Zidesamtinib Produces Durable Responses in TKI-Pretreated, ROS1+ NSCLC

ROS1+ NSCLC | Image by
Ashling Wahner & MJH Life Sciences
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The novel, brain-penetrant, selective ROS1 inhibitor zidesamtinib (NVL-520) was well tolerated and yielded durable responses in patients with advanced ROS1-positive non–small cell lung cancer (NSCLC) previously treated with at least 1 TKI, according to data from the phase 1/2 ARROS-1 trial (NCT05118789).1

Pooled findings from the phase 1 and 2 portions showed that all patients previously treated with at least 1 TKI (n = 117) who received zidesamtinib at the recommended phase 2 dose (RP2D) of 100 mg once daily achieved an objective response rate (ORR) of 44% (95% CI, 34%-53%); the 6-, 12-, and 18-month duration of response (DOR) rates were 84% (95% CI, 71%-92%), 78% (95% CI, 62%-88%), and 62% (95% CI, 28%-84%), respectively.

Furthermore, patients who had received only 1 prior ROS1 TKI—crizotinib (Xalkori) or entrectinib (Rozlytrek) with or without chemotherapy (n = 55)—experienced an ORR of 51% (95% CI, 37%-65%). The DOR rates at 6, 12, and 18 months were all 93% (95% CI, 74%-98%), and DOR data continue to mature.

Regarding safety, zidesamtinib was well tolerated in patients with advanced ROS1-positive NSCLC (n = 432) treated at the RP2D as of the data cutoff of March 21, 2025. The median duration of exposure was 5 months (range, 0-32). Notably, the most frequent treatment-emergent adverse effects (TEAEs) observed in at least 15% of patients included peripheral edema (36%), constipation (17%), increased blood CPK (16%), fatigue (16%), and dyspnea (15%).

TEAEs led to dose reductions in 10% of patients, and 2% of patients discontinued treatment due to TEAEs.

“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 frontline, and there is no clear targeted therapy care standard for TKI-pretreated patients," Alexander Drilon, MD, ARROS-1 trial investigator and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York, stated in a news release. "These data demonstrate the potential for zidesamtinib to deliver meaningful clinical outcomes for [patients who previously received] TKIs, 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 [AEs] through ROS1-selectivity.”

Of note, Nuvalent, the developer of zidesamtinib, completed a pre–new drug application (NDA) meeting with the FDA, in which the NDA submission will seek an indication for the novel inhibitor for the treatment of TKI-pretreated patients with locally advanced or metastatic ROS1-positive NSCLC. The developer plans on initiating a rolling NDA submission in July 2025, with completion aimed for the third quarter of 2025.

ARROS-1 Trial Design

The dose-escalation and -expansion study evaluated the safety and tolerability of zidesamtinib to determine the RP2D, along with antitumor activity in patients with advanced ROS1-positive NSCLC or solid tumors at least 18 years of age.2

Phase 1 of the trial included patients with histologically or cytologically confirmed, locally advanced or metastatic solid tumors with documented ROS1 rearrangements. Phase 2 of the study comprised cohorts 2a, 2b, 2c, and 2d, which included patients with histologically or cytologically confirmed, locally advanced or metastatic NSCLC with ROS1 rearrangements. Cohort 2e in phase 2 included patients 12 years of age or older weighing 40 kg or greater with histologically or cytologically confirmed, locally advanced or metastatic solid tumors with ROS1 rearrangements, excluding NSCLC.

Patients on the study were also required to have received prior anticancer treatment, except those in cohort 2a. In phase 1, patients needed evaluable target or nontarget disease per RECIST 1.1 criteria; those in phase 2 needed measurable disease according to RECIST 1.1 criteria. All patients, regardless of cohort, were required to have adequate baseline organ function and bone marrow reserve.

At data cutoff, 514 patients with ROS1-positive solid tumors were treated with zidesamtinib at any starting dose across both phases of the trial.1 Specifically, 432 patients with advanced ROS1-positive NCSLC received zidesamtinib at the RP2D.

The primary end point of phase 2 was ORR per RECIST 1.1 criteria by blinded independent central review (BICR).2 Key secondary end points include DOR, intracranial ORR (IC-ORR), and safety.

Primary Analysis Patient Population

In the primary analysis, the population included TKI pretreated patients (n = 117) with advanced ROS1-positive NSCLC measurable disease were treated with zidesamtinib at the RP2D before May 31, 2024. The DOR follow-up was at least 6 months for most responders. Notably, patients had received a median of 2 prior lines of treatment (range, 1-11), and 53% received prior chemotherapy.

The most commonly received TKI was crizotinib or entrectinib (with or without chemotherapy) in 47% of patients. In this subgroup, 51% of patients were previously treated with crizotinib, and 49% of patients were previously treated with entrectinib; 47% of these patients previously received chemotherapy. Moreover, 50% of patients had received 2 or more prior ROS1 TKIs with or without chemotherapy, with 93% having received prior lorlatinib (Lorbrena), repotrectinib (Augtyro), or taletrectinib (Ibtrozi). Secondary ROS1 resistant mutations were observed in 36% of patients, and 49% had active central nervous system (CNS) disease by BICR.

Additional Efficacy Data

In patients with ROS1 G2032R resistance mutations in the primary analysis population (n = 26), the ORR was 54% (95% CI, 33%-73%), and the 6- and 12-month DOR rates were 79% (95% CI, 47%-93%) and 60% (95% CI, 28%-81%), respectively. Those with a ROS1 G2032R mutation who had received 1 prior ROS1 TKI with or without chemotherapy (n = 6) achieved an ORR of 83% (95% CI, 36%-100%). The DOR rate at 6 and 12 months was 80% (95% CI, 20%-97%).

Preliminary data among TKI-naive patients (n = 35) showed that the ORR was 89%, and the DOR ranged from 1.9+ months to 13.9+ months. The 6- and 12-month DOR rates were both 96% (95% CI, 76%-99%). In patients with measurable intracranial lesions (n = 6), the IC-ORR was 83% and the intracranial CR rate was 67%. Of note, the IC-DOR ranged from 4.6 months to 11.1 months without CNS progression in responders.

Among patients with measurable CNS lesions per BICR at baseline (n = 56), the IC-ORR was 48%, including an intracranial complete response (CR) rate of 20% and 2 unconfirmed partial responses. The 12-month IC-DOR rate was 71% (95% CI, 46%-87%). Additionally, the IC-ORR was 85% in patients who only received prior crizotinib (n = 13), including 54% of patients who experienced intracranial CRs. Only 1 CNS progression event occurred in CNS responders in this group.

"Bringing a drug from ideation to pivotal data in just a few short years is a rare opportunity, and I would like to express my sincere gratitude for the tireless dedication of the Nuvalent team and for the patients, caregivers, and investigators that have helped us achieve this milestone for zidesamtinib," James Porter, PhD, chief executive officer at Nuvalent, added in the news release.1 "[This] announcement brings us a critical step closer to achieving our goal of becoming a fully integrated, commercial-stage biopharmaceutical company able to deliver a new, potential best-in-class treatment option to all patients with advanced ROS1-positive NSCLC."

References

1. Nuvalent announces positive pivotal data from ARROS-1 clinical trial of ziesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC. News Release. Nuvalent. June 24, 2025. Accessed June 27, 2025. https://investors.nuvalent.com/2025-06-24-Nuvalent-Announces-Positive-Pivotal-Data-from-ARROS-1-Clinical-Trial-of-Zidesamtinib-for-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC
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 27, 2025. https://clinicaltrials.gov/study/NCT05118789