Phase II Clinical Trial NCT05384626 by Nuvalent, Inc. A Study of NVL-655 in Patients with Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)
A Study of NVL-655 in Patients with Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)
https://clinicaltrials.gov/study/NCT05384626?term=NCT05384626&rank=1
Sponsor: Nuvalent, Inc.
Study Director: Viola Zhu, MD, PhD, Nuvalent Inc.
Study Contact: Tina Kehrig, 857-357-7000, clinicaltrials@nuvalent.com
Who is this trial for: 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 have activity 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”). In other words, it is for patients for whom other ALK TKIs have failed under certain conditions. 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, have proven to be minimal with NVL-655 in trial results published to date. It is expected that NVL-655’s unique molecular structure will make it a more durable treatment than prior ALK TKIs.
Scientific Rationale: Following treatment with 1st and/or 2nd generation ALK therapies, approximately 40% of patients develop the G1202R solvent front mutation (as determined by tissue or liquid biopsy), 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 with progressive disease following lorlatinib. While 30-40% 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%. NVL-655 has been designed to address these issues.
Inclusion Criteria: This is the Phase 2 portion of the original 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. Phase I began in May 2022, Phase II began in February 2024, and the trial is expected to be completed in March 2026 after enrolling 214 patients. An unusual and patient-friendly inclusion criterion is accepting patients age 12 and over (typically patients 18 and over are included). There are six cohorts in the Phase II trial. Cohort 2a: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed. Cohort 2b: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed. Cohort 2c: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed. Cohort 2d: 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. Cohort 2e: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts. Cohort 2f: 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.
Exclusion Criteria: Patients are not eligible for the trial if their cancer has a known oncogenic driver alteration other than ALK, if they have a known allergy/hypersensitivity to any inactive pharmaceutical ingredients of NVL-655, if they have had major surgery within 4 weeks of the study entry, if they have other anticancer therapy ongoing, or if they are actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.
Availability: As of September 21, 2024, 229 patients have been enrolled in the Phase II portion of this trial, with an expected total enrollment of 470. At the time of this writing the trial is open at fifty-four locations in the United States, Australia, Canada, France, Italy, Korea, Netherlands, Singapore, Spain, Taiwan, and the United Kingdom. Contact information can be found here: https://clinicaltrials.gov/study/NCT05384626?term=NCT05384626&rank=1#contacts-and-locations
Some Details: 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. At this writing the stock price is $90.70/share. As of June 30, 2024, the company reported cash, cash equivalents, and marketable securities of approximately $658.0M, and had a net loss of $101.6M for the six months ended June 30, 2024. A public offering in September 2024 raised an additional $575M of gross proceeds. Other investigational drugs in phase II and Phase I trials are for ROS1 and HER2 positive NSCLC respectively. Scientific advisors to Nuvalent include several key opinion leaders (KOLs) in the ALK field that are well known within the ALK NSCLC community. Amongst these are Dr. Ross Camidge (MD, PhD, Director of Thoracic Oncology and Joyce Zeff Chair in Lung Cancer Research at University of Colorado Cancer Centre, Denver), Dr. Aaron Hata (MD, PhD, Translational Research Advisor at Harvard Medical School, Mass General Cancer Center), and Dr. Pasi Jänne (MD, PhD, Clinical Advisor at Harvard Medical School, Dana Farber Cancer Institute). www.nuvalent.com
ALKOVE-1 Phase 1 Update at ESMO 2024: From June 2022 to February 2024, the Phase 1 portion of ALKOVE-1 enrolled 133 patients (131 NSCLC, 2 other solid tumors). Patients received NVL-655 orally at dose levels ranging from 15 to 200 mg daily, and 150 mg daily was selected as the recommended phase 2 dose (RP2D). The patient population was heavily pre-treated, with a median of 3 prior lines of therapy (range 1 – 9). 46% (61/133) of patients had ≥3 prior ALK TKIs, and 56% (74/133) had prior chemotherapy. Notably, 84% (111/133) of patients received prior lorlatinib and 51% (68/133) had any secondary ALK resistance mutation including 26% (34/133) with compound (≥2) ALK mutations, highlighting the differentiated nature of this population from prior trials of investigational ALK inhibitors. 56% (75/133) had history of CNS metastases, including cases of disease progression following treatment with the brain-penetrant TKI lorlatinib. As of the cut-off date of June 15, 2024, 103 heavily pre-treated patients with ALK-positive NSCLC treated across all doses were response-evaluable, of whom 39 were treated at the RP2D. The median follow-up for the all-treated population was 8.0 months (range 0.2, 22.5). Treatment with NVL-655 resulted in durable clinical responses (ORR by RECIST 1.1) across key subgroups of response-evaluable patients treated at the RP2D and across all dose levels.
See response data here: https://investors.nuvalent.com/2024-09-14-Nuvalent-Highlights-Presentation-of-Clinical-Data-at-ESMO-2024-for-Parallel-Lead-Programs-for-ROS1-and-ALK-positive-NSCLC-and-Accelerated-Development-Timelines
Jeffrey M. Sturm, BS, MA, MBA
ALK Positive www.alkpositive.org
Member, Research Acceleration Committee
Member, Clinical Trials Committee
Member, Board of Directors
Nine-year ALK NSCLC survivor