Nuvalent, Inc. announced preliminary data from the Phase 1 dose-escalation portion of its ongoing ALKOVE-1 Phase 1/2 clinical trial of NVL-655 for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors as reported in an abstract accepted for presentation at the 35th AACR-NCI-EORTC (ANE) Symposium in Boston, Massachusetts. Updated preliminary data will be presented at the conference and during a live webcast and conference call with management on October 13 at 8:00am EDT. NVL-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 tropomyosin receptor kinase (TRK) inhibition that may limit the use of currently available ALK TKIs.

NVL-655 is currently being evaluated in the ALKOVE-1 Phase 1/2 clinical trial, a first-in-human study of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors (NCT05384626). The Phase 1 dose escalation portion is enrolling ALK-positive NSCLC patients who have previously received at least one ALK TKI and patients with other ALK-positive solid tumors who have been previously treated with at least one prior systemic anticancer therapy. The primary objectives are to determine the recommended Phase 2 dose (RP2D) and if applicable, the maximum tolerated dose (MTD) of NVL-655 in patients with ALK-positive solid tumors.

Additional objectives include characterization of the overall safety, tolerability, and pharmacokinetic profile, and evaluation of the preliminary anti-tumor activity of NVL-655. As of June 12, 2023, 57 patients (54 NSCLC, 3 other solid tumors) received NVL-655 orally at dose levels ranging from 15 to 200 mg once daily in the Phase 1 dose escalation portion of ALKOVE-1. The patient population was heavily pre-treated and included: patients with baseline CNS metastases (51%); patients with ALK resistance mutations (47%), including compound ALK mutations (32%); patients who had received =3 prior ALK TKIs (53%); and, patients who had received =1 2nd generation ALK TKI (alectinib, brigatinib, ceritinib) and the 3rd generation ALK TKI lorlatinib (77%). Preliminary activity of NVL-655 was demonstrated in this heavily pre-treated patient population as measured by objective response rate (ORR) per RECIST 1.1. Partial responses were observed in 45% (15/33; 8 pending confirmation) of response-evaluable patients with ALK-positive NSCLC who received NVL-655 at doses ranging from 15-150 mg once daily.

An ORR of 65% (11/17) was observed in patients with baseline ALK resistance mutations, and an ORR of 41% (12/29) was observed in patients post-lorlatinib, including cases with compound resistance mutations. Early indicators of CNS activity were also observed. Preliminary pharmacokinetic analysis demonstrated dose-proportional exposure, and preliminary pharmacodynamic analysis showed reductions, including clearance, of ALK fusion and mutation variants in ctDNA.

NVL-655 was well-tolerated and treatment-related adverse events (TRAEs) were generally mild. The most frequent TRAEs were nausea (12%), transaminase elevation (12%), fatigue (9%), and constipation (7%). Grade =3 TRAEs were transaminase elevation (n=2), CPK elevation (n=1), and fatigue (n=1).

An MTD was not identified and Phase 1 was ongoing to determine the RP2D.