FDA Grants Breakthrough Therapy Designation to Taletrectinib for ROS1+ NSCLC

The FDA has granted a breakthrough therapy designation to taletrectinib (AB-106/DS-6051b) for use as a potential therapeutic option in adult patients with advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC) who were ROS1 inhibitor naïve or who previously received crizotinib (Xalkori).¹

The decision was based on preliminary findings from the phase 2 TRUST trial (NCT04395677), in which taletrectinib was found to elicit a confirmed objective response rate (cORR) of 92.5% (95% CI, 83.4%-97.5%) in evaluable Chinese patients with ROS1-positive NSCLC who were TKI naïve (n = 67) and a disease control rate (DCR) of 95.5% (95% CI, 87.5%-99.1%).2 In these patients, the median duration of response (DOR; range, 1.3+ to 16.6+) and median progression-free survival (PFS; range, 0+ to 18.0+) had not yet been reached (NR).

In those who previously received crizotinib (n = 38) taletrectinib produced an cORR of 50.0% (95% CI, 33.4%-66.6%) and a DCR of 78.9% (95% CI, 62.7%-90.4%). In this group of patients, the median DOR (range, 1.4+ to 12.3+) and the median PFS (range, 0+ to 13.6+) had not yet been reached.

Among those with brain metastasis and measurable brain lesions at baseline (n = 12), the ROS1 inhibitor produced an intracranial cORR of 91.7% (95% CI, 61.5%-99.8%) and an intracranial DCR of 100% (95% CI, 73.5%-100%).

“There is a high unmet need for this specific patient population in lung cancer, where very few treatment options are available,” Lian Li, MD, PhD, chief medical officer of AnHeart Therapeutics, stated in a press release. “In the TRUST phase 2 trial, taletrectinib showed promising antitumor activity against ROS1 fusion and resistant mutations in adult patients with ROS1-positive NSCLC with a favorable safety profile. Taletrectinib also showed better brain penetration and intracranial antitumor activity in comparison to other ROS1 inhibitors.”

The multicenter, open-label, single-arm phase 2 trial enrolled patients with a histologically or cytologically confirmed diagnosis of locally advanced or metastatic NSCLC who were at least 18 years of age, had an ECOG performance status of 0 or 1, harbored ROS1 fusions, and had at least 1 measurable lesion per RECIST v1.1 criteria.

The trial was comprised of 2 parts. The first portion was comprised of a lead-in dose titration period in which the agent was given at a dose of 400 mg daily (n = 3) or 600 mg daily (n = 3). In the second part of the trial, all participants were given taletrectinib at a daily dose of 600 mg in 2 cohorts: those naïve to ROS1 TKIs (n = 60) and those pretreated with crizotinib (n = 40).

The primary end point of the trial was ORR per RECIST v1.1 criteria and independent review committee (IRC) assessment. Secondary end points comprised ORR, DOR, PFS, intracranial ORR, intracranial DOR, and intracranial PFS per RECIST v1.1 criteria and IRC or investigator assessment.

Among the 109 patients analyzed, the median age was 54 years (range, 26-77), and 59.6% were female. Moreover, 74.3% had an ECOG performance status of 1, 93.6% had adenocarcinoma, and 90.8% had metastatic disease. Regarding prior anticancer treatment, 38.5% had a prior TKI, 26.6% previously received chemotherapy, and 12.8% had another anticancer therapy. Notably, 18.3% of patients had brain metastases at baseline per IRC assessment.

Taletrectinib was found to be generally well tolerated, with most treatment-emergent toxicities grade 1 or 2 in severity. The most common any-grade treatment-emergent adverse effects (TEAEs) included diarrhea (61.6%), increased aspartate aminotransferase (AST; 55.8%), increased alanine aminotransferase (ALT; 49.5%), nausea (47.4%), and vomiting (45.3%).

The most frequently experienced treatment-related toxicities comprised diarrhea (56.3%), increased AST (53.7%), increased ALT (49.5%), nausea (43.2%), vomiting (40.5%), anemia (21.6%), dizziness (14.2%), decreased appetite (15.8%), and decreased white blood cell counts (14.7%).

Moreover, 14.2% of patients experienced TEAEs that required dose reductions, and 5.3% had TEAEs that led to treatment discontinuation. A low incidence of neurological toxicities was reported.

Notably, common toxicities that are experienced with other ROS1 inhibitors, such as vision disorders, edema, headache, dizziness, and muscular disorder were observed less frequently with taletrectinib.

References

1. 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 August 22, 2022. https://bit.ly/3CG85UL
2. Nagasaka M, Sugawara S, Choi C-M, et al. TRUST-II: a global phase II study for taletrectinib in ROS1 fusion-positive lung cancer and other solid tumors. J Clin Oncol. 2022;40(suppl 16):TPS8601. doi:10.1200/JCO.2022.40.16_suppl.TPS8601