neladalkib (NVL-655) / Nuvalent - LARVOL DELTA

Nuvalent Announces Positive Topline Pivotal Data from ALKOVE-1 Clinical Trial of Neladalkib for TKI Pre-treated Patients with Advanced ALK-positive NSCLC (PRNewswire) - "In 253 ALK TKI pre-treated patients, ORR by BICR was 31% (95% CI: 26, 37), with initial estimated durability of response of 64% and 53% at the 12-month and 18-month landmarks, respectively. In the subset of 63 TKI pre-treated patients who were lorlatinib-naïve, ORR by BICR was 46% (95% CI: 33, 59), with initial estimated durability of response of 80% and 60% at the 12- and 18-month landmarks, respectively....Company plans to discuss pivotal data for the TKI pre-treated ALK-positive NSCLC population with the FDA at a pre-NDA meeting; detailed study results are planned for presentation at a future medical meeting."

P1/2 data • Non Small Cell Lung Cancer

Nuvalent…announced that the company will host a webcast and conference call on Monday, November 17, 2025 at 8:00 a.m. ET, to discuss topline pivotal data for neladalkib, an investigational ALK-selective inhibitor, in TKI pre-treated patients with advanced ALK-positive non-small cell lung cancer from the global ALKOVE-1 Phase 1/2 clinical trial (PRNewswire)

P1/2 data • Non Small Cell Lung Cancer

ALK.CAR-T Cells as a New Potential Treatment for ALK+ Merkel Cell Carcinoma (SITC 2025) - P1/2 | "(B) ALK and GD2 expression by FACS (C) MCC cell lines (ALK IHC) (D) Killing assay (E) Killing assay (neladalkib N or lorlatinib L). (B) Kaplan-Meier survival analysis (relative to A) (C) MKL1 tumor progression. (D) Kaplan-Meier survival analysis (relative to C)"

CAR T-Cell Therapy • IO biomarker • Endocrine Cancer • Merkel Cell Carcinoma • Neuroblastoma • Neuroendocrine Tumor • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • ALK • GZMB • IFNG

Successful and On-going Long-Term Disease Control (>24 Months) with Gilteritinib in an ALK+ NSCLC Patient with Brain Metastasis Who Has Progressed on Multiple ALK TKIs. A Case Report and Review of Literature on Gilteritnib. (PubMed, Lung Cancer (Auckl)) - P1 | "Despite the approval to date of 3 generations of ALK tyrosine kinase inhibitors (TKIs) and the clinical development of a 4th-generation ALK TKI, neladalkib (NVL-655), patients still eventually progress on sequential treatment of various generations of ALK TKIs...Since then, she has been treated with multiple ALK TKIs including crizotinib, alectinib, brigatinib, and lorlatinib sequentially (from age 75 to 80) but requiring dose reduction and interruption of lorlatinib due to neurocognitive toxicity from previous stereotactic brain radiation and resection and eventual discontinuation of lorlatinib...This is the first patient case report with >24 months on-going follow-up demonstrating that gilteritinib could be repurposed as a potent and tolerable ALK inhibitor based on previously reported pre-clinical activity and with potential CNS activity. A Phase 2 trial of gilteritnib in alectinib- or lorlatinib-refractory ALK+ NSCLC is being planned (NCT07140016)."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AXL • EML4 • ROS1

Neladalkib (NVL-655) efficacy and safety in patients with ALK-positive solid tumors in the ALKOVE-1 study (ESMO 2025) - P1/2 | "CNS activity, including complete resolution of CNS mets, in alectinib- and lorlatinib-pretreated pts was observed. Safety was consistent with its ALK-selective, TRK-sparing design. Enrollment is ongoing."

Clinical • Colorectal Cancer • Genito-urinary Cancer • Lung Adenocarcinoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Peritoneal Mesothelioma • Renal Cell Carcinoma • Sarcoma • Solid Tumor • ALK

Evaluation of neladalkib is ongoing in the ALKOVE-1 Phase 1/2 trial for patients with advanced ALK-positive NSCLC and other solid tumors: (Financial Times) - "The company is on track to report topline pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC by year-end 2025."

P1/2 data • Non Small Cell Lung Cancer

Enrollment is ongoing in ALKAZAR, the company’s global Phase 3 randomized, controlled trial designed to evaluate neladalkib for the treatment of patients with TKI-naïve ALK-positive NSCLC. (Financial Times)

Enrollment status • Non Small Cell Lung Cancer

Enrollment is ongoing in the global Phase 2 cohort of the ALKOVE-1 trial for adult and adolescent patients with advanced ALK-positive solid tumors other than NSCLC. (PRNewswire) - "The company remains on track to report topline data for patients with TKI pre-treated ALK-positive NSCLC from the ALKOVE-1 trial by the end of 2025."

Enrollment status • P1 data • Non Small Cell Lung Cancer

Nuvalent, Inc…announced preliminary data from the ongoing ALKOVE-1 Phase 1/2 clinical trial of neladalkib, an investigational ALK-selective inhibitor, in patients with advanced ALK-positive solid tumors outside of non-small cell lung cancer (NSCLC). (PRNewswire) - "Among all patients with advanced ALK-positive solid tumors treated with neladalkib, an objective response rate of 44% (15/34) was observed, including 9/13 patients who were ALK TKI-naïve and 6/21 who were ALK TKI pre-treated. 80% (12/15) of responders remained on treatment without disease progression as of the data cutoff date...Enrollment is ongoing in the global Phase 2 cohort of the ALKOVE-1 trial for adult and adolescent patients with advanced ALK-positive solid tumors other than NSCLC."

