Phase I Clinical Trial NCT05384626 by Nuvalent, Inc.
Study of NVL-655, ALKOVE-1, a fourth generation Anaplastic Lymphoma Kinase (ALK) Inhibitor in patients with advanced NSCLC and other solid tumors harboring the ALK rearrangement or activating ALK mutation.
https://clinicaltrials.gov/ct2/show/NCT05384626?term=nuvalent&draw=2&rank=1
NVL-655 is a 4th generation, brain-penetrant, ALK TKI inhibitor created to overcome several limitations observed with currently available therapies. NVL-655 is designed to remain active in tumors that have developed resistance to first, second, and third-generation ALK inhibitors, including tumors with the solvent front G1202R mutation or compound mutations G1202R/L1196M (“GRLM”), G1202R/G1269A (“GRGA”), or G1202R/L1198F (“GRLF”). NVL-655 has been optimized for CNS (central nervous system) penetration to improve treatment options for patients with CNS metastases. ALK-selectivity is emphasized to minimize CNS side effects related to off-target inhibition of other similar kinases (like NTRK in particular). Side effects of other ALK TKIs including cognitive impairment, mood disorders, sleep disorders, dizziness, ataxia (poor muscle control), and weight gain, among others, are hoped to be minimized. It is also hoped that NVL-655’s unique cell structure will make it a more durable treatment then prior ALK TKIs.
Following treatment with 1st and/or 2nd generation ALK therapies, approximately 40% of patients develop the G1202R solvent front mutation, which confers resistance to crizotinib, ceritinib, alectinib, and brigatinib. Third generation ALK TKI lorlatinib has been approved for treating patients who have previously received 1st and/or 2nd generation ALK therapies. However, compound mutations, including G1202R/L1196M, G1202R/L1198F, and G1202R/G1269A, have been observed in these patients after progressive disease following lorlatinib. While thirty-forty percent of ALK+ NSCLC patients have central nervous system (CNS) metastases at diagnosis, advanced patients with a history of ALK TKI treatments show a higher incidence of CNS metastases of about 60%. The pie charts below detail the incidence of various mutations after progression on second and third line TKIs.
This is a Phase 1/2, dose escalation and expansion study designed to evaluate the safety and tolerability of NVL-655, determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ALK- positive NSCLC and other solid tumors. Treatment consists of a pill (or pills) taken orally. It began in May, 2022, and is expected to be completed in March, 2026 after enrolling 214 patients, aged 12 and over (unusual, thankfully). There are five cohorts in the trial. Cohort 1 appears to be open to all patients with ALK mutation activating disease, perhaps in a first line setting (author’s speculation). Cohort 2a is for ALK+ NSCLC patients treated with 1 prior 2nd-generation ALK TKI therapy. Cohort 2b is for ALK+ NSCLC patients treated with 2-3 prior 1st or 2nd-generation ALK TKIs. Cohort 2c is for ALK+ NSCLC patients treated with 2-3 prior ALK TKIs, with lorlatinib in the 2nd or 3rd line. Cohort 2d is for ALK+ patients with solid tumors, including patients with NSCLC not eligible for cohorts 2a-c, treated with ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists. At this writing the trial is open at Sarah Cannon Research Institute in Nashville. Contact information can be found here: https://clinicaltrials.gov/ct2/show/NCT05384626?term=nuvalent&draw=2&rank=1#contacts
Nuvalent, Inc. is a clinical stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer. It is a publicly traded company that was founded in 2017, is listed on the NASDAQ exchange under ticker symbol NUVL, and is headquartered in Cambridge, Massachusetts. On August 2, 2021, the Company completed an initial public offering (IPO) at $17/share, raising approximately $174.3M. At this writing the stock price is $9.81/share. At December 31, 2021 the company reported cash of approximately $288M, showing a development-stage loss for that 2021 period of approximately $46.5M. The company reports the need to raise additional funding in the foreseeable future. Another Nuvalent drug, NVL-520 is also currently in phase 1/2 trial for patients with advanced NSCLC and other solid tumors harboring the ROS1 rearrangement (the ARROS-1 trial). Another Nuvalent drug in preclinical development is intended to address ALK NSCLC mutation I1171X/D1203N (X = N, S, or T), a mutation that occurs in some patients that have progressed on lorlatinib and is not covered by NUV-655.
Scientific advisors to Nuvalent include several key opinion leaders (KOLs) in the ALK field that are well known within the ALK NSCLC community, and to ALK Positive medical committee members. D. Ross Camidge, MD, PhD is Director of Thoracic Oncology and Joyce Zeff Chair in Lung Cancer Research at University of Colorado Cancer Centre, Denver. Aaron Hata, MD, PhD is Translational Research Advisor at Harvard Medical School, Mass General Cancer Center. Pasi Jänne, MD, PhD is Clinical Advisor at Harvard Medical School, Dana Farber Cancer Institute.
It is expected that additional trial sites will be opening periodically.
Jeffrey M. Sturm BS, MA, MBA
ALK Positive www.alkpositive.org
Member, Research Acceleration Committee
Member, Clinical Trials Committee