Pooled TRUST-I and TRUST-II Data Affirm Taletrectinib Benefits for Advanced ROS1+ NSCLC

Maurice Pérol, MD

Taletrectinib (AB-106) elicited high and durable overall response rates with favorable tolerability in the registrational cohorts of patients with advanced ROS1-positive non–small cell lung cancer (NSCLC)enrolled in the regional TRUST-I (NCT04395677) and global TRUST-II (NCT04919811) studies, according to data from an integrated analysis presented as a poster during the 2024 ESMO Congress.¹

In patients who were ROS1 TKI naive (n = 160), the confirmed overall response rate (cORR) with the taletrectinib was 88.8% (95% CI, 82.8%-93.2%) by independent review committee (IRC) assessment. At a median follow-up of 21.2 months (range, 3.6-46.6), the median duration of response (DOR) was 44.2 months (95% CI, 30.4–not reached [NR]), and the 24-month DOR rate was 70.2% (95% CI, 59.9%-78.3%). The median progression-free survival (PFS) was 45.6 months (95% CI, 29.0-NR), and the 24-month PFS rate was 63.9% (95% CI, 54.2%-72.1%). In those with measurable brain metastases (n = 17), the intracranial cORR (IC-cORR) was 76.5% (95% CI, 50.1%-93.2%).

In those who were ROS1 TKI pretreated (n = 113), the cORR with taletrectinib was 55.8% (95% CI, 46.1%-65.1%) by IRC assessment; further, in those whose tumors harbored G2032R mutations (n = 13), the cORR with the agent was slightly higher at 61.5% (95% CI, 31.6%-86.1%). At a median follow-up of 21.0 months (range, 3.9-45.4), the median DOR was 16.6 months (95% CI, 10.6-27.3), and the 12-month DOR rate was 61.1% (95% CI, 46.3%-73.1%). In this group, the median PFS was 9.7 months (95% CI, 7.4-12.0), and the 12-month PFS rate was 39.7% (95% CI, 29.6%-49.6%). In those with measurable brain metastases (n = 32), the IC-cORR was 65.6% (95% CI, 46.8%-81.4%).

“Integrated analysis from the TRUST-I and TRUST-II studies establishes taletrectinib as a potential best-in-class ROS1 TKI for people living with advanced ROS1-positive NSCLC,” Maurice Pérol, MD, of the Department of Medical Oncology at Léon Bérard Cancer Center in Lyon, France, and coauthors, wrote in the poster.

Taking a Closer Look at TRUST-I and TRUST-II

The regional, open-label, single-arm, phase 2 TRUST-I study, which was conducted in China, examined the oral, selective, next-generation ROS1 TKI in patients with ROS1-positive NSCLC; the trial had two patient cohorts: those who had received prior ROS1 TKI treatment and those who did not. The multicenter, open-label, single-arm, global phase 2 TRUST-II study evaluated the agent in patients with ROS1-positive NSCLC and other solid tumors. This trial had 5 cohorts; cohort 1 included those who were naive to ROS1 TKIs, cohort 2 included those who were ROS1 TKI pretreated, and cohorts 3 to 5 were exploratory and included in the safety analysis.

For both trial cohorts, patients needed to have locally advanced or metastatic NSCLC with evidence of a ROS1 fusion. Patients were required to be at least 18 years of age, have an ECOG performance status of 0 or 1, and at least 1 measurable lesion by RECIST 1.1 criteria. Those with stable central nervous system involvement were permitted.

For the pooled analysis, investigators examined only the cohorts of patients who were ROS1 TKI naive or pretreated. All patients had received taletrectinib at 600 mg once daily. Three patients enrolled in TRUST-I started the agent at 400 mg; 2 escalated to 600 mg. The primary end point was cORR per IRC assessment and RECIST 1.1 criteria. Secondary end points included IC-cORR by modified RECIST 1.1 criteria, DOR, PFS, and safety.

Data from TRUST-I showed that in TKI-naive patients (n = 106), taletrectinib elicited a cORR of 90.6% (95% CI, 83.33%-95.38%).² At a median follow-up of 22.1 months and 23.5 months, respectively, the median DOR and median PFS had not yet been reached. The 24-month DOR rate was 78.6% (95% CI, 66.86%-86.56%), and the 24-month PFS rate was 70.5% (95% CI, 59.17%-79.16%). In TKI-naive patients with measurable baseline brain metastases (n = 8), the IC-cORR was 87.5% (95% CI, 47.35%-99.68%).

In those pretreated with crizotinib (Xalkori; n = 66), the cORR with the agent was 51.5% (95% CI, 38.88%-64.01%). At a median follow-up of 8.4 months and 9.7 months, the median DOR was 10.6 months (95% CI, 6.31-NR) and the median PFS was 7.6 months (95% CI, 5.52-11.96). The 9-month DOR and PFS rates were 69.8% (95% CI, 47.94%-83.84%) and 47.4% (95% CI, 33.50%-60.02%), respectively. In the crizotinib-pretreated patients with measurable baseline brain metastases (n = 15), the IC-cORR was 73.3% (95% CI, 44.90%-92.21%).

