お知らせ • Apr 18
Nuvalent Inc Presents New Clinical and Preclinical Data for Zidesamtinib
Nuvalent, Inc. announced new clinical and preclinical data for zidesamtinib, an investigational ROS1-selective inhibitor, to be presented during poster sessions at the American Association for Cancer Research (AACR) Annual Meeting 2026 being held April 17-22 in San Diego. The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for zidesamtinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC who received at least 1 prior ROS1 TKI, and assigned a Prescription Drug User Fee Act (PDUFA) target action date of September 18, 2026. Pending FDA review, Nuvalent anticipates U.S. commercial launch of zidesamtinib in 2026. Additionally, the company plans to submit data to the FDA to support a potential label expansion of zidesamtinib in TKI-naïve patients with advanced ROS1-positive NSCLC in the second half of 2026. Zidesamtinib is being evaluated in ARROS-1, a first-in-human, single-arm Phase 1/2 clinical trial in patients with advanced ROS1-positive NSCLC and other solid tumors. Clinical data presented are from a subgroup of patients with advanced ROS1-positive NSCLC in ARROS-1 who had been previously treated with the dual TRK/ROS1 TKIs repotrectinib and/or taletrectinib. No available ROS1 TKIs have demonstrated activity in this heavily pre-treated population. Patients received at least 1 dose of zidesamtinib at 100 mg QD as of a data cut-off date of September 22, 2025. The population for this analysis was unique and heavily pre-treated: 46 efficacy-evaluable patients had received prior repotrectinib, 19 had received prior taletrectinib, and 3 had previously received both; 85% (39/46) of repotrectinib-treated patients and 89% (17/19) of taletrectinib-treated patients had received =2 prior ROS1 TKIs; 63% (29/46) of repotrectinib-treated patients and 53% (10/53) of taletrectinib-treated patients had received prior chemotherapy; Active CNS disease was assessed by BICR in 46% (21/46) of repotrectinib-treated patients and 53% (10/19) of taletrectinib-treated patients at baseline; and Secondary ROS1 resistance mutations were reported in 35% (16/46) of repotrectinib-treated patients and 42% (8/19) of taletrectinib-treated patients, with a ROS1 G2032R mutation identified in 26% (12/46) and 21% (4/19), respectively. Treatment with zidesamtinib resulted in clinically meaningful activity in this population, including in patients with the ROS1 G2032R resistance mutation and those with CNS disease. As of the data cut-off date: Efficacy Parameter Prior repotrectiniba Prior taletrectinibb (RECIST v1.1, BICR) ORR, % (n/n) 41% (19/46) 47% (9/19) [95% CI] [27, 57] [24, 71] CR, n (%) 7% (3/46) c 5% (1/19) mDOR, months d 15.7 NR [95% CI] [5.6, NE] [5.2, NE] ROS1 G2032R resistance mutation ORR, % (n/n) 67% (8/12) 50% (2/4) e [95% CI] [35, 90] [7, 93] CR, n (%) 8% (1/12) 0 % mDOR, months d 15.7 NR [95% CI] [3.5, NE] [NE, NE] Intracranial Activity f IC-ORR, % (n/n) 44% (8/18) 71% (5/7) [95% CI] [22, 69] [29, 96] IC-CR, n (%) 11% (2/18) 43% (3/7) mIC-DOR, months d NR NR [95% CI] [5.2, NE] [5.2, NE] IC-DOR =6 months d 86% 80% [33, 98] [20, 97] BICR, blinded independent central review; CI, confidence interval; CR, complete response; IC, intracranial; IC-DOR, intracranial duration of response; mDOR, median duration of response; NE, not estimable; NR, not reached; ORR, objective response rate. a Prior repotrectinib ± other ROS1 TKIs and/or chemotherapy. b Prior taletrectinib ± other ROS1 TKIs and/or chemotherapy. c Includes one single time-point CR pending confirmation in an ongoing patient who previously experienced confirmed PR. d Kaplan-Meier estimates. e Responses also observed in pts with ROS1 D2033N (n=1) and L2086F (n=1). f Includes patients with measurable (=5mm) CNS lesions by BICR at baseline. The safety profile of zidesamtinib in this population was consistent with the previously reported safety results from ARROS-1 for patients with advanced ROS1-positive NSCLC, including low rates of dose reductions and treatment discontinuations, and the avoidance of TRK-related neurologic adverse events. Data presented are from preclinical analyses of the brain penetrance and intracranial ROS1 G2032R antitumor activity of zidesamtinib compared to the dual TRK/ROS1 inhibitors repotrectinib and taletrectinib. Among the three ROS1 TKIs, all of which have reported activity against the ROS1 G2032R mutation, zidesamtinib demonstrated: Highest cell permeability in MDCK-MDR1 cell lines and highest brain-to-plasma partitioning in rats, supporting zidesamtinib's potential for high brain penetrance; Most sustained intracranial efficacy in a mouse ROS1 G2032R brain tumor model, with all mice surviving to study end; and, Efficacy after progressive disease on earlier-line taletrectinib treatment in a mouse ROS1 G2032R brain tumor model. Data demonstrating that switching from repotrectinib to zidesamtinib resulted in more sustained tumor suppression in the same preclinical model have been previously reported. Zidesamtinib is an investigational, brain-penetrant, ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Based on results for tyrosine kinase inhibitor (TKI) pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) enrolled in the global registrational ARROS-1 Phase 1/2 clinical trial, the U.S. Food and Drug Administration (FDA) has accepted for filing Nuvalent's NDA submission for zidesamtinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC who received at least 1 prior ROS1 TKI. The application has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of September 18, 2026. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic NSCLC who have been previously treated with 2 or more ROS1 TKIs and orphan drug designation for ROS1-positive NSCLC.