Taletrectinib Displays Efficacy, Tolerability in ROS1+ NSCLC in Multiple Clinical Trials

With the development of the next-generation ROS1 TKI taletrectinib, investigators are aiming to add a treatment option for patients with ROS1-positive non–small cel lung cancer (NSCLC) that has the potential to produce superior efficacy compared with currently available ROS1 inhibitors with a tolerable safety profile and other enhanced characteristics such as central nervous system (CNS) penetration.1

“There are 2 first-generation ROS1 inhibitors that are approved by the FDA: crizotinib [Xalkori] and entrectinib [Rozlytrek],” Jessica Lin, MD, an attending physician in the Center for Thoracic Cancers and Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital, and an associate professor of medicine at Harvard Medical School, in Boston, said in an interview with OncLive®. “[Those agents have displayed] a median progression-free survival [PFS) in the range of 16 to 19 months. There is also 1 next-generation ROS1 inhibitor that was approved [by the FDA] this past year, repotrectinib [Augtyro], which has a median PFS of approximately 35 months. This is a field where we still need other effective therapy options.”

“The key characteristics [of taletrectinib] include the ability to penetrate the CNS, activity against ROS1 resistance mutations such as G2032R and, importantly, sparing the tropomyosin receptor kinase B [TrkB] receptors, which are responsible for some of the adverse effects [AEs] that we see in other ROS1 TKIs. We are hoping that this will result in a better safety profile,” Lyudmila A. Bazhenova, MD, a medical oncologist and professor of medicine at UC San Diego Health, added in an interview with OncLive.

TRUST-I Data Demonstrate Durable Responses With Taletrectinib in ROS1+ NSCLC

In August 2022, the FDA granted breakthrough therapy designation to taletrectinib in adult patients with advanced or metastatic ROS1-positive NSCLC who did not undergo prior treatment with a ROS1 inhibitor or who received prior crizotinib.2 The regulatory decision was supported in part by preliminary findings from the phase 2 TRUST-I trial (NCT04395677).

TRUST-I is an ongoing Chinese study that enrolled adult patients with locally advanced or metastatic NSCLC with an ECOG performance status of 1 or less harboring a ROS1 fusion.1 The study enrolled 2 cohorts: cohort A included patients who were ROS1 TKI naive and cohort B consisted of patients who previously received crizotinib. Both cohorts received daily taletrectinib at a dose of 600 mg.

The primary end point is confirmed objective response rate (ORR) per RECIST 1.1. Secondary end points include duration of response (DOR), PFS, best overall response, disease control rate (DCR), time to response (TTR), and safety.

At a data cutoff of November 29, 2023, updated data from TRUST-I presented during the 2024 ASCO Annual Meeting demonstrated that patients in cohort A (n = 106) achieved a confirmed ORR by independent review committee (IRC) assessment of 90.6% (95% CI, 83.33%-95.38%). The DCR was 95.3% (95% CI, 89.33%-98.45%) and the median TTR was 1.4 months (95% CI, 1.38-1.41). Notably, at a median follow-up of 23.5 months, the median DOR was not reached (NR; 95% CI, 30.4-NR) and the median PFS was also NR (95% CI, 29.1-NR); the 24-month PFS rate was 70.5%.

In cohort B (n = 66), the IRC-assessed confirmed ORR was 51.5% (95% CI, 38.88%-64.01%) and the DCR was 83.3% (95% CI, 72.13%-91.38%). 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 and PFS were 10.6 months (95% CI, 6.3-NR) and 7.6 months (95% CI, 5.5-12.0), respectively.

Among patients with measurable baseline metastases in cohort A (n = 8) and cohort B (n = 15), the confirmed ORRs were 87.5% (95% CI, 47.35%-99.68%) and 73.3% (95% CI, 44.90%-92.21%), respectively. The DCRs were 100.0%% (95% CI, 63.06-100.0%), and 93.3% (95% CI, 68.05%-99.83%), respectively.

In the overall safety population (n = 173), patients experienced treatment-emergent AEs (TEAEs) leading to treatment interruption (40.5%), dose reduction (19.1%), and treatment discontinuation (5.2%). Common any-grade TEAEs included increased aspartate aminotransferase (AST) levels (76.3%), diarrhea (69.9%), and increased alanine aminotransferase (ALT) levels (67.6%). Notably, the rates of any-grade neurologic TEAEs were low, including dizziness (23%) and dysgeusia (10%). The median exposure time to taletrectinib was 12.2 months (range, 0.23-40.04).