Interim data from cohorts 1 and 2 of the TRUST-II trial were shared during the 2023 ESMO Congress and showed that the agent induced a cORR of 92.0% (95% CI, 74.0%-99.0%) per IRC assessment in evaluable TKI-naive patients (n = 25).3 In the TKI-pretreated population (n = 21), the cORR was 57.1% (95% CI, 34.0%-78.2%). The IC-cORR 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.

Updated data were shared at the 2024 IASLC World Conference on Lung Cancer and indicated that at a median follow-up of 15.8 months (range, 3.6-29.8), taletrectinib elicited a cORR of 85.2% (95% CI, 72.88%-93.38%) in the TKI-naive group (n = 54).4 For TKI-pretreated patients (n = 47), the cORR was 61.7% (95% CI, 46.38%-75.49%) at a median follow-up of 15.7 months (range, 3.9-29.8). DOR and PFS data were immature in both cohorts at the time of the analysis.

Integrated Analysis: Additional Information and Efficacy Data

The presentation at the 2024 ESMO Congress featured a “more mature integrated analysis from the largest efficacy population [n = 273] of people living with advanced ROS1-positive NSCLC from pivotal studies,” according to the study authors. As of June 7, 2024, a total of 273 patients were enrolled; of these patients, 172 (63%) were from TRUST-I and 101 (37%) were from TRUST-II.

The median patient age was 56 years (range, 26-82), 57% of patients were female, and 94% had stage IV disease. With regard to smoking status, 67% were never smokers, 30% were former smokers, and 4% were current smokers. In terms of geographic region, most patients were from a Western region (83%) and the remainder were from an Asian region (17%). Thirty percent of patients had an ECOG performance status of 0 and 70% had a status of 1. Moreover, 20% of those in the TKI-naive group received prior chemotherapy vs 37% of those in the TKI-pretreated group. Brain metastases were observed in 23% and 49% of patients in the TKI-naive and -pretreated cohorts, respectively.

“Response rates were consistent among the subgroups analyzed,” the authors noted.

Within the TKI-naive group, those from a Western region (n = 21) experienced a cORR of 81.0% (95% CI, 58.09%-94.55%) and those from an Asian region (n = 139) experienced an cORR of 89.9% (95% CI, 83.68%-94.38%). Those with (n = 37) and without (n = 123) brain metastases, experienced cORRs of 86.5% (95% CI, 71.23%-95.46%) and 89.4% (95% CI, 82.60%-94.25%), respectively. Those who received prior chemotherapy (n = 32) experienced a cORR of 87.5% (95% CI, 71.01%-96.49%); those who did not (n = 128) had a cORR of 89.1% (95% CI, 82.33%-93.89%).

In the TKI-pretreated group, the cORRs in those from Western (n = 36) and Asian (n = 87) regions were 65.4% (95% CI, 44.33%-82.79%) and 52.9% (95% CI, 41.87%-63.67%), respectively. Those with brain metastases (n = 55) had a cORR of 56.4% (95% CI, 42.32%-69.70%); in those who did not (n = 58), the cORR was 55.2% (95% CI, 41.54%-68.26%). Those who did (n = 42) or did not (n = 71) receive prior chemotherapy experienced respective cORRs of 59.5% (95% CI, 43.28%-74.37%) and 53.5% (95% CI, 41.29%-65.45%).

A Spotlight on Safety Takeaways

The median duration of exposure to taletrectinib was 11.1 months (range, 0.1-64.1).

The most common treatment-emergent adverse effects (TEAEs) to occur in at least 15% of patients with ROS1-positive NSCLC treated with the agent at a once-daily 600 mg dose (n = 337) included increased aspartate aminotransferase (any grade, 72.1%; grade ≥3, 7.7%), increased alanine aminotransferase (68.0%; 10.1%), diarrhea (63.2%; 2.1%), nausea (47.2%; 1.5%), vomiting (43.3%; 1.5%), anemia (37.4%; 3.6%), constipation (21.1%; 0%), dizziness (21.1%; 0.3%), QT prolongation (19.3%; 3.6%), increased blood creatinine (18.1%; 0%), increased blood bilirubin (17.5%; 1.2%), increased blood CPK (16.6%; 2.1%), decreased neutrophil count (16.6%; 4.2%), decreased appetite (15.7%; 0.3%), and decreased white blood cell count (15.7%; 1.5%).

TEAEs led to a dose reduction for 28.8% of patients; 6.5% of patients experienced TEAEs that led to discontinuation of taletrectinib.

“Overall, taletrectinib demonstrated a favorable benefit-risk profile at the recommended phase 2 dose of 600 mg [once daily],” the study authors concluded.

References

1. Pérol M, Li W, Pennell NA, et al. Pooled efficacy and safety from 2 pivotal phase 2 trials of taletrectinib in patients with advanced or metastatic ROS1+ non–small cell lung cancer. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Poster 1289.
2. Li W, Xiong A, Yang N, et al. Efficacy and safety of taletrectinib in Chinese patients with ROS1+ non–small cell lung cancer: the phase II TRUST-I study. J Clin Oncol. 2024;42(22):2660-2670. doi:10.1200/JCO.24.00731
3. Pérol M, Yang N, Choi C-M, et al. 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(suppl 2):S788-S789. doi:10.1016/j.annonc.2023.09.2406
4. 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.