KEY TAKEAWAYS
- The ARROS-1 phase 1&2 trial aimed to investigate the efficacy and safety of zidesamtinib in ROS1+ NSCLC.
- Researchers noticed that zidesamtinib showed promising efficacy and a favorable safety profile in ROS1+ NSCLC.
Zidesamtinib is a brain-penetrant, TRK-sparing, highly selective ROS1 tyrosine kinase inhibitor (TKI) with activity against various ROS1 fusions and resistance mutations, including G2032R.
Benjamin Besse and the team aimed to evaluate the drug’s efficacy and safety in patients with ROS1+ Non -Small Cell Lung Cancer (NSCLC), focusing on those who have previously undergone treatment and those with CNS metastases.
They performed an inclusive analysis in the global ARROS-1 Phase 1 study (NCT05118789), which enrolled patients with heavily pretreated advanced/metastatic ROS1+ solid tumors. The study aimed to identify the recommended Phase 2 dose (RP2D) and assess both safety and efficacy, using RECIST 1.1 criteria and investigator assessments.
About 104 patients (99 with NSCLC, 5 with other cancers) received zidesamtinib (25-150 mg orally once daily [QD]) in Phase 1. Patients had a median of 3 prior anticancer therapies (range: 1-11), including any ROS1 TKI (99%); lorlatinib (55%), repotrectinib (repo; 21%), or either (67%); ≥2 ROS1 TKIs (69%); and chemotherapy (66%). A history of CNS metastases was present in 53% of patients.
The RP2D of 100 mg QD was selected, with no observed dose relationships for safety or efficacy. No dose-limiting toxicity or treatment-related adverse event (TRAE) led to discontinuation. TRAE resulted in dose reduction in 5.8% of cases. The most common TRAEs were peripheral edema (18%) and transaminase increase (12%); TRAEs were grade ≥3 in 7.7%.
Among 73 patients with ROS1+ NSCLC who were evaluable for response, the overall response rate (ORR) in those with known ROS1 G2032R was 65% (11/17) with a median duration of response (mDOR) of 15.8 months (range: 6, not evaluable) in repo-naïve patients and 38% (3/8) in repo-pretreated patients.
In patients with measurable intracranial (IC) metastases and ≥2 prior ROS1 TKIs (all having prior lorlatinib and/or repo), the IC ORR was 57% (4/7), and the IC DOR ranged from 1.9+ to 17.3+ months with no IC progression observed.
The study concluded that zidesamtinib demonstrated promising efficacy and durability in patients with pretreated ROS1+ NSCLC, including those with ROS1 resistance mutations like G2032R and CNS metastases. The safety profile was favorable, aligning with its ROS1-selective and TRK-sparing design. Phase 2 enrollment is ongoing with registrational intent for both TKI-naïve and pretreated patients with ROS1+ NSCLC.
The trial was sponsored by AstraZeneca and funded by Nuvalent Inc.
Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/105
Clinical Trial: https://clinicaltrials.gov/study/NCT05118789
Besse B, Drilon A.E, Cho B.C, et al. (2024). “Phase I/II ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumours.” Presented at ESMO 2024. (Abstract 1256MO).
