Dr Mok on the Efficacy of Taletrectinib in ROS1+ NSCLC

Tony S. K. Mok, BMSc, MD, FASCO, Li Shu Fan Medical Foundation Endowed Professor, chairman, Department of Clinical Oncology, Chinese University of Hong Kong, discusses efficacy findings from a pooled analysis of the phase 2 TRUST-I (NCT04395677) and TRUSTII (NCT04919811) trials investigating taletrectinib (AB-106) in advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC).

This pooled analysis showed the efficacy of the second-generation ROS1 TKI taletrectinib in patients with ROS1-positive NSCLC. In the TKI-naive cohort, the confirmed overall response rate (cORR) with taletrectinib was 88.8% (95% CI, 82.8%-93.2%). In total, 20% of patients in this cohort had received prior chemotherapy. Additionally, the median progression-free survival (PFS) was 45.6 months (95% CI, 29.0-not reached [NR]), and the median duration of response was 44.2 months (95% CI, 30.4-NR), highlighting the long-term benefit of this agent, Mok says.

Among patients in the TKI-pretreated cohort, the cORR was 55.8% (95% CI, 46.1%-65.1%). In total, 37% of the patients in this cohort had received prior chemotherapy. The study also provided notable insights into outcomes among patients harboring the G2320R resistance mutation, Mok emphasizes. Of the 13 TKI-pretreated patients who expressed this mutation, 8 responded to treatment with taletrectinib. This translated to a cORR of 61.5% (95% CI, 31.6%-86.1%). Furthermore, the median PFS was 9.7 months (95% CI, 7.4-12.0), and the median DOR was 16.6 months (95% CI, 10.6-27.3) in all TKI-pretreated patients.

These efficacy findings underscore the efficacy of taletrectinib within the broader context of ROS1-targeted therapy, Mok explains. Although the TKI crizotinib (Xalkori) generated notable PFS outcomes in earlier studies of patients with ROS1-positive NSCLC, second- and third-generation TKIs, such as entrectinib (Rozlytrek) and lorlatinib (Lorbrena), have also demonstrated enhanced efficacy, he says. No head-to-head comparisons of these agents have been conducted; however, newer second-generation TKIs, including taletrectinib, likely offer superior PFS, ORR, and central nervous system efficacy, he reports.

Notably, in the pooled analysis of TRUST-I and TRUST-II, taletrectinib led to an intracranial ORR of 76.5% (95% CI, 50.1%-93.2%) in TKI-naive patients. These data reinforce the agent’s potential utility as a first-line therapy for patients with ROS1-positive NSCLC, particularly those with brain metastases, Mok concludes.

The most common treatment-related adverse effects (TEAEs) were elevated liver enzyme levels and gastrointestinal issues. Neurologic TEAEs included dizziness in 21.1% of patients and dysgeusia in 14.5% of patients; most neurologic TEAEs were grade 1. 

Videos

Tony S. K. Mok, BMSc, MD, FASCO, discusses efficacy findings from a pooled analysis of the TRUST-I and TRUST-II trials of taletrectinib in ROS1+ NSCLC.

Dr Patel on Findings From the TRUST-II Trial in ROS1+ NSCLC

Jyoti Patel, MD, professor medicine (hematology and oncology), associate vice chair, Clinical Research, Department of Medicine, Northwestern University; medical director, Thoracic Oncology, assistant director, Clinical Research, Lurie Cancer Center, Feinberg School of Medicine, Northwestern Medicine, discusses the findings and clinical implications of the phase 2 TRUST-II trial (NCT04919811) in patients with locally advanced or metastatic 

-positive non–small cell lung cancer (NSCLC), regardless of prior TKI exposure.

At the 2024 IASLC World Conference on Lung Cancer, investigators presented data from the global, single-arm, open-label, multicenter TRUST-II trial, which evaluated the taletrectinib (AB-106) in this patient within this population. At a median follow-up of 15.8 months (range, 3.6-29.8), the next-generation ROS1 TKI demonstrated a confirmed overall response rate (cORR) of 85.2% (95% CI, 72.88%-93.38%) in patients without prior exposure to a ROS1 TKI (n = 54). Conversely, 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).

