neladalkib (NVL-655) / Nuvalent - LARVOL DELTA

Neladalkib (NVL-655), a highly selective anaplastic lymphoma kinase (ALK) inhibitor, compared to alectinib in first-line treatment of patients with ALK-positive advanced non-small cell lung cancer: The phase 3 ALKAZAR study. (ASCO 2025) - P3 | "Clinical Trial Registration Number: NCT06765109 The abstract will be released to the public on May 22, 2025 at 4:00 PM CDT"

Clinical • Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Mutagenesis screens support potential best-in-class profile for neladalkib (NVL-655), a brain-penetrant and TRK-sparing ALK inhibitor (AACR 2025) - "Cells were treated with ENU for 1 day followed by alectinib (2G), lorlatinib (3G), or NVL-655 for 28 days. This preclinical study indicates the potential for NVL-655 to prevent acquisition of on-target resistance and thereby provide deeper and more durable target inhibition. The broad preclinical activity against ALK and diverse ALK mutations, together with its brain penetrance and TRK-sparing design, suggests NVL-655 as a potential best-in-class ALK therapy."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EML4

Nuvalent to Present Trial in Progress Posters for the ALKAZAR Trial of Neladalkib and HEROEX-1 Trial of NVL-330 at the 2025 American Society of Clinical Oncology Annual Meeting (PRNewswire) - "The first 'Trial in Progress' poster will include background and study design for ALKAZAR (NCT06765109), a global, randomized, controlled Phase 3 trial designed to evaluate neladalkib versus the current standard of care for the treatment of patients with TKI-naïve ALK-positive non-small cell lung cancer (NSCLC)....The company plans to initiate the ALKAZAR trial in the first half of 2025. The second poster will include background and study design for the ongoing HEROEX-1 Phase 1a/1b clinical trial (NCT06521554) evaluating the overall safety and tolerability of NVL-330 for pre-treated patients with HER2-altered NSCLC."

Clinical protocol • Trial status • Non Small Cell Lung Cancer

Nuvalent to Present New Preclinical Data on ALK-Selective Inhibitor, Neladalkib, and ROS1-Selective Inhibitor, Zidesamtinib, at AACR Annual Meeting 2025 (PRNewswire) - "Nuvalent...announced upcoming poster presentations further characterizing the preclinical profiles of its novel ALK-selective inhibitor, neladalkib, and novel ROS1-selective inhibitor, zidesamtinib, at the American Association for Cancer Research (AACR) Annual Meeting 2025 from April 25-30, 2025, in Chicago."

Preclinical • Oncology

Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting. (PubMed, Lung Cancer) - "For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI...For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib...In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib...Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in..."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • ROS1

ALKAZAR: Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Nuvalent Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

NVL-655-EAP: Expanded Access Program of Neladalkib (NVL-655) for Patients with Advanced ALK+ NSCLC (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Nuvalent Inc.

New trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Nuvalent Details Strategy to Seek First Potential Approval in 2026 and Outlines Key Anticipated 2025 Milestones (PRNewswire) - "As part of this plan, Nuvalent anticipates the following 2025 milestones: Report pivotal data for tyrosine kinase inhibitor (TKI) pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) from its ARROS-1 Phase 1/2 trial of zidesamtinib in the first half of 2025; Submit a New Drug Application (NDA) for zidesamtinib with initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC by mid-year 2025; Report pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC from its ALKOVE-1 Phase 1/2 trial of neladalkib (NVL-655) by year-end 2025; Initiate the ALKAZAR Phase 3 randomized, controlled trial of neladalkib for TKI-naïve patients with ALK-positive NSCLC in the first half of 2025; and Progress the HEROEX-1 Phase 1a/1b trial of NVL-330 for patients with advanced HER2-altered NSCLC."

FDA filing • P1/2 data • Trial status • Non Small Cell Lung Cancer

ALKAZAR: NVL-655 for TKI-naive Patients With Advanced ALK-Positive NSCLC (clinicaltrials.gov) - P3 | N=450 | Not yet recruiting | Sponsor: Nuvalent Inc.

