Taletrectinib Elicits Durable Responses in TKI-Naïve and Crizotinib-Pretreated ROS1+ NSCLC

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Taletrectinib (AB-106) continued to demonstrate meaningful efficacy in the form of a durable objective response rate (ORR) and a high intracranial ORR (IC-ORR) with acceptable tolerability in both TKI-naïve and crizotinib (Xalkori)-pretreated patients with ROS1-positive non–small cell lung cancer (NSCLC), according to updated data from the phase 2 TRUST-I trial (NCT04395677).¹

Data presented during the 2023 European Lung Cancer Congress indicated that in evaluable patients who were TKI naïve (n = 67), taletrectinib induced a confirmed ORR of 92.5% (95% CI, 83.4%-97.5%) per independent review committee (IRC) assessment, with a median time to response (TTR) of 1.4 months (range, 1.2-4.2) and a median duration of response (DOR) that was not yet reached (NR; range, 1.3-27.6). In this group, the disease control rate (DCR) was 95.5% (95% CI, 87.5%-99.1%). The median progression-free survival (PFS) was NR (range, 0.0-29.0).

In the evaluable patients who were pretreated with crizotinib (n = 38), the IRC-assessed ORR achieved with taletrectinib was 52.6% (95% CI, 35.8%-69.0%), with a median TTR of 1.4 months (range, 1.2-4.1) and a median DOR that was NR (range, 1.4-22.2). In this group, the DCR was 81.6% (95% CI, 65.7%-92.3%), and the median PFS was 9.8 months (range, 0.0-23.5). Notably, the agent induced responses in 4 of 5 patients (80%) whose tumors harbored the G2032R resistance mutation.

In the 12 patients who had measurable brain metastases, taletrectinib elicited an IC-ORR of 91.7% (95% CI, 61.5%-99.8%). The intracranial DCR in these patients was 100% (95% CI, 73.5%-100.0%).

“Taletrectinib continued to demonstrate meaningful clinical efficacy, including a high and durable ORR and prolonged PFS in TKI-naïve and crizotinib-pretreated patients. Robust IC-ORR, and activity against a secondary resistance mutation such as G2023R was observed,” lead study author Wei Li, MD, of the Department of Medical Oncology at Shanghai Pulmonary Hospital and Thoracic Cancer Institute and Tongji University School of Medicine, in Shanghai, China, said in a presentation of the data. “Taletrectinib [also] demonstrated tolerable safety, with a low incidence of neurological adverse effects [AEs].”

Patients with locally advanced or metastatic NSCLC who were at least 18 years of age, had an ECOG performance status of 0 or 1, and showcased evidence of a ROS1 fusion in tumor tissue were enrolled to the TRUST-I trial.

The study was comprised of two stages: the lead-in stage, which enrolled 6 patients and examined taletrectinib at daily doses of 400 mg and 600 mg, and stage 2, in which patients were split into two cohorts based on whether they were TKI naïve (cohort 1; n = 67) or they had received prior crizotinib (cohort 2; n = 42). Those in second stage of the trial received the study drug at a daily dose of 600 mg.

IRC-assessed cORR by RECIST v1.1 criteria served as the primary end point of the trial. Key secondary end points included DOR, DCR, IC-ORR, PFS, TTR by RECIST v1.1 criteria, and overall survival.

Preliminary data from the trial showed early signs of safety and tolerability with the agent in those with NSCLC harboring ROS1 fusions.² Moreover, at a data cutoff of June 16, 2021, taletrectinib elicited a confirmed ORR of 90.5% (n = 19/21) in crizotinib-naïve patients; the DCR was 90.5% (n = 19). In 16 patients who were pretreated with crizotinib, the confirmed ORR was 43.8% (n = 7), with a DCR of 75.0% (n = 12). In August 2022, the FDA granted a breakthrough therapy designation to taletrectinib for use as a potential therapeutic option in adult patients with advanced or metastatic ROS1-positive NSCLC who were ROS1 inhibitor naïve or who received prior crizotinib. The decision was supported by preliminary findings from the TRUST-I trial.³

In the total population of 109 patients, the median age was 54 years (range, 26-77). Moreover, 40.4% of patients were male, 93.5% had adenocarcinoma, 95.4% were nonsmokers, and 22% had brain metastases. Regarding performance status, 25.7% had a status of 0, and 74.3% had a status of 1. Moreover, 26.6% of patients previously received chemotherapy.

