16%), fatigue (16%), and dyspnea (15%). Notably, the only treatment-related AE that occurred in at least 15% of patients was peripheral edema (29%). Dose reductions and treatment discontinuation due to TEAEs occurred in 10% and 2%, respectively.

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. News release. Nuvalent. November 19, 2025. Accessed November 20, 2025. https://tinyurl.com/2wukrj6d
2. Drilon AE, Cho BC, Lin JJ, et al. Pivotal ARROS-1 efficacy and safety data: zidesamtinib in TKI pretreated patients with advanced/metastatic ROS1+ NSCLC. Presented at the 2025 International Association for the Study of Lung Cancer World Conference on Lung Cancer 2025; September 6-9, 2025; Barcelona, Spain.