Zidesamtinib May Yield Meaningful Outcomes in Advanced ROS1+ NSCLC

"These data demonstrate the potential for zidesamtinib to deliver meaningful clinical outcomes for TKI pre-treated patients, including those progressing with brain metastases or treatment-emergent resistance mutations, and to offer a favorable tolerability profile consistent with its goal of avoiding off-target [adverse] effects through ROS1-selectivity," according to study investigator Alexander Drilon, MD.

Treatment with zidesamtinib (NVL-520) demonstrated responses and clinical activity across subsets of patients with advanced ROS1-positive non–small cell lung cancer (NSCLC) who previously received tyrosine kinase inhibitors (TKIs), according to a press release on findings from the phase 1/2 ARROS-1 trial (NCT05118789).¹

Among 117 patients with TKI-pretreated disease who received the recommended phase 2 dose (RP2D) of 100 mg once daily, the objective response rate (ORR) was 44% (95% CI, 34%-53%). Regarding duration of response (DOR), 84% (95% CI, 71%-92%), 78% (95% CI, 62%-88%), and 62% (95% CI, 28%-84%) of patients experienced responses lasting for at least 6 months, 12 months, and 18 months, respectively. Among those with G2032R-mutated disease (n = 26), the ORR was 54% (95% CI, 33%-73%), with responses for at least 6 months and 12 months observed in 79% (95% CI, 47%-93%) and 60% (95% CI, 28%-81%) of responders, respectively.

In 55 patients who received 1 prior ROS1 TKI with or without chemotherapy, zidesamtinib yielded an ORR of 51% (95% CI, 37%-65%). Responses were sustained from at least 6 to 18 months in 93% (95% CI, 74%-98%) of responders. Of those with G2032R mutations in this subset (n = 6), the ORR was 80% (95% CI, 36%-100%), with 80% (95% CI, 20%-97%) of responses sustained for at least 6 months and 12 months.

Of 56 patients with measurable central nervous system (CNS) lesions at baseline, the intracranial ORR (IC-ORR) was 48%, with 71% (95% CI, 46%-87%) of these responses lasting for a minimum of 12 months. In those who received prior crizotinib (Xalkori) with or without chemotherapy (n = 13), the IC-ORR was 85%, which included 54% (n = 7/13) with intracranial complete responses (CRs).

Among 35 patients without prior TKI therapy, the preliminary ORR was 89% (n = 31/35), with responses lasting anywhere from 1.9+ to 13.9+ months. A DOR of at least 6 months and 12 months was noted in 96% (95% CI, 76%-99%) of those with responses. Among 6 with measurable intracranial lesions, the IC-ORR was 83% (n = 5/6), with an intracranial CR rate of 67% (n = 4/6).

“Continued innovation for patients with ROS1-positive NSCLC is needed. Limitations of currently available ROS1 TKIs can lead to trade-offs between efficacy and tolerability in the front line, and there is no clear targeted therapy care standard for TKI pre-treated patients,” trial investigator Alexander Drilon, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, stated in the press release.¹ “These data demonstrate the potential for zidesamtinib to deliver meaningful clinical outcomes for TKI pre-treated patients, including those progressing with brain metastases or treatment-emergent resistance mutations, and to offer a favorable tolerability profile consistent with its goal of avoiding off-target [adverse] effects through ROS1-selectivity.”

According to the press release, developers have completed a pre-new drug application (NDA) meeting with the FDA regarding an application submission for zidesamtinib as a treatment for patients with locally advanced or metastatic ROS1-positive NSCLC. As part of the Real-Time Oncology Review pilot program, developers anticipate launching a rolling NDA submission in July 2025 and look to complete the application process in the third quarter of 2025.

Investigators of the first-in-human phase 1/2 ARROS-1 trial are evaluating zidesamtinib as a treatment for patients with advanced ROS1-positive NSCLC and other solid tumors. With a data cutoff of March 21, 2025, 514 patients with ROS1-positive solid tumors received zidesamtinib at any starting dose across the phase 1 and 2 portions; 432 patients with ROS1-positive NSCLC received the agent at the RP2D.

Patients 18 years and older with histologically or cytologically confirmed locally advanced or metastatic NSCLC harboring ROS1 rearrangements and adequate baseline organ function were eligible for enrollment in cohorts 2a, 2b, 2c, and 2d of the ARROS-1 trial.²

Among patients with ROS1-positive NSCLC who received zidesamtinib at the RP2D, the most common treatment-emergent adverse effects (TEAEs) included peripheral edema (36%), constipation (17%), blood CPK increase (16%), fatigue (16%), and dyspnea (15%). Additionally, 10% of patients required dose reductions following TEAEs, and 2% discontinued therapy due to TEAEs.

“Ongoing research and efforts to develop more effective, targeted therapies for people living with ROS1-positive lung cancer align closely with our mission at The ROS1ders,” Janet Freeman-Daily, co-founder and president of The ROS1ders, stated in the press release.¹ “Today's announcement brings renewed hope to our community—for more options and the potential for more precious time with our loved ones.”

References

1. Nuvalent announces positive pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC. News release. Nuvalent, Inc. June 24, 2025. Accessed June 24, 2025. https://tinyurl.com/4xbnacf9
2. A study of NVL-520 in patients with advanced NSCLC and other solid tumors harboring ROS1 rearrangement (ARROS-1). ClinicalTrials.gov. Updated March 7, 2025. Accessed June 24, 2025. https://tinyurl.com/5ek2dbrf