“The safety profile of taletrectinib caught my eye; there wasn’t as much neurologic toxicity as is seen with the other available ROS1 inhibitors,” Lin said. “Entrectinib and repotrectinib inhibit not just ROS1, but also tropomyosin receptor kinase [TRK] proteins and because of that, we can see neurologic AEs arise. With taletrectinib, there was dizziness noted, but most of the treatment-related AEs had to do with AST and ALT [level elevation] and increase in gastrointestinal AEs, so there may be a distinction there in terms of the tolerability profile.”

The updated findings from TRUST-I supported the acceptance of 2 new drug applications (NDAs) for taletrectinib for the first and second-line treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC by the Chinese Center for Drug Evaluation of the National Medical Products Administration.3 Both NDAs also received priority review designations.

Taletrectinib Shows Consistent Activity and Safety Irrespective of Prior TKI Therapy

Following the positive findings from TRUST-I, the phase 2 TRUST-II trial (NCT04919811) was initiated to examine taletrectinib in patients with locally advanced or metastatic ROS1-positive NSCLC.4 The global, single-arm, open-label study enrolled adult patients with a ROS1 fusion and an ECOG performance status of 0 or 1. Stable brain metastases were permitted.

“TRUST-II was complementary to TRUST-I, which was conducted in China alone; TRUST-II was global, but did include a lot of Asian patients,” Jyoti D. Patel, MD, said in an interview with OncLive. “Similar to TRUST-I, in TRUST-II there was a high overall and intracranial response rate. There are two groups of patients: those that were TKI naive and those that were TKI pretreated. Those pretreated patients, by-and-large, were treated with crizotinib or entrectinib.”

Patel is the medical director of Thoracic Oncology and the assistant director for Clinical Research in the Lurie Cancer Center, as well as the associate vice chair for Clinical Research in the Department of Medicine and a professor of medicine (Hematology and Oncology), at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Following enrollment, patients were divided into cohort 1 or 2. Cohort 1 included ROS1 TKI–naive patients and cohort 2 enrolled patients with prior ROS1 TKI exposure. Both cohorts received taletrectinib at a daily dose of 600 mg.

The primary end point was confirmed ORR by IRC per RECIST 1.1. Secondary end points included DOR, DCR, PFS, TTR, and safety.

During the 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC), investigators presented data from TRUST-II, which demonstrated that at a median follow-up of 15.8 months (range, 3.6-29.8) patients in cohort 1 (n = 54) achieved a confirmed ORR of 85.2% (95% CI, 72.88%-93.38%). The confirmed ORRs among patients from Asia (n = 33) and non-Asia regions (n = 21) were 87.9% (95% CI, 71.80%-96.60%) and 81.0% (95% CI, 58.09%-94.55%), respectively.

At a median follow up of 15.7 months (range, 3.9-29.8) patients in cohort 2 (n = 47) experienced a confirmed ORR of 61.7% (95% CI, 46.38%-75.49%). The confirmed ORRs among patients from Asia (n = 21) and non-Asia regions (n = 26) were 57.1% (95% CI, 34.02%-78.18%) and 65.4% (95% CI, 44.33%-82.79%), respectively.

In both cohorts, DOR and PFS results were immature at the time of the data analysis. Patients with measurable baseline brain metastases in cohort 1 (n = 9), achieved an intracranial ORR of 66.7% (95% CI, 29.93%-92.51%), with a complete response (CR) rate of 22.2%. Among these patients in cohort 2 (n = 16), the intracranial ORR was 56.3% (95% CI, 29.88%-80.25%), including a 6.3% CR rate.

“These are very high response rates [and] the next question we have is, ‘what is the durability?’” Stephen Liu, MD, director of Thoracic Oncology and Developmental Therapeutics, as well as an associate professor of medicine at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, DC, said in an interview with OncLive. “What is the median DOR? What does the average response look like? We don’t have that information yet because most of the responses are still ongoing. We will need [those data] to mature to see that, but we’re very excited about what we see [now]. Although we need to wait for the study to mature a bit, I believe this has the potential to be a best-in-class drug.”

In terms of safety, patients in the overall population (n = 159) experienced TEAEs leading to dose reduction (37.1%) and/or treatment discontinuation (7.5%); no TEAEs leading to death occurred. The most common any-grade TEAEs included increased ALT levels (67.9%), increased AST levels (67.3%), and diarrhea (56.6%). The median duration of exposure to taletrectinib was 8.4 months (range, 0.1-28.9).

“If we look towards the next steps, when we have a drug [such as taletrectinib] that’s better tolerated, we can consider giving it for longer periods of time,” Liu added. “That opens up the enticing possibility of using these agents in earlier stages and in patients who’ve had surgery or resection for an early-stage lung cancer; we know those cancers have very high chances of coming back.”

