Taletrectinib in ROS1+ Non-Small Cell Lung Cancer: TRUST

Abstract

Purpose: Taletrectinib is an oral, potent, CNS-active, selective, next-generation ROS1 tyrosine kinase inhibitor (TKI). We report integrated efficacy and safety from registrational taletrectinib studies in ROS1+ non-small cell lung cancer.

Methods: TRUST-I and TRUST-II were phase II, single-arm, open-label, nonrandomized, multicenter trials. Efficacy outcomes were pooled from TRUST-I and TRUST-II pivotal cohorts. The safety population comprised all patients treated with once-daily oral taletrectinib 600 mg pooled across the taletrectinib clinical program. The primary end point was independent review committee-assessed confirmed objective response rate (cORR). Secondary outcomes included intracranial (IC)-ORR, progression-free survival (PFS), duration of response (DOR), and safety.

Results: As of June 7, 2024, the efficacy-evaluable population included 273 patients in TRUST-I and TRUST-II. Among TKI-naïve patients (n = 160), the cORR was 88.8% and the IC-cORR was 76.5%; in TKI-pretreated patients (n = 113), the cORR was 55.8% and the IC-cORR was 65.6%. In TKI-naïve patients, the median DOR and median PFS were 44.2 and 45.6 months, respectively. In TKI-pretreated patients, the median DOR and median PFS were 16.6 and 9.7 months. The cORR in patients with G2032R mutation was 61.5% (8 of 13). Among 352 patients treated with taletrectinib 600 mg once daily, the most frequent treatment-emergent adverse events (TEAEs) were GI events (88%) and elevated AST (72%) and ALT (68%); most were grade 1. Neurologic TEAEs were infrequent (dizziness, 21%; dysgeusia, 15%) and mostly grade 1. TEAEs leading to discontinuations (6.5%) were low.

Conclusion: Taletrectinib showed a high response rate with durable responses, robust IC activity, prolonged PFS, favorable safety, and low rates of neurologic adverse events in TKI-naïve and pretreated patients.

Trial registration: ClinicalTrials.gov NCT04919811 NCT04395677.

FIG 1.

Analysis populations. Data cutoff: June 7, 2024. Patient flowcharts in the (A) efficacy and (B) safety populations. ^aREP included patients with ROS1+ NSCLC with ≥one measurable baseline lesion per RECIST v1.1 by IRC receiving ≥one dose of taletrectinib. One patient from TRUST-I was excluded from the REP because of a secondary malignancy. ^bThe integrated safety population described reflects exposure to taletrectinib as a single agent dosed at 600 mg orally once daily until disease progression or unacceptable toxicity in 352 patients with ROS1+ NSCLC (N = 337) and other solid tumors (n = 15). IRC, independent review committee; NSCLC, non–small cell lung cancer; REP, response-evaluable population; TKI, tyrosine kinase inhibitor.

FIG 2.

IRC-assessed BOR of taletrectinib in TKI-naïve and TKI-pretreated patients with ROS1+ NSCLC. Overall best percent change in the sum of diameters of target lesions from baseline in (A) TKI-naïve (n = 160; three patients with confirmed BOR as not evaluable are not displayed in the waterfall plot) and (B) TKI-pretreated (n = 113; six patients with confirmed BOR as not evaluable are not displayed in the waterfall plot) patients and IC best percent change in the sum of diameters of IC measurable lesions from baseline in (C) TKI-naïve (n = 17; one patient confirmed with BOR as not evaluable is not displayed in the waterfall plot) and (D) TKI-pretreated (n = 32; one patient confirmed with BOR as not evaluable is not displayed in the waterfall plot) patients. ^aOne patient had a best percent change of 0 and BOR as SD. BOR, best overall response; CR, complete response; IC, intracranial; IRC, independent review committee; NSCLC, non–small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.

FIG 3.

DOR and PFS by IRC assessment of taletrectinib in TKI-naïve and TKI-pretreated patients with ROS1+ NSCLC. (A) DOR in TKI-naïve patients, (B) PFS in TKI-naïve patients, (C) DOR in TKI-pretreated patients, and (D) PFS in TKI-pretreated patients. DOR, duration of response; IRC, independent review committee; NSCLC, non–small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

FIG A1.

Study designs of (A) TRUST-I (ClinicalTrials.gov identifier: NCT04395677) and (B) TRUST-II (ClinicalTrials.gov identifier: NCT04919811). ^aA dose-confirmation lead-in stage evaluated the safety of taletrectinib 400 mg once daily (n = 3) and 600 mg once daily (n = 3). ^bSafety was analyzed in patients receiving ≥one dose of taletrectinib until 30 days after the last dose of taletrectinib or the start date of new anticancer therapy minus 1 day, whichever occurred first. ^cOr ≥20 years, as required by local regulations. ^dOne previous ROS1 TKI (crizotinib or entrectinib). BOR, best overall response; cORR, confirmed ORR; CT, chemotherapy; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; IC, intracranial; IRC, independent review committee; mRECIST, modified RECIST; NSCLC, non–small cell lung cancer; ORR, objective response rate; PFS, progression-free survival; TTR, time to response; TKI, tyrosine kinase inhibitor.

FIG A2.

Change in size of target lesions relative to baseline over time in (A) TKI-naïve and (B) TKI-pretreated patients. Reduction in target lesion size over time in (A) TKI-naïve patients (three patients had confirmed BOR as not evaluable and are not displayed) and (B) TKI-pretreated patients (the target lesion sum of diameters from baseline of one patient had increased 136.5%, which was cut at 100% in the figure because of page size limit; six patients had confirmed BOR as not evaluable and are not displayed in the spider plot). BOR, best overall response; CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.

FIG A3.

Responses per IRC by subgroup in the response-evaluable population in (A) TKI-naïve and (B) TKI-pretreated patients. ORR in (A) TKI-naïve patients and (B) TKI-pretreated patients. ECOG, Eastern Cooperative Oncology Group; IRC, independent review committee; mRECIST, modified RECIST; ORR, objective response rate; TKI, tyrosine kinase inhibitor.