NVL-520 Earns FDA Breakthrough Therapy Designation in ROS1+ NSCLC

Supporting data for the breakthrough therapy designation came from the phase 1 portion of the phase 1/2 ARROS-1 trial (NCT05118789) assessing NVL-520 in patients with ROS1-positive NSCLC and other solid tumors.

The FDA has granted breakthrough therapy designation to NVL-520 as a treatment for patients with ROS1-positive metastatic non–small cell lung cancer (NSCLC) who received prior treatment with at least 2 ROS1 tyrosine kinase inhibitors (TKIs), according to a press release from Nuvalent, the developers of NVL-520.¹

Supporting data for the breakthrough therapy designation came from the phase 1 portion of the phase 1/2 ARROS-1 trial (NCT05118789) assessing NVL-520 in patients with ROS1-positive NSCLC and other solid tumors.

With a cutoff of September 1, 2022, preliminary data highlighted that NVL-520 elicited partial responses in 48% (n = 10/21) of evaluable patients with NSCLC.² Additionally, the objective response rate (ORR) was 78% (n = 7/9) among those with ROS1 G2032R mutations, 73% (n = 8/11) in those with prior central nervous system (CNS) metastases, and 53% (n = 9/17) among those who received at least 2 prior lines of ROS1 TKIs and 1 or more lines of chemotherapy. The ORR for patients who received prior treatment with lorlatinib (Lorbrena) or repotrectinib (Augtyro) was 50% (n = 9/18).

“Currently approved and investigational ROS1 TKIs are important treatment options for advanced ROS1 fusion-positive cancers. However, these drugs can have key limitations. These include the inability to treat on-target resistance and brain metastases effectively, and an association with neurologic [AEs],” study investigator Alexander Drilon, MD, chief of Early Drug Development Service at Memorial Sloan Kettering Cancer Center, said in a press release on these findings.²

“These preliminary data support NVL-520 as a potential best-in-class ROS1-selective inhibitor that may combine, for the first time, potent and selective targeting of diverse ROS1 fusions and secondary ROS1 resistance mutations including G2032R, brain penetrance, and the avoidance of TRK inhibition that can be dose limiting.”

Investigators reported that 76% (n = 16/21) of evaluable patients remained on study treatment at the time of the data cutoff. Additionally, there were no dose-limiting toxicities, treatment-related serious adverse effects (SAEs), treatment-emergent dizziness, or AEs resulting in dose reductions or treatment discontinuation at the time of the analysis.

In the phase 1 portion of the ARROS-1 trial, patients received oral NVL-520 at 5 dose levels ranging from 25 mg once a day to 125 mg once a day.

The trial’s primary end points include the maximum tolerated dose and recommended phase 2 dose (RP2D) in phase 1 and ORR per blinded independent central review (BICR) in phase 2. Secondary end points include treatment-emergent AEs, duration of response, clinical benefit rate, time to response, progression-free survival, overall survival, and rate of CNS progression.

“In line with our commitment to bringing new potential best-in-class medicines to patients with cancer as quickly as possible, we are always looking for opportunities to further accelerate our programs,” James Porter, PhD, chief executive officer at Nuvalent, said in the press release.¹ “We’re very encouraged by today’s announcement of FDA breakthrough therapy designation for NVL-520, as it recognizes the continued need for innovation for patients with ROS1-positive NSCLC who have [no] available therapies.”

Developers announced that they initiated the phase 2 portion of the ARROS-1 trial in September 2023.³ The trial was set to proceed with a RP2D of 100 mg once a day.

“With the advancement of the first of our parallel lead programs into a phase 2 trial with registrational intent, the Nuvalent team demonstrates its continued ability to scale while maintaining ambitious timelines towards our goal of delivering precisely targeted therapies to patients with cancer,” Porter said in a press release at the time of the initiation of the phase 2 portion.³ “We look forward to providing an update from the ARROS-1 trial at a medical meeting in 2024.”

References

1. Nuvalent receives U.S. FDA breakthrough therapy designation for NVL-520. News release. Nuvalent, Inc. February 27, 2024. Accessed February 28, 2024. http://tinyurl.com/5dsfu6au
2. Nuvalent reports preliminary phase 1 clinical data from ARROS-1 trial that support best-in-class potential of NVL-520 for patients with ROS1-positive NSCLC. News release. Nuvalent, Inc. October 28, 2022. Accessed February 28, 2024. http://tinyurl.com/pw6wchp8
3. Nuvalent initiates the phase 2 portion of ARROS-1 clinical trial for patients with ROS1-positive NSCLC and other solid tumors. News release. Nuvalent, Inc. September 5, 2023. Accessed February 28, 2024. http://tinyurl.com/9bnh6ab4