P1 data • Trial status • Peritoneal Mesothelioma • Solid Tumor

Preclinical Prediction of Resistance Mutations and Proposal of Sequential Treatment Strategies for ALK-positive Lung Cancer Using Next-generation ALK Inhibitors. (PubMed, Pharm Res) - "• A PCR-based mutation prediction system was successfully applied to fourth-generation ALK inhibitors. • Neladalkib showed efficacy against G1202R-positive relapses with minimal evidence of secondary resistance mutations. • Sequential combinations of gilteritinib with either neladalkib or ensartinib may sustain efficacy and delay resistance in I1171N-positive relapses."

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

Optimizing Treatment Sequencing to Maximize Survival in ALK+ Advanced Non-Small Cell Lung Cancer: A Modeling Study (IASLC-WCLC 2025) - "Additional ALKis, such as NVL-655 is under investigation...Results : 1L lorlatinib sequences yielded the longest PFS overall, with ~5 years of additional PFS vs 1L therapy with alectinib or brigatinib (Table and Figure)...Conclusions : Based on current evidence and modeling assumptions, initial treatment with 1L lorlatinib may yield the longest PFS vs 2nd gen TKIs, regardless of types of subsequent treatments. This highlights the importance of initiation of 1L treatment with the longest demonstrated PFS upfront."

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

DYNAMALK: DYNAMic ct-DNA in ALK+ NSCLC Under the Australasian Thoracic Cancers Longitudinal Cohort Biobank Study (AURORA) (IASLC-WCLC 2025) - P | "In Arm B, 15/20 (75%) received Lorlatinib, 5/20 (25%) Neladalkib. Longer term follow up will provided information on molecular evolution of ALK-rearranged NSCLC, receiving next-generation and novel therapeutic sequencing and may help inform treatment personalisation. Acknowledge-funders - LFA, TOGA, ALK+, RCA, Pfizer, G360"

Circulating tumor DNA • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • ALK • EGFR • MET • MYC • PTEN • RB1 • TP53

ALKAZAR: Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC (clinicaltrials.gov) - P3 | N=450 | Recruiting | Sponsor: Nuvalent Inc. | Initiation date: Mar 2025 ➔ Jul 2025

Trial initiation date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Nuvalent Highlights Pipeline and Business Achievements, Reiterates Key Anticipated Milestones, and Reports Second Quarter 2025 Financial Results (PRNewswire) - "Evaluation of neladalkib is ongoing in the ALKOVE-1 Phase 1/2 trial for patients with advanced ALK-positive NSCLC and other solid tumors: The company expects to report pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC by year-end 2025. The company will present preliminary data from the Phase 2 exploratory cohort for patients with ALK-positive solid tumors beyond NSCLC during a poster presentation at the European Society for Medical Oncology (ESMO) Congress 2025, taking place October 17-21, 2025, in Berlin, Germany."

P1/2 data • P2 data • Non Small Cell Lung Cancer

Prediction of potential drug-resistant ALK mutations against fourth-generation inhibitors NVL-655 and TPX-0131. (PubMed, Int J Biol Macromol) - "Specifically, V1180W, M1199W, and L1256S are the common mutations with decreased binding free energy concerning both inhibitors. These findings highlight important residues and mutations that may impact the clinical efficacy of NVL-655 and TPX-0131, and this pipeline provides an efficient and accurate framework to predict drug-resistant mutations and facilitate the rational design of next-generation ALK inhibitors."

Journal • Oncology • ALK

A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1) (clinicaltrials.gov) - P1/2 | N=840 | Recruiting | Sponsor: Nuvalent Inc. | N=470 ➔ 840 | Trial completion date: Mar 2026 ➔ Jan 2028 | Trial primary completion date: Feb 2026 ➔ Dec 2027

Enrollment change • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK

Nuvalent Announces Initiation of ALKAZAR Phase 3 Randomized, Controlled Trial Evaluating Neladalkib for Patients with TKI-naïve ALK-positive NSCLC (PRNewswire) - "Nuvalent...announced that the first patient has been dosed in ALKAZAR, the company's global Phase 3 randomized, controlled trial evaluating neladalkib for TKI-naïve patients with advanced ALK-positive non-small cell lung cancer (NSCLC), versus ALECENSA (alectinib), a front-line standard of care....The ALKAZAR trial is designed to enroll approximately 450 TKI-naïve patients with advanced ALK-positive NSCLC. Patients will be randomized 1:1 to receive neladalkib monotherapy or alectinib monotherapy, reflecting input from collaborating physician-scientists and alignment with global regulatory agencies. The primary endpoint is progression free survival (PFS) based on Blinded Independent Central Review (BICR)....The company expects to report topline pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC from the Phase 2 portion of ALKOVE-1 by year-end 2025."

P2 data • Trial status • Non Small Cell Lung Cancer

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 | "Additional analyses will be conducted to investigate candidate biomarkers and molecular mechanisms of response and resistance to neladalkib and alectinib. The study is open to accrual."

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

Nuvalent Outlines Recent Pipeline and Business Progress, Reiterates Key Anticipated Milestones, and Reports First Quarter 2025 Financial Results (PRNewswire) - "Evaluation of neladalkib, its novel ALK-selective inhibitor, is ongoing in the ALKOVE-1 Phase 1/2 trial for patients with advanced ALK-positive NSCLC and other solid tumors. The company expects to report pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC and other solid tumors by year-end 2025."

P1/2 data • Non Small Cell Lung Cancer

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