Taletrectinib Shows Consistent Efficacy, Safety in ROS1+ NSCLC Independent of Prior TKI Exposure

The next-generation ROS1 TKI taletrectinib (AB-106) induced robust overall and intracranial responses in patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC), regardless of prior TKI exposure and geographic region, according to updated data from the phase 2 TRUST-II trial (NCT04919811) presented during the2024 IASLC World Conference on Lung Cancer.¹

At a median follow-up of 15.8 months (range, 3.6-29.8), taletrectinib produced a confirmed overall response rate (cORR) of 85.2% (95% CI, 72.88%-93.38%) among patients without prior exposure to a ROS1 TKI (n = 54). The cORRs between patients from Asia (n = 33) vs non-Asian regions (n = 21) were similar, at 87.9% (95%, 71.80%-96.60%) vs 81.0% (95% CI, 58.09%-94.55%), respectively.

For patients previously treated with a ROS1 TKI (n = 47), the cORR with taletrectinib was 61.7% (95% CI, 46.38%-75.49%) at a median follow-up of 15.7 months (range, 3.9-29.8). When broken down by geographic region, the cORRs were 57.1% (95% CI, 34.02%-78.18%) vs 65.4% (95%, 44.33%-62.79%) in patients from Asia (n = 21) vs other regions (n = 26), respectively.

Notably, duration of response (DOR) and progression-free survival (PFS) data remained immature in both cohorts at the time of this analysis.

Assessment of intracranial responses among patients with measurable baseline brain metastases showed an intracranial ORR (IC-ORR) of 66.7% (95% CI, 29.93%-92.51%) in the TKI-naive group (n = 9); this comprised a complete response (CR) rate of 22.2% and partial response (PR) rate of 44.4%. For TKI-pretreated patients (n = 16), the IC-ORR was 56.3% (95% CI, 29.88%-80.25%), comprising a CR rate of 6.3% and PR rate of 50.0%.

“With the full enrollment of patients in this geographically diverse region, we were able to demonstrate meaningful efficacy in both TKI-naive and TKI-pretreated patients with ROS1-positive NSCLC,” Geoffrey Liu, MD, MSc, lead study author and a senior scientist at Princess Margaret Cancer Centre in Ontario, Canada, stated in an oral presentation of the data. “[Additionally], the efficacy and safety of taletrectinib in the global TRUST-II trial remains highly consistent with findings from the regional [phase 2] TRUST-I trial [NCT04395677].”

TRUST-II Overview and Trial Design

The single-arm, open-label, multicenter study enrolled patients 18 years of age or older with locally advanced or metastatic NSCLC who displayed evidence of a ROS1 fusion and had an ECOG performance status of 0 or 1.

Upon enrollment, patients were divided into 1 of 2 cohorts, based on prior TKI exposure.^1,2 Cohort 1 comprised TKI-naive patients, and cohort 2 included TKI-pretreated patients. In both cohorts, taletrectinib was administered at 600 mg once daily in 21-day cycles.

The study’s primary end point was cORR per RECIST 1.1 criteria as assessed by an independent review committee (IRC). DOR, best ORR, time to response, IC-ORR, disease control rate, PFS, and safety served as secondary end points.¹

At the data cutoff date of June 7, 2024, 55 and 50 patients had enrolled onto cohorts 1 and 2, respectively. The median age in the overall population was 56.0 years (range, 27-63). The majority of patients were female (56.0%), never smokers (56.6%), had stage IV disease (95%), and had an ECOG performance status of 1 (58.5%).Regarding geographic region, 46.5% of patients were from Asia, and 53.5% of patients were from non-Asian regions.Brain metastases were reported in 45.3% of patients at baseline. Prior anticancer chemotherapy was administered to 40.3% of patients. A total of 51.6% and 17.0% of patients were previously treated with crizotinib (Xalkori) and entrectinib (Rozlytrek), respectively.

“It appears that taletrectinib works just as well in pretreated patients with crizotinib or entrectinib. The same data are [seen in patients with] measurable baseline brain metastases,” Liu noted.

Interim data from cohorts 1 and 2 of the trial were presented during the 2023 ESMO Congress, which showed a cORR of 92.0% (95% CI, 74.0%-99.0%) per IRC assessment among efficacy-evaluable patients in the TKI-naive population (n = 25). In the TKI-pretreated population (n = 21), the cORR was 57.1% (95% CI, 34.0%-78.2%). Notably, the IC-ORR was 80% (95% CI, 28.4%-99.5%) in patients with measurable brain metastases who were TKI-naive and 62.5% (95% CI, 24.5%-91.5%) in those who were TKI-pretreated.³

Taletrectinib Demonstrates Favorable Safety Profile

The median duration of exposure to taletrectinib was 8.4 months (range, 0.1-28.9).¹ Treatment-emergent adverse effects (TEAEs) leading to dose reduction occurred in 37.1% of patients, 16.4% of which were due to elevated liver enzymes. TEAEs leading to treatment discontinuation were reported in 7.5% if patients; 1.3% of these events were deemed treatment related. No TEAEs leading to death were reported.

The most common TEAEs reported in at least 15% of patients (n = 159) were increased alanine aminotransaminase (any-grade, 67.9%; grade ≥3, 15.1%), increased aspartate aminotransaminase (67.3%; 6.9%), diarrhea (56.6%; 0.6%), nausea (51.6%; 1.9%), vomiting (33.3%; 1.3%), constipation (25.2%; 0.0%), anemia (20.1%; 4.4%), dysgeusia (19.5%; 0.0%), increased blood creatine phosphokinase (18.2%; 3.8%), dizziness (17.0%; 0.0%), and prolonged QT (15.1%; 3.1%).

“The majority [of gastrointestinal toxicities] were grade 1 and actually quite self-limiting in nature,” Liu stated. “Of the noted toxicities, one would want to look at the neurological ones based on other ROS1 TKIs. In this case, dysgeusia and dizziness were practically all grade 1 in nature, and none of them were grade 3 [or higher].”

References

1. Liu G, Yang N, Choi CM, et al. Efficacy and safety of taletrectinib in patients with ROS1+ non-small cell lung cancer: the global TRUST-II study. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract MA06.03.
2. Taletrectinib phase 2 global study in ROS1 positive NSCLC (TRUST-II). ClinicalTrials.gov. Updated February 15, 2024. Accessed September 10, 2024. https://clinicaltrials.gov/study/NCT04919811
3. Efficacy and safety of taletrectinib in patients (Pts) with ROS1+ non-small cell lung cancer (NSCLC): Interim analysis of global TRUST-II study. Ann Oncol. 2023;34(2):S755-S785. doi:10.1016/annonc/annonc1331