On January 13, 2025 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported pipeline progress and outlined key anticipated milestones towards its first potential U.S. Food and Drug Administration (FDA) approval under its "OnTarget 2026" operating plan (Filing, 8-K, Nuvalent, JAN 14, 2025, View Source [SID1234649711]).

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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.

With the achievement of these milestones, the company anticipates that the first potential approval from its pipeline of novel kinase inhibitors will be for zidesamtinib for the treatment of TKI pre-treated ROS1-positive NSCLC in 2026.

"2025 marks our opportunity to transition to becoming a fully integrated commercial-stage biopharmaceutical company. Throughout this period of growth and evolution, our strategy remains rooted in our commitment to our core value of Patient Impact, and our responsibility to the patients and treating physicians who continue to support our clinical trials," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "Enrollment momentum in the Phase 2 portions of our ARROS-1 and ALKOVE-1 clinical trials has further accelerated following our presentation of updated Phase 1 data at ESMO (Free ESMO Whitepaper) 2024, reinforcing our plan to report pivotal data from both programs this year. We believe this enthusiasm is a clear demonstration of the medical need for patients with ROS1- and ALK-positive NSCLC, and of our responsibility to bring new treatment options to TKI pre-treated patients as quickly as possible."

"Parallel development paths are in place towards our ultimate goal to provide new, potential best-in-class treatment options to all patients with ROS1- or ALK-positive NSCLC," said Darlene Noci, A.L.M., Chief Development Officer at Nuvalent. "For zidesamtinib, we plan to submit an NDA this year with an initial target indication for TKI pre-treated patients with ROS1-positive NSCLC, where we believe zidesamtinib has demonstrated the potential to address a medical need. We expect to report topline pivotal data from this population in the first half of 2025. In parallel, we continue a collaborative dialogue with the FDA on accelerated opportunities towards a potential line-agnostic indication supported by our ongoing TKI-naïve cohort in the Phase 2 portion of our ARROS-1 trial."

Ms. Noci continued, "Similarly for neladalkib, we expect our initial NDA submission to be for TKI pre-treated patients with ALK-positive NSCLC, supported by topline pivotal data from the ALKOVE-1 trial that we expect to report by year-end 2025. Additionally, we remain on-track to initiate the Phase 3 randomized, controlled ALKAZAR trial for TKI-naïve patients in the first half of this year, a critical step towards our ultimate goal of moving neladalkib up the treatment paradigm."

"We believe we have the right team in place and are well resourced with cash runway into 2028 to support the advancement of our clinical programs and ongoing buildout of a commercial infrastructure," said Alexandra Balcom, Chief Financial Officer at Nuvalent. "Beyond our parallel-lead programs, we remain committed to advancement of our HEROEX-1 Phase 1a/1b trial and robust discovery pipeline for sustainable long-term growth."

Enrollment Updates for ARROS-1 and ALKOVE-1

ARROS-1 for ROS1-positive NSCLC

•As of December 31, 2024, a total of 430 Phase 1 and Phase 2 patients had been enrolled in the ongoing ARROS-1 Phase 1/2 trial of zidesamtinib for patients with advanced ROS1-positive NSCLC and other solid tumors, which is designed with registrational intent for TKI pre-treated and TKI-naïve patients with advanced ROS1-positive NSCLC. Updated Phase 1 data were presented in September 2024 at the ESMO (Free ESMO Whitepaper) Congress.

ALKOVE-1 for ALK-positive NSCLC

•As of December 31, 2024, a total of 596 Phase 1 and Phase 2 patients had been enrolled in the ongoing ALKOVE-1 Phase 1/2 trial of neladalkib for patients with advanced ALK-positive NSCLC and other solid tumors, which is designed with registrational intent for TKI pre-treated patients. Updated Phase 1 data were presented in September 2024 at the ESMO (Free ESMO Whitepaper) Congress.

Presentation at 43rd Annual J.P. Morgan Healthcare Conference

Dr. Porter will present at the 43rd Annual J.P. Morgan Healthcare Conference in San Francisco on Tuesday, January 14, 2025 at 9:00 a.m. PT. A live webcast will be available in the Investors section of Nuvalent’s website at www.nuvalent.com, and will be archived for 30 days following the conference.

About Zidesamtinib

Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.

About Neladalkib (NVL-655)

Neladalkib is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. Neladalkib is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, neladalkib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. Neladalkib has received breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

About NVL-330

NVL-330 is a novel brain-penetrant HER2-selective tyrosine kinase inhibitor designed to address the combined medical need of treating HER2-mutant tumors, including those with HER2 exon 20 insertion mutations, avoiding treatment related adverse events due to off-target inhibition of wild-type EGFR, and treating brain metastases.