Nuvalent, Inc. announced the initiation of the Phase 2 portion of ARROS-1, its Phase 1/2 clinical trial of NVL-520 for patients with ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors, following alignment with the US Food and Drug Administration (FDA) on a recommended Phase 2 dose (RP2D) of 100 mg daily. NVL-520 is a novel brain-penetrant ROS1-selective tyrosine kinase inhibitor (TKI) created with the aim to simultaneously overcome the clinical challenges of emergent treatment resistance, off-target central nervous system (CNS) adverse events associated with TRK inhibition, and brain metastases that may limit the use of currently available ROS1 TKIs. In the Phase 1 portion of ARROS-1, six dose levels (25 mg to 150 mg daily) of NVL-520 were evaluated in heavily pre-treated patients with ROS1-positive solid tumors.

A maximum tolerated dose (MTD) was not reached, and no clinically significant exposure-response relationships for safety and efficacy were observed across the dose levels evaluated. The RP2D of 100 mg daily maintained steady state plasma levels above all target efficacy thresholds (ROS1 wild type and ROS1 G2032R in both the periphery and in the CNS). ARROS-1 Phase 2 Design: The Phase 2 portion of the ARROS-1 trial will be conducted globally across North America, Europe, Asia and Australia with planned enrollment of approximately 225 TKI naïve and TKI pre-treated patients with ROS1-positive NSCLC and other solid tumors.

The single arm, open label Phase 2 cohorts are designed to evaluate NVL-520 across the treatment paradigm for patients with ROS1-positive NSCLC, and include both potentially registration-directed pivotal cohorts and an additional exploratory cohort: Potential Pivotal Cohorts: Cohort 2a: Patients with advanced/metastatic ROS1-positive NSCLC naïve to TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed. Cohort 2b: Patients with advanced/metastatic ROS1-positive NSCLC treated with 1 prior ROS1 TKI (either crizotinib or entrectinib) and no prior chemotherapy or immunotherapy allowed.

Cohort 2c: Patients with advanced/metastatic ROS1-positive NSCLC treated with 1 prior ROS1 TKI (either crizotinib or entrectinib) and 1 prior line of platinum-based chemotherapy with or without immunotherapy. Cohort 2d: Patients with advanced/metastatic ROS1-positive NSCLC treated with at least 2 prior ROS1 TKIs (with crizotinib or entrectinib as the initial ROS1 TKI) and up to 1 line of chemotherapy and/or immunotherapy. Exploratory Cohort: Cohort 2e: Patients with any advanced/metastatic ROS1-positive solid tumor (including patients with ROS1-positive NSCLC not otherwise eligible for any other cohorts) and progressed on any prior therapy (includes, but is not limited to, patients who have progressed on prior ROS1 TKIs).

Selection of NVL-520 RP2D: The selection of 100 mg daily as the RP2D for NVL-520 was discussed and supported by FDA based on clinical data from the Phase 1 dose escalation portion of the ARROS-1 trial with a data cut-off of May 17, 2023. These data included a safety database of 87 ROS1-positive patients enrolled across six dose levels from 25 mg to 150 mg daily, including 37 patients at dose levels of =100 mg daily. The selection was based on the following considerations: The dose level of 100 mg daily maintained steady state plasma levels above all target efficacy thresholds (ROS1 wild type and ROS1 G2032R in both the periphery and in the CNS).

Favorable tolerability of NVL-520 was observed across all dose levels to date. No clinically significant exposure-response relationships for safety and efficacy were observed across the dose levels evaluated (25 mg ? 150 mg daily).

Based on these data, early anti-tumor activity continued to be observed in ROS1-positive NSCLC patients, including objective responses (RECIST 1.1) in heavily pre-treated patients, patients previously treated with lorlatinib or repotrectinib, patients with ROS1 G2032R resistance mutations, and patients with CNS metastases. A favorable preliminary safety profile continued to suggest the potential for a highly ROS1-selective, TRK sparing design. Overall, the company believes these findings to be consistent with the conclusions from a preliminary data disclosure in October 2022 with data cut-off date of September 13, 2022, and believes that these data continue to support the opportunity for NVL-520 as a potential best-in-class therapy that may be able to move up the treatment paradigm for patients with ROS1-positive NSCLC.

The company expects to share an update from the ARROS-1 trial at a medical meeting in 2024.