Nuvalent, Inc. announced the initiation of the Phase 2 portion of ALKOVE-1, its Phase 1/2 clinical trial of NVL-655 for patients with ALK-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 150 mg once daily (QD). VL-655 is a novel brain-penetrant ALK-selective tyrosine kinase inhibitor (TKI) created with the aim to simultaneously overcome the clinical challenges of emergent treatment resistance, brain metastases, and off-target central nervous system (CNS) adverse events associated with inhibition of the structurally-related tropomyosin receptor kinase (TRK) family that may limit the use of currently available ALK TKIs. In the Phase 1 portion of ALKOVE-1, six dose levels (15 mg to 200 mg QD) of NVL-655 were evaluated in heavily pre-treated patients with ALK-positive solid tumors, and a maximum tolerated dose was not reached. The RP2D of 150 mg QD maintained steady state plasma levels above target efficacy thresholds (ALK wild type fusions and ALK single and compound mutations in both the periphery and in the CNS). The Phase 2 portion of the ALKOVE-1 trial will be conducted globally across North America, Europe, Asia, and Australia. The single arm, open label Phase 2 portion is designed with registrational intent for TKI pre-treated patients with ALK-positive NSCLC and to enable preliminary investigation for patients with ALK-positive NSCLC who are TKI naïve. The Phase 2 cohorts are designed to evaluate NVL-655 in: TKI Pre-Treated ALK-Positive NSCLC; 2 ? 3 Prior TKIs: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs. Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
1 Prior 2G TKI: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior second-generation (2G) ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed. 1 Prior 3G TKI: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib (third-generation, 3G) as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed. TKI-Naïve ALK-Positive NSCLC; Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed. Other; Other ALK-Positive NSCLC: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts. Other ALK-Positive Solid Tumors: Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received =1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.