NVL-520 Demonstrates Preliminary Clinical Activity in ROS1-Positive NSCLC

Alexander Drilon, MD

The novel brain-penetrant ROS1-selective inhibitor NVL-520 elicited clinical activity and was well tolerated in heavily pretreated patients with ROS1 fusion–positive non–small cell lung cancer (NCSLC), according to data from the dose-escalation portion of the ongoing phase 1/2 ARROS-1 trial (NCT05118789).

The objective response rate (ORR) was 48% among 21 patients with NSCLC harboring ROS1 fusions evaluable for response. All 10 responders had a partial response. Additionally, patients with ROS1 G2032R mutations (n = 9) experienced an ORR of 78%, and those with a history of central nervous system (CNS) metastases (n = 11) achieved an ORR of 73%.

Furthermore, patients who received 2 or more prior ROS1 TKIs and 1 or more prior line of chemotherapy (n = 17) had an ORR of 53%. Patients who were previously treated with lorlatinib (Lorbrena) or repotrectinib (n = 18) experienced an ORR of 50%.

“Currently approved and investigational ROS1 TKIs are important treatment options for advanced ROS1fusion-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 adverse events,” Alexander Drilon, MD, chief of Early Drug Development Service at Memorial Sloan Kettering Cancer Center and presenting investigator of the ARROS-1 trial, stated in a press release.

“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.”

ARROS-1 is a first-in-human study of NVL-520 in patients with advanced ROS1 fusion–positive NSCLC and other solid tumors. The dose-escalation portion of the trial is enrolling patients with NSCLC harboring ROS1fusions who have previously received at least 1 ROS1 TKI, or patients with other previously treated ROS1fusion–positive solid tumors.

Patients were treated in 5 dose cohorts of 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg of NVL-520 once daily. The co-primary end points of the study are dose-limiting toxicities, establishing the recommended phase 2 dose (RP2D), and ORR. Secondary end points include duration of response, progression-free survival, overall survival, pharmacokinetics, pharmacodynamics, and safety.

Among the 35 patients enrolled on the trial as of September 1, 2022, 34 had ROS1 fusion–positive NSCLC, and 51% had a history of CNS metastases. Additionally, 77% of patients had received 3 or more prior lines of anti-cancer therapy, 71% had received 2 or more prior ROS1 TKIs and 1 or more lines of chemotherapy, and 80% had received a ROS1 TKI other than crizotinib (Xalkori) or entrectinib (Rozlytrek), including lorlatinib (57%) or repotrectinib (34%).

Regarding safety, investigators observed no DLTs, treatment-related serious adverse effects (AEs), no treatment-related dizziness, and no AEs leading to dose reduction or discontinuation of NVL-520 through the preliminary data cutoff date. Most treatment-related AEs were low-grade and manageable.

Notably, the favorable preliminary safety profile allowed for exposure levels well above target thresholds for both ROS1 and ROS1 resistance variants in both the CNS and the periphery.

A maximum tolerated dose has not been reached. The phase 1 trial to determine the RP2D is ongoing. As of the preliminary data cut-off date, 76% of response-evaluable patients remained on NVL-520 treatment.

“We are excited to present the first look at the safety and clinical activity of NVL-520 from our ARROS-1 clinical trial, which we believe supports NVL-520 as a potential best-in-class ROS1-selective inhibitor that may be capable of overcoming the limitations of current approved and investigational ROS1 TKIs,” Christopher Turner, MD, chief medical officer of Nuvalent, said.

“Across all evaluated dose levels, NVL-520 exhibited activity in a heavily pre-treated patient population, many of whom have exhausted all available treatment options and would have been excluded from other investigational ROS1 TKI studies. Importantly, the favorable safety profile and lack of dose reductions or discontinuations due to adverse events reflected in this preliminary data suggest that NVL-520 has the potential to provide deep and durable responses and may be able to move up in the treatment paradigm for patients with ROS1-driven cancers.”

Reference

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. October 28, 2022. Accessed October 28, 2022. https://bit.ly/3DC5dHl