Nuvalent Showcases ESMO 2024 Clinical Data for ROS1 and ALK-positive NSCLC Programs and Fast-Track Development

Nuvalent, Inc., a biopharmaceutical company specializing in targeted cancer therapies, recently showcased updated data from its ARROS-1 and ALKOVE-1 Phase 1 trials at the ESMO Congress 2024 in Barcelona, Spain. These trials involve the investigational drugs zidesamtinib and NVL-655, respectively. Zidesamtinib is a ROS1-selective inhibitor, while NVL-655 targets ALK. Both drugs have shown potential best-in-class profiles, particularly for patients with advanced non-small cell lung cancer (NSCLC) who are either treatment-naïve or pre-treated with tyrosine kinase inhibitors (TKIs).

The ARROS-1 trial focuses on zidesamtinib for patients with advanced ROS1-positive NSCLC and other solid tumors. Between September 2023 and September 2024, 227 patients were enrolled in the Phase 2 portion of this single-arm, multi-cohort trial. The primary objective is to gather data that could support regulatory approval. Nuvalent expects to release pivotal data from this trial in 2025.

The ALKOVE-1 trial involves NVL-655 for patients with advanced ALK-positive NSCLC and other solid tumors. From February to September 2024, 229 patients were enrolled in its Phase 2 portion. Like the ARROS-1 trial, this study aims to generate registrational data, with key results anticipated in 2025.

Nuvalent also revealed plans to initiate the ALKAZAR Phase 3 trial of NVL-655 in the first half of 2025. This global, randomized, controlled trial will compare NVL-655 against alectinib (ALECENSA®) in treatment-naïve patients with advanced ALK-positive NSCLC. The trial will enroll approximately 450 patients, with the primary endpoint being progression-free survival based on Blinded Independent Central Review (BICR). Secondary endpoints include overall survival, intracranial objective response rate, and safety.

Dr. Christopher Turner, Nuvalent's Chief Medical Officer, emphasized that the Phase 1 data from ARROS-1 and ALKOVE-1 trials establish a preliminary proof-of-concept for both zidesamtinib and NVL-655. The drugs are designed to penetrate the brain and spare the TRK pathways, offering a favorable safety profile and durable responses across different patient subsets. Turner highlighted the potential of these drugs to fill unmet medical needs in third-line therapy where no approved treatments currently exist, and even in second-line settings for patients with CNS metastases or resistance mutations.

Darlene Noci, Chief Development Officer at Nuvalent, noted the accelerated enrollment in the Phase 2 portions of both trials, which underscores the high level of investigator enthusiasm. Nuvalent aims to report pivotal datasets from these trials in 2025.

The ALKAZAR trial aims to set a new standard for TKI-naïve patients with advanced ALK-positive NSCLC. Its design benefits from input from physician-scientists and aligns with the U.S. FDA recommendations. Nuvalent's CEO, Dr. James Porter, expressed pride in the company's achievements and optimism for the future. He pointed to the foundation of encouraging Phase 1 data, strong enrollment in Phase 2 trials, and FDA alignment as factors that will help advance their programs efficiently.

From January 2022 to August 2023, the Phase 1 portion of the ARROS-1 trial enrolled 104 patients, predominantly with NSCLC. Patients received zidesamtinib at doses ranging from 25 to 150 mg once daily, with 100 mg identified as the recommended Phase 2 dose. The heavily pre-treated patient population had a median of three prior lines of therapy. Zidesamtinib showed durable clinical responses, particularly among patients with the ROS1 G2032R resistance mutation and those with CNS metastases. The drug was well-tolerated, with the most common adverse events being peripheral edema, ALT and AST increase, and weight gain.

Similarly, the Phase 1 portion of the ALKOVE-1 trial enrolled 133 patients, mostly with NSCLC, from June 2022 to February 2024. NVL-655 was administered at doses ranging from 15 to 200 mg once daily, with 150 mg established as the Phase 2 dose. This heavily pre-treated group had a median of three prior therapies. NVL-655 demonstrated durable responses, including complete intracranial responses in patients with CNS lesions. The drug was well-tolerated, with the most frequent adverse events being ALT and AST increases, constipation, dysgeusia, and nausea.

In summary, Nuvalent's targeted therapies, zidesamtinib and NVL-655, show promising clinical profiles for treating advanced NSCLC, particularly in patients who have exhausted other treatment options. With pivotal data expected in 2025, the company is well-positioned to advance these therapies through the clinical development pipeline.