New P3 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Novel ALK-Selective TKI Looks Promising Based on Findings From ALKOVE-1 Trial (IASLC Lung Cancer News (ILCN)) - "'NVL-655 was well tolerated at the recommended phase II dose of 150 milligrams daily. Durable responses were observed in a heavily pretreated population, including patients who had [exhibited] disease progression on lorlatinib, as well as those whose cancers harbored single or compound ALK resistance mutations,' Dr. Drilon said. 'Durable intracranial responses were also observed, including central nervous system partial response following prior lorlatinib treatment.'"

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Nuvalent Returns to ALKtALK (YouTube) - "Nuvalent's Christopher Turner, MD...and Viola Zhu MD, PhD...present data on the Phase 1 study of NVL-655."

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Phase 1/2 ALKOVE-1 Study of NVL-655 in ALK-positive (ALK+) Solid Tumors (OncLive) - "Dr. Alexander Drilon presents an update from the Phase 1/2 ALKOVE-1 study, investigating the efficacy and safety of NVL-655, a selective ALK inhibitor, in patients with ALK-positive solid tumors, highlighting durable responses in heavily pre-treated populations, including those with compound ALK resistance mutations and central nervous system involvement."

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Metastatic Lung Adenocarcinoma Resulting in Malignant Gastric Outlet Obstruction (ACG 2024) - "Case Description/ An 81 year old female with stage IV LA on NVL-655, an enterally absorbed chemotherapy agent, presented with an 11 day history of intractable nausea and vomiting...C, H&E stain of duodenal biopsy showing a small cluster of neoplastic cells within the lymphatics. D, TTF-1 stain confirming neoplastic cells were of pulmonary origin."

Metastases • Gastric Cancer • Gastrointestinal Disorder • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor • NKX2-1

MSK Researchers Report Exciting Cancer Research Advances at ESMO Congress 2024 (Memorial Sloan Kettering Cancer Center) - "Thoracic medical oncologist Alexander Drilon, MD, Chief of MSK’s Early Drug Development Service, presented an update of results from the international ALKOVE-1 phase 1/2 study (NCT05384626) evaluating the recommended dose, overall safety, tolerability, and preliminary antitumor activity of NVL-655 for patients with advanced solid tumors harboring an ALK fusion or activating mutation."

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NVL-655 showed encouraging activity in heavily pretreated patients with advanced ALK+ NSCLC, including in those who previously received lorlatinib, according to the phase 1 ALKOVE-1 study. @alexdrilon @MSKCancerCenter @myESMO #ESMO24 #oncology #lcsm

NVL-655 Shows Strong Efficacy in Heavily Pretreated ALK+ NSCLC (OncLive) - "In preclinical studies, NVL-655 had potent activity against ALK-driven cell lines, including in single ALK mutations, compound mutations of 2 or more, and EML4-ALK fusions. Additionally, the agent avoids other targets like TRK, Drilon noted, and has a high level of brain penetrance, which in preclinical data was higher than lorlatinib. Based on a preliminary assessment of findings from the study, the FDA granted the agent a breakthrough therapy designation in May 2024. This designation was for those who received 2 or more prior ALK TKIs."

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NVL-655: 4th-generation, #ALK-selective TKI w/ CNS penetration targeting diverse #ALK-mutant oncoproteins, including lorlatinib-resistant compound mutations. ✅>50-fold selectivity for ALK over 96% of the kinome tested & brain penetrant ✅≥100-fold⬆️ potency against ALK G1202R single & compound mut vs approved ALK TKIs in vitro. ✅ Induced regression across 12 tumor models in vivo. Ongoing

Characterization of NVL-655 in ALK+ lung cancer now out in @CD_AACR from @JessicaJLinMD @alexdrilon and colleagues. @ALKPositiveinc @ALKpositiveINT #LCSM

Phase I/II ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumours (ESMO 2024) - P1/2 | "NVL-655 demonstrated encouraging efficacy & durability in heavily pretreated ALK+ NSCLC pts, including pts who exhausted available therapies (including lorlatinib), with ALK single and compound resistance mutations, and with CNS metastases. Safety was favorable, consistent with the ALK-selective, TRK-sparing design. Ph 2 enrollment is ongoing with registrational intent for previously treated pts."

