Taletrectinib Leads to Durable Responses in Patients With ROS1+ NSCLC

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Treatment with taletrectinib (AB-106) led to a high rate of responses with durable in patients with ROS1-positive non–small cell lung cancer (NSCLC), including in those who previously received crizotinib (Xalkori), according to follow-up data from the phase 2 TRUST-I trial (NCT04395677) presented at the 2024 ASCO Annual Meeting.¹

The next-generation ROS1 inhibitor elicited an independent review committee (IRC)-assessed confirmed objective response rate (ORR) of 90.6% (95% CI, 83.33%-95.38%) in patients with ROS1-positive NSCLC who had not received a prior TKI (n = 106); the disease control rate (DCR) was 95.3% (95% CI, 89.33%-98.45%) and the median time to response (TTR) was 1.4 months (95% CI, 1.38-1.41). At a median follow-up of 23.5 months, the median duration of response (DOR) was not reached (NR; 95% CI, 30.4-NR) and the median progression-free survival (PFS) was NR (95% CI, 29.1-NR), with a 24-month PFS rate of 70.5%.

Additionally, patients who previously received crizotinib (n = 66) achieved a median confirmed ORR of 51.5% (95% CI, 38.88%-64.01%) when treated with taletrectinib. The DCR was 83.3% (95% CI, 72.13%-91.38%) and the median TTR was 1.4 months (95% CI, 1.38-1.41). At a median follow-up of 9.7 months, the median DOR was 10.6 months (95% CI, 6.3-NR) and the median PFS was 7.6 months (95% CI, 5.5-12.0) with a 9-month PFS rate of 47.4%. Further, among patients with G2032R mutations treated with taletrectinib, the confirmed ORR was 66.7%.

“Prolonged PFS was observed regardless of line of therapy,” Wei Li, MD, of the Department of Medical Oncology at Shanghai Pulmonary Hospital and Thoracic Cancer Institute and Tongji University School of Medicine, in China, said in a presentation of the data. “Taletrectinib [also] demonstrated activity against resistance mutations including G2032R.”

Based on these findings from TRUST-I, 2 new drug applications for taletrectinib for the first- and second-line treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC have been accepted by the Center for Drug Evaluation of the National Medical Products Administration of China, and granted priority review designations.²

TRUST-I was conducted in China and enrolled adult patients with ROS1-positive locally advanced or metastatic NSCLC and an ECOG performance status of 0 or 1 to receive taletrectinib monotherapy. Cohort A included patients who were treatment naive to a ROS1 TKI and cohort B included patients previously treated with crizotinib; all patients received taletrectinib 600 mg daily and a dose confirmation lead-in stage evaluated the safety of the agent administered at 400 mg and 600 mg daily in 3 patients each. The median exposure to taletrectinib was 12.2 months (range, 0.23-40.04) in the study.¹

The primary end point of TRUST-I was IRC-assessed confirmed ORR per RECIST 1.1 criteria and secondary end points encompassed DOR, intracranial (IC)-ORR, DCR, TTR, PFS, safety, and best overall response.

Additionally, patients enrolled were a median age of 55.0 years (range, 26-78) and 26.6% had brain metastases. Most patients were female (57.8%) and had stage IV disease (93.6%), never smoked (73.4%), and an ECOG performance score of 1 (77.5%). Twenty-six percent of patients also received prior anticancer therapy.

Furthermore, patients with measurable brain metastases at baseline who had not received a prior TKI (n = 8) achieved a median IC-confirmed ORR of 87.5% (95% CI, 47.35%-99.68%) and a DCR rate of 100.0% (95% CI, 63.06%-100.0%) when treated with taletrectinib. Among those with measurable brain metastases who previously received crizotinib (n = 15), the IC-confirmed ORR was 73.3% (95% CI, 44.90%-92.21%) and the DCR was 93.3% (95% CI, 68.05%-99.83%).¹

Regarding toxicities, 40.5% of patients in the safety population (n = 173) experienced a treatment-emergent adverse effect (TEAE) leading to treatment interruption; 19.1% of patients had a TEAE leading to dose reduction and 5.2% of patients discontinued therapy due to a TEAE. Three patients experienced grade 5 taletrectinib-related TEAEs including hepatic failure, pneumonia, and abnormal hepatic function in a patient who previously received crizotinib.

The most common any grade TEAEs observed with taletrectinib treatment included increased aspartate aminotransferase levels (76.3%), diarrhea (69.9%), increased alanine aminotransferase levels (67.6%), vomiting (53.2%), anemia (49.1%), nausea (42.2%), decreased neutrophil count (26.0%), abnormal hepatic function (25.4%), and decreased white blood cell count (25.4%). Investigators noted rates of neurological TEAEs were low and mostly grade 1, including dizziness and dysgeusia occurring in 23% and 10% of patients, respectively.

The global phase 2 TRUST-II trial (NCT04919811) is currently ongoing evaluating the potent, central nervous system-active, and selective ROS1 TKI as monotherapy in patients with advanced or metastatic ROS1-positive NSCLC and other solid tumors in the US, Europe, and Asia.

REFERENCES:

1. Li W, Xiong A, Yang N, et al. Efficacy and safety of taletrectinib in patients with advanced or metastatic ROS1+ non–small cell lung cancer: The phase 2 TRUST-I study. J Clin Oncol. 2024;42(suppl 16):8520. doi:10.1200/JCO.2024.42.16_suppl.8520

2. Innovent announces taletrectinib (ROS1 inhibitor)updated data from pivotal phase 2 TRUST-I study of are published in the JCO and orally presented at 2024 ASCO Annual Meeting. News release. June 2, 2024. Accessed June 2, 2024. https://tinyurl.com/33dbxmth