Taletrectinib is a next-generation, highly potent, central nervous system–active, selective inhibitor of the ROS1 tyrosine kinase, which has shown remarkable and durable overall response rates (ORRs), high intracranial (IC) response rates, extended progression-free survival (PFS), and strong activity against ROS1G2032R, all while exhibiting a favorable safety profile in patients diagnosed with ROS1-positive non-small cell lung cancer (NSCLC) in the regional TRUST-I study. The pooled data derived from the regional TRUST-I (NCT04395677) and global TRUST-II (NCT04919811) pivotal studies were presented at ESMO 2024.
TRUST-I and TRUST-II are pivotal phase 2 studies that are multicenter, single-arm, and open-label, evaluating the efficacy of taletrectinib administered orally at a dosage of 600 mg once daily. The primary end point of these studies included clinical overall response rate (cORR) as assessed by an independent review committee using RECIST v1.1 criteria. Key secondary end points included IC-cORR per RECIST v1.1 criteria, duration of response (DOR), PFS, and safety profiles.
As of June 7, 2024, a total of 273 patients were assessed for efficacy from the TRUST-I (63%) and TRUST-II (37%) studies. Patients had a median age of 56 years, comprising 57% females, 83% Asians, and 67% individuals who had never smoked. In the tyrosine kinase inhibitor (TKI)-naive group, 20% had a history of chemotherapy, while 23% presented with brain metastases. Conversely, in the cohort with 1 prior ROS1 TKI, 37% had undergone chemotherapy previously, and 49% had brain metastases. The cORR for TKI-naive patients was 88.8% and the IC-cORR was 76.5%. For patients with 1 prior ROS1 TKI, the cORR was 55.8% and the IC-cORR was 65.6%. In the TKI-naive group, the median DOR and median PFS was 45.6 months and 44.2 months, respectively. However, for those with 1 prior ROS1 TKI, the median DOR was 16.6 months, and the median PFS was 9.7 months. Among 331 individuals diagnosed with ROS1-positive NSCLC who were administered 600 mg daily in phase 1 and 2 studies, the predominant treatment-emergent adverse events (TEAEs) observed were increased levels of aspartate aminotransferase (72.1%; 7.7% at grade ≥3), increased levels of alanine aminotransferase (68.0%; 10.1% at grade ≥3), and diarrhea (63.1%; 2.1% at grade ≥3). Neurologic TEAEs were infrequent, with dizziness occurring in 21.1% of patients, mostly at grades 1 and 2. The occurrences of treatment discontinuation and dose modifications due to TEAEs were low, recorded at 6.5% and 28.8%, respectively.
In a combined analysis of 2 key studies, taletrectinib demonstrated significant and lasting overall responses, strong inhibitory activity against the intended target, and a favorable safety profile characterized by minimal occurrences of neurological adverse events.
Source: Pérol M, Li W, Pennell NA, et al. Pooled efficacy and safety from 2 pivotal phase II trials of taletrectinib in patients (Pts) with advanced or metastatic ROS1+ non-small cell lung cancer (NSCLC). Barcelona, Spain, & online: presented at ESMO Congress 2024; abstract 1289P.