Pooled Analysis Results Reinforce Benefit of Taletrectinib

During the 2024 ESMO Congress, investigators presented more mature data from TRUST-I and TRUST-II in a pooled analysis.5 The analysis represented the largest efficacy population of patients with advanced ROS1-positive NSCLC from pivotal studies. Nearly all patients included in the analysis were treated with daily taletrectinib at a dose of 600 mg; 3 patients in TRUST-I started taletrectinib at a dose of 400 mg, 2 of whom escalated to the 600-mg dose. The primary end point was IRC-assessed confirmed ORR per RECIST 1.1. Secondary end points included DOR, PFS, intracranial confirmed ORR, and safety.

“The rationale for this pooled analysis was to take a more global look at the activity and safety of this drug,” Alexander Drilon, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York, said in an interview with OncLive. “TRUST-I was run in China and TRUST-II was representative of several different centers from around the world. Since the trials both had a unified population of ROS1 fusion–positive lung cancers, this analysis helped aggregate the numbers so that we would have further confidence in the activity of the drug in the population of interest.”

Data from the pooled analysis showed that patients who did not receive a prior ROS1 TKI (n = 160) achieved a confirmed ORR of 88.8% (95% CI, 82.8%-93.2%). At a median follow-up of 21.2 months (range, 3.6-46.6), the median DOR and PFS were 44.2 months (95% CI, 30.4-NR) and 45.6 months (95% CI, 29.0-NR), respectively. The 24-month DOR and PFS rates were 70.2% (95% CI, 59.9%-78.3%) and 63.9% (95% CI, 54.2%-72.1%), respectively.

In the ROS1 TKI–pretreated cohort (n = 113), the confirmed ORR per IRC was 55.8% (95% CI, 46.1%-65.1%), including a confirmed ORR of 61.5% (95% CI, 31.6%-86.1%) among patients with G2032R mutations (n = 13). 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), with a 12-month DOR rate of 61.1% (95% CI, 46.3%-73.1%). The median PFS was 9.7 months (95% CI, 7.4-12.0), with a 12-month PFS rate of 39.7% (95% CI, 29.6%-49.6%).

“Taletrectinib [relative to first-generation ROS1 inhibitors] has shown a substantial increase in median PFS and DOR,” Drilon noted. “I believe this is a consequence of the fact that we’re using a next-generation ROS1 inhibitor, meaning you’re using your best drug up front. We’ve seen this paradigm with EGFR-mutated lung cancers where if you use a better drug up front, you get more durability, and in ALK-fusion positive lung cancers.”

Among patients with measurable brain metastases in the ROS1 TKI–naive (n = 17) and pretreated (n = 32) cohorts, the intracranial confirmed ORRs were 76.5% (95% CI, 50.1%-93.2%) and 65.6% (95% CI, 46.8%-81.4%), respectively.

Safety data from the pooled analysis revealed that, following a median duration of exposure to taletrectinib of 11.1 months (range, 0.1-64.1), patients in the total population (n = 337) experience TEAEs leading to dose reduction or treatment discontinuation at rates of 28.8% and 6.5%, respectively. The most common any-grade TEAEs included increased AST levels (72.1%), increased ALT levels (68.0%), and diarrhea (63.2%).

“This [next]-generation TKI is probably better than crizotinib in terms of PFS and response rate, and especially in terms of CNS efficacy,” Tony S. K. Mok, MD, FASCO,BMSc, the Li Shu Fan Medical Foundation Endowed Professor and chairman of the Department of Clinical Oncology, Chinese University of Hong Kong, said in an interview with OncLive. “I believe that taletrectinib can now be considered as an option for first-line [treatment of patients with] ROS1-positive lung cancer.”

References

1. 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. J Clin Oncol. 2024;42(suppl 16):8520. doi:10.1200/JCO.2024.42.16_suppl.8520
2. 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 November 15, 2024. bit.ly/3CG85UL
3. 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. Innovent Biologics, Inc. June 2, 2024. Accessed November 15, 2024. bit.ly/3Zf4Jmi
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. J Thorac Oncol. 2024;19(10):S72-S73. doi:10.1016/j.jtho.2024.09.131
5. Pérol M, Li W, Pennell NA, et al. Pooled efficacy and safety from 2 pivotal phase II trials of taletrectinib in patients (pts) with advanced or metastatic ROS1+ non–small cell lung cancer (NSCLC). Ann Oncol. 2024;35(suppl 2):S821. doi:10.1016/j.annonc.2024.08.1346