The TRUST-II study demonstrated high overall and intracranial response rates across 2 patient groups: TKI-naive patients and those previously treated with TKIs, Patel begins. In the pretreated cohort, most of the patients had received prior treatment with crizotinib (Xalkori) or entrectinib (Rozlytrek), she reports, adding that during the trial, patients in both cohorts received taletrectinib at a dose of 600 mg once daily. Notably, the intracranial response rates among patients who were TKI naive (n = 9) and TKI pretreated (n = 16) were 66.7% (95% CI, 29.93%-92.51%) and 56.3% (95% CI, 29.88%-80.25%), respectively, Patel explains.

The treatment was generally well tolerated, although dose reductions were required in 37.1% of patients, 16.4% of which were due to elevated liver enzymes, she explains. Notably, taletrectinib has shown efficacy in patients with 

 translocations, which are notoriously difficult to treat, Patel emphasizes.

Jyoti Patel, MD, discusses the implications of the TRUST-II trial in locally advanced or metastatic ROS1-positive NSCLC, regardless of prior TKI exposure.

Dr Drilon on Efficacy Results With Taletrectinib in ROS1+ NSCLC

Alexander Drilon, MD, thoracic oncologist, chief, early drug development service, Memorial Sloan Kettering Cancer Center, discusses efficacy findings from an integrated analysis of the regional TRUST-I (NCT04395677) and global TRUST-II (NCT04919811) trials which investigated treatment with taletrectinib (AB-106) in patients with 

-positive non–small cell lung cancer (NSCLC).

Data from the pooled analysis were presented during the 

, and showed that taletrectinib elicited high, durable responses and had favorable tolerability in the registrational cohorts, Drilon begins. Among the 160 patients with ROS1 TKI–naive NSCLC, the confirmed overall response rate (cORR) by independent review committee (IRC) assessment was 88.8% (95% CI, 82.8%-93.2%), he reports. At a median follow-up of 21.2 months, the median duration of response (DOR) was 44.2 months (95% CI, 30.4-not reached [NR]), with a 24-month DOR rate of 70.2% (95% CI, 59.9%-78.3%). Furthermore, the median progression-free survival (PFS) reached 45.6 months (95% CI, 29.0-NR), and the 24-month PFS rate was 63.9% (95% CI, 54.2%-72.1%), he adds.

In patients with measurable brain metastases (n = 17), the intracranial cORR was 76.5% (95% CI, 50.1%-93.2%), indicating strong activity against brain lesions. Notably, deep responses observed on the waterfall plot revealed substantial disease regression in the majority of patients treated with taletrectinib, Drilon notes.

When compared with earlier-generation ROS1 TKIs, such as entrectinib (Rozlytrek) or crizotinib (Xalkori), and even other next-generation TKIs like repotrectinib (Augtyro), taletrectinib demonstrated superior or comparable response rates, Drilon states. Importantly, the durability of response and PFS seen with taletrectinib marked a significant improvement over older TKIs, reflecting the advantage of using a more potent, next-generation ROS1 inhibitor as frontline therapy, he explains.

 fusion–positive lung cancer, where second- or third-generation TKIs have replaced earlier-generation agents in the first-line setting due to their ability to achieve more durable responses and longer PFS, Drilon says. The results reinforce taletrectinib’s potential to become a preferred option for 

Alexander Drilon, MD, discusses efficacy findings from the TRUST-I and TRUST-II trials in patients with ROS1+ non–small cell lung cancer.

Taletrectinib (AB-106) elicited high and durable overall response rates with favorable tolerability in the registrational cohorts of patients with advanced 

-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 

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 

-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 

-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 

-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 

 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%).

 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 

-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%).

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 

-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.

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.

Li W, Xiong A, Yang N, et al. Efficacy and safety of taletrectinib in Chinese patients with 

non–small cell lung cancer: the phase II TRUST-I study. 

. 2024;42(22):2660-2670. doi:10.1200/JCO.24.00731

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. 

. 2023;34(suppl 2):S788-S789. doi:10.1016/j.annonc.2023.09.2406

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.

Articles

Taletrectinib (AB-106) has shown promising efficacy and tolerability in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) across the TRUST-I and TRUST-II studies. In ROS1 TKI-naive patients, the overall response rate (cORR) was 88.8%, with a median duration of response of 44.2 months. For pretreated patients, the cORR was 55.8%. The drug demonstrated significant intracranial activity, particularly in TKI-naive patients. Safety data indicated manageable treatment-emergent adverse effects, supporting taletrectinib's potential as a best-in-class ROS1 TKI for this patient population.