At the meeting, Dr Li shared phase 1 and 2 pooled data on taletrectinib. At a median follow-up of 18.0 months for those who were TKI naïve and received the study drug, the median PFS was 33.2 months (95% CI, 22.1-NR). The Kaplan-Meier estimated DOR at 18 months in this group was 81.3%. With a median follow-up of 15.9 months for crizotinib-pretreated patients, the median PFS with taletrectinib was 11.8 months (95% CI, 5.6-18.4). At 18 months, the Kaplan-Meier estimated DOR was 56.9% for these patients.

The median duration of exposure to taletrectinib on the trial was 7.6 months (range, 0.2-64.1). Pooled phase 1 and 2 data on the 178 patients who comprised the safety population indicated that 20.2% of patients experienced a treatment-emergent AE (TEAE) that required a dose reduction; 5.1% of patients experienced a TEAE that resulted in discontinuation.

“Most TEAEs were of grade 1 or 2,” Li noted. “The incidence of neurological TEAEs was low, with most just grade 1 [in severity].”

The most common any-grade TEAEs that occurred in at least 15% of patients included increased aspartate aminotransferase (AST; 70.8%), increased alanine aminotransferase (ALT; 64.0%), diarrhea (61.2%), vomiting (43.3%), nausea (42.1%), anemia (35.4%), decreased white blood cell (WBC) count (22.5%), decreased neutrophil count (21.3%), abnormal hepatic function (20.8%), dizziness (20.8%), increased blood bilirubin (18.0%), decreased appetite (18.0%), constipation (16.3%), hyperuricemia (16.9%), and increased blood creatinine (15.7%).

The most common grade 3 TEAE was increased ALT (7.3%), followed by increased AST (6.7%), abnormal hepatic function (6.7%), decreased neutrophil count (4.5%), diarrhea (3.4%), anemia (2.2%), decreased WBC count (2.2%), vomiting (1.7%), nausea (1.1%), dizziness (0.6%), and hyperuricemia (0.6%). Five grade 4 TEAEs were reported; this included 4 cases of decreased neutrophil count and 1 case of increased blood bilirubin.

The ongoing global, multicenter, single-arm, open-label, phase 2 TRUST-II trial (NCT04919811) is further examining the safety and efficacy of single-agent taletrectinib in patients with advanced NSCLC.⁴

Dr Li did not declare any conflicts of interest.

References

1. Li W, Yang N, Li K, et al. Updated efficacy and safety of taletrectinib in patients with ROS1+ non–small cell lung cancer. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 14MO.
2. Innovent and AnHeart announce interim data from phase 2 trial (TRUST study) of taletrectinib in ROS1-positive NSCLC at the CSCO 2021 Annual Meeting. Press release. Innovent Biologics, Inc. September 27, 2021. Accessed March 31, 2023. https://www.innoventbio.com/InvestorsAndMedia/
3. AnHeart Therapeutics receives FDA breakthrough therapy designation for taletrectinib in ROS1-positive non-small cell lung cancer. News release. AnHeart Therapeutics. August 3, 2022. Accessed March 31, 2023. https://www.anhearttherapeutics.com/news/press-releases/080322/
4. Taletrectinib phase 2 global study in ROS1 positive NSCLC (TRUST II). ClinicalTrials.gov. Updated February 16, 2023. Accessed March 31, 2023. https://clinicaltrials.gov/ct2/show/NCT04919811