Taletrectinib, a potent, next-generation ROS1 tyrosine kinase inhibitor (TKI), demonstrated meaningful efficacy outcomes in both TKI-naїve and crizotinib-pretreated patients with ROS1-positive non-small cell lung cancer (NSCLC). High and durable objective response rate (ORR) was observed in both TKI-naїve and crizotinib-pretreated patients, high intracranial ORR regardless of line of therapy, prolonged progression-free survival (PFS) in TKI-naїve and crizotinib-pretreated patients, and activity against G2032R were also of high clinical significance.
The findings from the pivotal TRUST-I study conducted in patients from China are reported at ASCO 2024 Annual Meeting along with a simultaneous publication by Dr. Caicun Zhou of the Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine in Shanghai, China and colleagues on 1 June 2024 in the JCO. The ongoing pivotal, global, phase II TRUST-II study will further shed light on the generalisability of taletrectinib efficacy and safety profile across regions and ethnicities.
Tumours positive for ROS1 gene fusions account for 0.9-2.6% of NSCLC; most are lung adenocarcinomas. ROS1 rearrangements in NSCLC are generally mutually exclusive, as newly diagnosed patients typically test negative for other known oncogenic alterations such as ALK rearrangements and EGFR mutations. Patients with ROS1-positive NSCLC tend to be female, younger than patients with NSCLC without driver mutations, and most are never smokers.
The authors wrote in the background that crizotinib was the first TKI approved for treatment of metastatic ROS1-positive NSCLC, but most patients relapse within 2 years because of emergence of acquired resistance mutations (i.e. G2032R) or development of brain metastases. Crizotinib has limited central nervous system (CNS) penetration. Entrectinib has intracranial activity, but is ineffective against G2032R resistance mutations.
However, improved intracranial activity came with the cost of higher neurologic adverse events, with patients experiencing dysgeusia and dizziness. Although repotrectinib showed activity against G2032R, high incidence of neurologic adverse events such as dizziness, dysgeusia, peripheral neuropathy, dyspnoea, ataxia, fatigue, muscular weakness, and memory impairment likely affect patient quality-of-life. Unmet treatment needs remain for ROS1-positive NSCLC to optimise disease control and tolerability.
Taletrectinib is a highly potent, CNS-active, ROS1 TKI. In cell-based studies, taletrectinib has low nanomolar potency against ROS1 fusions including G2032R and other acquired resistance mutations. In vitro, taletrectinib shows enzymatic selectivity for ROS1 wild-type and resistant mutations. Taletrectinib has excellent blood-brain barrier penetration and promising preclinical intracranial activity. In an orthotopic CNS model of ROS1-positive NSCLC, taletrectinib showed sustained brain penetration and improved survival versus vehicle or repotrectinib in rodents with intracranial patient-derived xenograft tumours. In two phase I studies and interim analysis of TRUST-I, taletrectinib demonstrated clinically meaningful efficacy and a favourable safety profile.
TRUST-I evaluated taletrectinib in TKI-naїve and crizotinib-pretreated patients. The primary endpoint was confirmed ORR by independent review committee; key secondary endpoints included duration of response (DoR), PFS, and safety.
As of November 2023, 173 patients were enrolled; median age was 55 years, 58% were female, 73% never smoked, 106 patients were TKI-naїve and 67 crizotinib-pretreated. In TKI-naїve patients, confirmed ORR and intracranial confirmed ORR were 91% and 88%, while 52% and 73% in crizotinib-pretreated patients. In TKI-naїve patients, median DoR and median PFS were not reached with 22.1-month and 23.5-month follow-up. In crizotinib-pretreated patients, the median DoR was 10.6 months with 8.4-month follow-up, and the median PFS was 7.6 months with 9.7 month of follow-up. Eight of 12 patients (67%) with G2032R mutations responded.
The most frequent treatment-emergent adverse events were increased AST (76%), diarrhoea (70%), and increased ALT (68%), most of which were grade 1-2. Incidences of neurologic treatment-emergent adverse events were low (dizziness 23% and dysgeusia 10%) and mostly grade 1. Discontinuations (5%) and dose reductions (19%) due to treatment-emergent adverse events were low.
The authors commented that observed efficacy profile of taletrectinib adds a new emerging option to the ROS1 TKI therapeutic landscape. While geographically limited, TRUST-I represents the largest prospective clinical study to date conducted in patients with ROS1-positive NSCLC.
The study findings suggest taletrectinib can overcome common mechanisms of resistance to crizotinib and provide benefit in the crizotinib-pretreated setting. Similar resistance mutation mechanisms were observed after entrectinib treatment, which is ineffective against G2032R mutations. The efficacy of taletrectinib in patients receiving prior entrectinib or repotrectinib for metastatic ROS1-positive NSCLC, was not assessed in TRUST-I.
However, after 11.7 months of follow-up, all four patients receiving entrectinib in the ongoing TRUST-II responded to taletrectinib, including one complete response. Longer follow-up with additional patients will further examine the efficacy of taletrectinib in patients experiencing treatment failure after entrectinib or repotrectinib.
A central question in the treatment of metastatic ROS1-positive NSCLC is defining optimal first-line therapy. TRUST-I findings suggest a longer PFS achieved with taletrectinib than that historically reported with first-generation ROS1 TKIs crizotinib and entrectinib and are reminiscent of PFS with repotrectinib in TRIDENT-1.
TRIDENT-3 is a phase III study comparing repotrectinib with crizotinib in TKI-naïve ROS1-positive NSCLC. Emerging data from such studies, TRUST-II, and studies evaluating other next-generation TKIs like zidesamtinib, a ROS1-selective TKI under investigation in a global phase II ARROS-1 study including in TKI-naïve patients, will collectively refine the first-line treatment paradigm for metastatic ROS1-positive NSCLC.
In an accompanied editorial article, Drs. Sarah Waliany and Jessica J. Lin of the Cancer Center and Department of Medicine, Massachusetts General Hospital in Boston, MA, US wrote that several important questions remain. First, appraising in totality the systemic and CNS efficacy and long-term tolerability from multiple ongoing trials will be imperative in crystallising optimal treatment sequencing for metastatic ROS1-positive NSCLC.
In addition, to date, most data on mechanisms of ROS1 TKI resistance are from the post-crizotinib context. As next-generation ROS1 TKIs begin moving into first-line use, the resulting ROS1 resistance landscape merits investigation to inform subsequent therapeutic strategies. ROS1 mutations refractory to next-generation TKIs will still emerge. Indeed, ROS1 L2086F, resistant to all type I ROS1 TKIs, has already been reported in the taletrectinib-refractory setting. Finally, all currently approved ROS1 inhibitors are for NSCLC indication only, with limited data on non-NSCLC ROS1-positive tumours.
The study was supported by AnHeart Therapeutics, a Nuvation Bio Company.
References
- Li W, Xiong A, Yang N, et al. Efficacy and Safety of Taletrectinib in Chinese Patients With ROS1+ Non–Small Cell Lung Cancer: The Phase II TRUST-I Study. JCO; Published online 1 June 2024. DOI: https://doi.org/10.1200/JCO.24.00731
- Waliany S, Lin JJ. Taletrectinib: TRUST in the Continued Evolution of Treatments for ROS1 Fusion–Positive Lung Cancer. JCO; Published 28 June 2024. DOI: https://doi.org/10.1200/JCO.24.01062