Taletrectinib elicited high and durable overall response rates with favorable tolerability in patients with advanced ROS1-positive NSCLC. 

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

The next-generation ROS1 TKI taletrectinib (AB-106) induced robust overall and intracranial responses in patients with locally advanced or metastatic 

-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 the

2024 IASLC World Conference on Lung Cancer

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 

-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].”

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 

 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.

 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.

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

 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.

Taletrectinib Demonstrates Favorable Safety Profile

The median duration of exposure to taletrectinib was 8.4 months (range, 0.1-28.9).

 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].”

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

Efficacy and safety of taletrectinib in patients (Pts) with ROS1+ non-small cell lung cancer (NSCLC): Interim analysis of global TRUST-II study. 

 2023;34(2):S755-S785. doi:10.1016/annonc/annonc1331

Taletrectinib was safe and generated durable responses in both TKI-naive and -pretreated patients with ROS1-positive non–small cell lung cancer.

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

Dr Bazhenova on Updated Data From the TRUST-I Trial of Taletrectinib in ROS1+ NSCLC

Lyudmila A. Bazhenova, MD, clinical professor, medicine, The University of California, San Diego (UCSD); medical oncologist, Moores Cancer Center, UCSD Health, discusses updated efficacy data from the phase 2 TRUST-I study (NCT04395677) investigating taletrectinib (AB-106) in patients with ROS1-positive advanced or metastatic non–small cell lung cancer (NSCLC) and highlights the agent's potential role in the NSCLC treatment paradigm. 

The multicenter, single-arm, open-label, pivotal TRUST-I trial evaluated taletrectinib and was conducted in China. TRUST-I comprised both a cohort of patients who were TKI-naive and a cohort of patients pretreated with crizotinib (Xalkori). Findings from a larger patient sample were presented at the 2024 ASCO Annual Meeting, and they were found to be consistent with previously reported data, Bazhenova reports. With longer follow-up, taletrectinib demonstrated durable overall responses; robust intracranial and ROS1 G2032R activity; and a safety profile with a low incidence of neurologic adverse effects (AEs), she says. 

In the TKI-naive cohort (n = 106), the overall response rate (ORR) was 90.6% (95% CI, 83.33%-95.38%) per independent central review assessment. Notably, the median progression-free survival (PFS) was not yet reached (NR; 95% CI, 29.1-NR) at a median follow-up of 23.5 months; the 2-year PFS rate was 70.5%. The PFS data were particularly impressive considering the aggressive nature of the disease, Bazhenova says. 

In the crizotinib-pretreated cohort (n = 66), the ORR was 51.5% (95% CI, 38.88%-64.01%), and at a median follow-up of 9.7 months, the median PFS was 7.6 months (95% CI, 5.5-12.0). This cohort highlighted taletrectinib's efficacy against the ROS1 G2032R mutation—the most common resistance mutation to other ROS1-targeted TKIs, Bazhenova explains. For patients with this mutation (n = 12), the ORR was 66.7%. 

Moreover, the data underscored the central nervous system (CNS) efficacy of taletrectinib, Bazhenova notes. Among patients with measurable CNS lesions, the intracranial confirmed ORR was 87.5% (95% CI, 47.35%-99.68%) in the TKI-naive cohort (n = 8) and 73.3% (95% CI, 44.90%-92.21%) in the crizotinib-pretreated cohort (n = 15). 

Given these results, taletrectinib may be positioned for use as the first ROS1-targeted TKI and in the post-TKI setting, Bazhenova says. In TKI-naive patients, the ORR and durability of responses make the agent a strong candidate for patients who have not been exposed to a TKI. In the post-TKI setting, taletrectinib’s efficacy against resistant mutations such as ROS1 G2032R offers a valuable treatment option for patients who have progressed on other therapies, she explains. 

However, taletrectinib's optimal role will be clearer after a full analysis of the data, Bazhenova adds. Regulatory agencies may require head-to-head clinical trials against currently approved standard-of-care treatments to make informed decisions about its approval and use. Until then, taletrectinib remains a TKI of interest with substantial potential to improve outcomes for patients with ROS1-positive NSCLC, Bazhenova concludes.

Lyudmila A. Bazhenova, MD, discusses updated efficacy data from the TRUST-I study of taletrectinib in ROS1-positive advanced non–small cell lung cancer.

