Nuvalent’s NVL-655 and Zidesamtinib Data Highlight Best-in-Class Potential

Nuvalent, Inc., a clinical-stage biopharmaceutical company, has announced updates on its ALKOVE-1 and ARROS-1 clinical trials, which will be presented at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain. These presentations will focus on the Phase 1 data for the ALK-selective inhibitor NVL-655 and the ROS1-selective inhibitor zidesamtinib, along with new preclinical data on the intracranial activity of zidesamtinib.

The ALKOVE-1 clinical trial is investigating the use of NVL-655 in ALK-positive solid tumors. NVL-655 is a brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to overcome limitations of previous ALK TKIs, such as resistance mutations and brain metastases. The Phase 1 portion of the trial enrolled 133 patients, including those who had been heavily pre-treated with a median of three prior anticancer therapies. The trial aimed to determine the recommended Phase 2 dose (RP2D), safety, and efficacy of NVL-655.

Results from the trial indicated that NVL-655 demonstrated promising efficacy and durability, especially in patients who had exhausted other treatment options and those with CNS metastases. The RP2D was determined to be 150 mg QD, with the most common treatment-related adverse events (TRAEs) being increases in ALT and AST, constipation, nausea, and dysgeusia. Importantly, CNS activity, including the complete resolution of CNS metastases in lorlatinib-experienced patients, was observed.

The ARROS-1 clinical trial focuses on zidesamtinib (NVL-520), a brain-penetrant, ROS1-selective TKI for ROS1-positive solid tumors. Zidesamtinib aims to address resistance mutations and brain metastases that limit the effectiveness of existing ROS1 inhibitors. The Phase 1 portion of the trial enrolled 104 patients, who had been heavily pre-treated with a median of three prior anticancer therapies. The key objectives were to determine the RP2D and evaluate safety and efficacy.

Results showed that zidesamtinib demonstrated encouraging efficacy and durability, particularly in patients with ROS1 resistance mutations and CNS metastases. The RP2D was set at 100 mg QD, with no dose-limiting toxicity observed. The most common TRAEs were peripheral edema and transaminase increase. Among response-evaluable patients, zidesamtinib showed a significant objective response rate (ORR), particularly in those with known ROS1 G2032R mutations and measurable intracranial metastases.

In addition to clinical data, Nuvalent also presented preclinical findings on the intracranial activity of zidesamtinib compared to other ROS1 inhibitors. The study involved a preclinical ROS1 G2032R brain tumor model and demonstrated that zidesamtinib had more durable intracranial activity at clinically relevant plasma concentrations compared to repotrectinib and taletrectinib. These findings support the potential of zidesamtinib as a best-in-class ROS1-selective therapy, particularly for patients with brain metastases.

Overall, the updated data from the ALKOVE-1 and ARROS-1 trials support the ongoing Phase 2 investigations of NVL-655 and zidesamtinib for treating ALK-positive and ROS1-positive non-small cell lung cancer (NSCLC). The promising results indicate that these therapies could offer meaningful improvements over existing treatments, especially for patients who have exhausted other options or have CNS metastases.

Nuvalent plans to host a conference call on September 14, 2024, following the ESMO presentations to discuss these findings and provide further updates on their clinical programs.