Taletrectinib Signals Activity in ROS1-Positive Non–Small Cell Lung Cancer

The investigational next-generation ROS1/NTRK inhibitor taletrectinib (AB-106) has demonstrated preliminary activity in patients with ROS1-positive non–small cell lung cancer (NSCLC), according to interim result from the phase 2 TRUST clinical trial announced in a press release by Innovent Biologics, Inc and AnHeart Therapeutics Co., Ltd.¹

Taletrectinib was designed to effectively target ROS1 and NTRK fusion mutations, which are identified in 2%-3% and 0.5% of patients with NSCLC, respectively.

“We are pleased with the interim phase 2 data, which have shown taletrectinib to be safe and tolerable, a very promising novel therapy for patients with ROS1 fusion-positive lung cancer. Responses appear particularly impressive in crizotinib treatment-naïve patients, and while the number of crizotinib pre-treated patients is limited, so far, most patients continue to show benefit from the drug,” said Caicun Zhou, MD, director of the Department of Oncology in Shanghai Pulmonary Hospital, in the press release.

TRUST is a multicenter open-label, single-arm study (NCT04395677) conducted in 2 parts. During the first stage of the study, the safety and pharmacokinetics of taletrectinib were assessed, and during stage 2, efficacy and safety are analyzed. In stage 1 of the study, half of the patients receive 400 mg once daily and the other half received 600 mg once daily. A stage 2, all patients received 600 mg of taletrectinib. The primary end point of the study is best overall response, and the secondary end points include the number of patients who experience treatment-related adverse events (TRAEs), duration of response, time to response, progression-free survival (PFS), intracranial best response, and overall survival.²

Interim findings from the TRUST study were recently presented during the Chinese Society of Clinical Oncology 2021 Annual Meeting.¹

Interim efficacy was evaluated in 21 patients who were treatment-naïve as well as in 16 patients who were previously treated with crizotinib (Xalkori). In the treatment-naïve population, the confirmed objective response rate (ORR) was 90.5% and the disease control rate (DCR) was also 90.5%. Among those who were pretreated with crizotinib, the confirmed ORR was 43.8% and the DCR was 75.0%.

During the analysis, responses were evaluated in the group of patients with ROS1 G2032R resistant mutations, which included 3 patients. Results showed that partial responses were achieved in 2 patients and 1 patient had stable disease. Further, an intracranial responses rate of 83.3% was observed the group of patients with assessable brain metastases at pre-enrollment, per investigator assessment.

In terms of safety, taletrectinib appeared to be well-tolerated in the patient population. The majority of the TRAEs observed were gastrointestinal events, reversible increase in aspartate aminotransferase, and increase in alanine aminotransferase.

The study is actively recruiting up to 106 patients who are at least 18 years old with histologically or cytologically confirmed advanced or metastatic NSCLC. All patients must test positive for ROS1 fusions, have an ECOG performance status of 0 or 1, measurable disease, a life expectancy of at least 3 months, and adequate organ function.²

“Our team is focused on completing patient enrollment for our phase 2 TRUST trial. The interim data presented builds a strong foundation for our ongoing global pivotal taletrectinib clinical program. We sincerely thank the patients, their families, and investigators in the TRUST trial and look forward to advancing development of taletrectinib for all ROS1 fusion-positive patients with NSCLC, an area of significant unmet medical needs,” stated Bing Yan, MD, co-founder and chief medical officer of AnHeart Therapeutics, in the press release.¹

Another phase 2 study of taletrectinib in patients with ROS1-positive NSCLC and other solid tumors (TRUST-II, NCT04919811) will recruit up to 119 patients. The study will explore the primary end point of ORR, as well as the secondary end points of progression-free survival, safety/tolerability, and pharmacokinetics.³

To be eligible for enrollment, patients must be aged 18 years or older with histologically or cytologically confirmed disease and evidence of a ROS1 fusion in their tumor tissue. Patients are also required to have at least 1 measurable extracranial unirradiated lesion per RECISTs v1.1, an ECOG performance status of 0 or 1, a life expectancy of at least 1 2 weeks., and adequate organ function. Those with central nervous system involvement are permitted, and female of child-bearing age must cannot be pregnant.

Patients enroll in TRUST-II will be divided into 4 cohorts based on prior treatment with a tyrosine kinase inhibitor for NSCLC harboring a ROS1 fusion. Taletrectinib will be administered at 600 mg once daily for 21 cycles. Treatment will continue in the study until trial completion or disease progression. Study investigators will regularly evaluate patients for response, and long-term survival follow up will also be carried out.

_References:

_{1. Innovent and AnHeart Announce interim data from phase 2 trial of taletrectinib in ros1-positive NSCLC at the CSCO 2021 Annual Meeting. https://bit.ly/2Zq3NyX}

_{2. A Study of AB-106 in subjects with Advanced NSCLC harboring ROS1 fusion gene. Clinicaltrials.gov. Accessed September 27, 2021.}

_{3. Taletrectinib in ROS1 positive lung cancer phase 2 global study (TRUST-II). Clinicaltrials.gov. Accessed September 27, 2021.}