Dr Lin on the Efficacy and Safety of Taletrectinib in ROS1 Fusion+ NSCLC

Jessica Lin, MD, associate professor, medicine, Harvard Medical School; attending physician, Center for Thoracic Cancers, Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital, discusses key findings from the phase 2 TRUST-I trial (NCT04395677) of taletrectinib (AB-106) in patients with ROS1 fusion–positive non–small cell lung cancer (NSCLC).

TRUST-I, which was conducted in China, evaluated the next-generation ROS1 inhibitor in patients with metastatic ROS1 fusion–positive NSCLC. Currently, 2 first-generation ROS1 inhibitors are FDA approved: crizotinib (Xalkori) and entrectinib (Rozlytrek). Both agents induce median progression-free survival (PFS) outcomes ranging from approximately 16 to 19 months, Lin says. Additionally, the next-generation ROS1 and TRK inhibitor repotrectinib (Augtyro) was 

 in 2023 for patients with locally advanced or metastatic ROS1-positive NSCLC. In the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116), repotrectinib elicited a median PFS of 35.7 months (95% CI, 27.4-not estimable) in patients who had not previously received a ROS1 TKI.

 were presented from both the TKI-naive (n = 106) and crizotinib-pretreated (n = 67) patient populations. In the TKI-naive population, taletrectinib generated a confirmed overall response rate (cORR) of 90.6% (95% CI, 83.33%-95.38%), and the median PFS was not reached (NR; 95% CI, 29.1-NR) after a median follow-up of 23.5 months. In crizotinib-pretreated patients, the cORR was 51.5% (95% CI, 38.88%-64.01%), and the median PFS was 7.6 months (95% CI, 5.5-12.0) at a median follow-up of 9.7 months. These findings support the use of taletrectinib as an effective therapy for patients with ROS1 fusion–positive NSCLC who have received prior ROS1 inhibitors. Currently, repotrectinib is the only FDA approved agent for such cases, and additional therapies are needed for this patient population, Lin emphasizes.

Taletrectinib also has central nervous system activity. In TRUST-I, the intracranial cORRs were 87.5% (95% CI, 47.35%-99.68%) and 73.3% (95% CI, 44.90%-92.21%) in patients with baseline brain metastases who were TKI naive (n = 8) and crizotinib pretreated (n = 15), respectively.

The safety profile of taletrectinib is also noteworthy, Lin explains. Entrectinib and repotrectinib, which inhibit both ROS1 and TRK proteins, can accordingly cause neurologic adverse effects (AEs) due to TRK inhibition. In TRUST-I, however, taletrectinib was associated with few neurologic AEs, Lin notes. Although dizziness was observed in the trial, most treatment-related AEs were related to increases in aspartate aminotransferase/alanine aminotransferase levels and gastrointestinal AEs, indicating that taletrectinib may have a more favorable safety profile vs other agents in its class, according to Lin.

Jessica Lin, MD, discusses key findings from the phase 2 TRUST-I trial in patients with ROS1 fusion–positive NSCLC. 

Treatment with taletrectinib (AB-106) yielded high and durable responses in patients with 

-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 

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 

-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 

-positive NSCLC have been accepted by the Center for Drug Evaluation of the National Medical Products Administration of China, and granted priority review designations.

TRUST-I was conducted in China and enrolled adult patients with 

-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.

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%).

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 

-positive NSCLC and other solid tumors in the US, Europe, and Asia.

Disclosures: Dr Li did not have any disclosures to cite.

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. 

. 2024;42(suppl 16):8520. doi:10.1200/JCO.2024.42.16_suppl.8520

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://www.prnewswire.com/apac/news-releases/innovent-announces-taletrectinibros1-inhibitorupdated-data-from-pivotal-phase-2-trust-i-study-of-are-published-in-the-jco-and-orally-presentedat-2024-asco-annual-meeting-302161197.html

Taletrectinib (AB-106) demonstrated high and durable responses in ROS1-positive NSCLC patients, including those previously treated with crizotinib, according to phase 2 TRUST-I trial data. Treatment-naive patients showed a 90.6% ORR and a 95.3% DCR, with a median follow-up of 23.5 months. Patients previously treated with crizotinib had a 51.5% ORR and an 83.3% DCR. Taletrectinib also showed efficacy against resistance mutations, including G2032R. The trial's success led to new drug applications in China for first- and second-line treatments of ROS1-positive NSCLC.

Taletrectinib demonstrated high response rates and a tolerable safety profile in patients with ROS1-positive non–small cell lung cancer.

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