P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

We are pleased to share this article out today in @CD_AACR on the preclinical development and proof-of-concept clinical activity of NVL-655 ✅4th-generation, #ALK-selective TKI ✅CNS-penetrant ✅Broad coverage of ALK fusions and mutations, including lorlatinib-refractory compound mutations 🔥Fills an important unmet need for pts with ALK+ lung cancer and other solid tumors 📢Tune in for updated...

Nuvalent Announces Publication in Cancer Discovery Detailing Design and Characterization of ALK-selective inhibitor NVL-655 (PRNewswire) - "Nuvalent...announced the publication of a manuscript in Cancer Discovery...The manuscript details the design principles underlying the activity of NVL-655 against ALK single and compound resistance mutations, including the most commonly occurring resistance mutation, ALK G1202R..Preclinical characterization of the activity and selectivity of NVL-655 is presented, including in vivo xenograft studies, preclinical assessments of brain penetrance and intracranial activity, and a comparison of eight ALK TKIs across multiple biochemical and cellular assays....Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, designed with registrational intent."

Enrollment status • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations. (PubMed, Cancer Discov) - "These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Updated ALKOVE-1 Phase 1 Data (PRNewswire) - P1/2 | N=470 | NCT05384626 | Sponsor: Nuvalent Inc. |"Updated Phase 1 data from ALKOVE-1...clinical trial to be presented at the ESMO Congress 2024....As of the data cut-off date of March 23, 2024, 133 patients (131 NSCLC, 2 other) received NVL-655 (15-200 mg orally once daily (QD)) in Phase 1. Patients were heavily pre-treated with a median of 3 (range: 1-8) prior anticancer therapies and included: patients treated with a 2G ALK TKI (alectinib, brigatinib, ceritinib) or the 3G ALK TKI lorlatinib (100%); patients who had received ≥1 2G ALK TKI and the 3G ALK TKI lorlatinib (79%); patients who had received ≥3 prior ALK TKIs (46%); patients who had also received prior chemotherapy (56%); and, patients with a history of treated/untreated CNS metastases (56%). A maximum tolerated dose was not reached."

P1 data • Non Small Cell Lung Cancer

Nuvalent Highlights Pipeline Progress, Reiterates Key Anticipated Milestones, and Reports Second Quarter 2024 Financial Results (PRNewswire) - "Enrollment is ongoing in the HEROEX-1 Phase 1a/1b clinical trial evaluating NVL-330 for pre-treated patients with HER2-altered NSCLC (NCT06521554)...2024: Execute on Global Registrational Strategies: Progress the Phase 2 portion of its ARROS-1 trial of zidesamtinib in patients with advanced ROS1-positive NSCLC with registrational intent; Initiate the Phase 2 portion of its ALKOVE-1 trial of NVL-655 in patients with advanced ALK-positive NSCLC with registrational intent; Launch the front-line development strategy for its ALK program; Initiate the Phase 1 trial for its HER2 program. Present interim data from its ongoing ARROS-1 and ALKOVE-1 clinical trials at medical meetings; and, 2025: First Pivotal Data: 2026: First Approved Product."

Clinical data • Enrollment status • New P1 trial • P1/2 data • Trial status • Non Small Cell Lung Cancer • HER-2

Nuvalent to Present Updated Data for ROS1-Selective Inhibitor, Zidesamtinib, and ALK-Selective Inhibitor, NVL-655, at the ESMO Congress 2024 (PRNewswire) - "Nuvalent...announced that updated data from the ARROS-1 Phase 1/2 clinical trial of zidesamtinib and ALKOVE-1 Phase 1/2 clinical trial of NVL-655, will be presented during two oral presentations at the European Society for Medical Oncology (ESMO) Congress 2024 taking place September 13-17, 2024, in Barcelona, Spain....Additionally, the company will present new preclinical data further characterizing the intracranial activity of zidesamtinib during a poster session."

P1/2 data • Preclinical • Non Small Cell Lung Cancer