Treatment with the next-generation ROS1 TKI taletrectinib (AB-106) yielded robust, durable, and consistent overall and intracranial responses in patients with locally advanced or metastatic 

-positive non–small cell lung cancer (NSCLC) who were ROS1 TKI naive and with prior exposure to a ROS1 TKI, according to data from the phase 2 TRUST-II trial (NCT04919811) that were presented during the 

Interim results from cohorts 1 and 2 of the trial demonstrated that efficacy-evaluable patients in the TKI-naive population (n = 25) experienced a confirmed overall response rate (cORR) of 92.0% (95% CI, 74.0%-99.0%) per independent review committee (IRC) assessment. This was entirely composed of partial responses (PR).

Patients who were previously exposed to a ROS1 TKI (n = 21) achieved a cORR of 57.1% (95% CI, 34.0%-78.2%), including a confirmed complete response (cCR) rate of 19.0% and a confirmed PR rate of 38.1%. Stable disease was achieved in 28.6% of patients, and 14.3% experienced disease progression.

Moreover, patients with measurable brain metastases who were TKI-naive achieved an intracranial confirmed overall response rate (IC-cORR) of 80% (95% CI, 28.4%-99.5%); the IC-cORR in the TKI-pretreated group was 62.5% (95% CI, 24.5%-91.5%).

“I'm excited about the data that we see with taletrectinib…” Jason Porter, MD, medical oncologist, hematologist, director, Lung Cancer Disease Research Group, West Cancer Center and Research Institute, said regarding the agent’s potential future role in NSCLC. “[These results are in] a small patient population, but when you're that patient, you want the best, most effective drug with the least [AEs], as well as the one that's going to keep you safe by working in your central nervous system [CNS]. It’s got a bright future,” he added.

taletrectinib breakthrough therapy designation

for adult patients with advanced or metastatic 

-positive NSCLC who had not previously been treated with a ROS1 inhibitor as well as those who had experienced progression on crizotinib (Xalkori).

 The agent was also granted priority review status on December 18, 2023, by China’s National Medical Products Administration for patients with advanced or metastatic 

-positive NSCLC who were previously treated with ROS1 TKIs.

Both regulatory decisions were supported by initial data from TRUST-1, in which TKI-naive and -exposed patients experienced an IRC-assessed cORR of 92.5% (95% CI, 83.4%-97.5%) and 52.6% (95% CI, 35.8%-69.0%), respectively.

“Some of the ROS1 inhibitors are also NTRK inhibitors. Although inhibiting NTRK allows you to use the drug in an 

 fusion­–positive cancer, it also introduces some [neurologic] toxicities. Therefore, the selectivity of taletrectinib hopefully leads to less dizziness, less of those neurologic effects,” said Stephen V. Liu, MD, an associate professor, of medicine, Georgetown University, director, Thoracic Oncology, head, Developmental Therapeutics, Georgetown Lombardi Comprehensive Cancer Center. “The key [question when] looking at ROS1 inhibition is: can we deliver something [that is] effective over time and is well tolerated to maintain quality of life?”

In TRUST-II, investigators aimed to validate results from the TRUST-I trial in a global population. The data cutoff date for the current analysis was July 12, 2023.

TRUST-II is a global, multicenter, open-label, single-arm study that enrolled patients at least 18 years of age with locally advanced or metastatic NSCLC, an ECOG performance status of 0 or 1, at least 1 measurable lesion, and evidence of 

 fusion in tumor tissue. Notably, patients displaying stable CNS involvement were allowed to enroll in the study.

“That's critical for any drug being developed in this space. It is not going to be useful to us unless it's very active in the brain,” Liu emphasized during an interview with 

Patients were enrolled onto 1 of 4 patient cohorts, and all received 600 mg of oral taletrectinib once a day in 21-day cycles. The cohorts included patients with NSCLC who were TKI naive and had received no more than 1 prior line of chemotherapy (cohort 1), exposed to 1 prior ROS1 TKI and no more than 1 prior line of chemotherapy (cohort 2), or exposed to 2 or more prior ROS1 TKIs and no more than 1 prior line of chemotherapy (cohort 3). Cohort 4 comprised patients with 

-positive NSCLC who were ineligible for cohorts 1 through 3. Patients with NSCLC were eligible if previously treated with no more than 3 prior ROS1 TKIs and 2 lines of chemotherapy.

The trial’s primary end point was IRC-assessed cORR per RECIST 1.1 criteria. Key secondary end points included duration of response (DOR), disease control rate (DCR), intracranial cORR, progression-free survival (PFS), overall survival (OS), time to response (TTR), and safety.

All patients who received 1 or more doses of taletrectinib were evaluable for safety.

A total of 46 patients were enrolled in the study at the time of data analysis, 25 of whom were in cohort 1 and 21 who were included in cohort 2. The median age of patients was 58 years old (interquartile range, 52.8-67.0), 46% were female, and 63% had an ECOG performance status of 1. Half of the patients were never smokers, followed by former smokers (46%) and current smokers (4%). Fifty-two percent of patients who previously had chemotherapy and 52% who had brain metastasis were TKI-exposed. Notably, 81% and 19% of patients in cohort 2 had previously received crizotinib or entrectinib (Rozlytrek), respectively.

Additional data showed that the median PFS was not reached (NR; 95% CI, 12.0-NR) and the 12-month PFS rate was 82.3% (95% CI, 59.2%-93.0%) in cohort 1 at a median follow-up of 8.1 months (range, 5.6-11.7). After a median follow-up of 11.7 months (range, 5.5-15.8) in cohort 2, median PFS and PFS rate were 11.7 months (95% CI, 4.0-NR) and 42.6% (95% CI, 18.0%-65.5%), respectively.

Although the median DOR was not mature in either cohort, Kaplan-Meier estimates showed that patients achieved 6- and 12-month DOR rates of 89.5% in cohort 1 and 81.5% in cohort 2, respectively.

In the safety-evaluable population (n = 107), the median duration of treatment exposure was 4.9 months (range, 0.09-18.9). Common any-grade treatment-emergent adverse effects (TEAEs) in 15% or more of this population included alanine aminotransferase increase (64%), aspartate aminotransferase increase (63%), diarrhea (43%), nausea (43%), vomiting (29%), dysgeusia (18.7%), anemia (16.8%), constipation (16.8%), and blood CPK increase (15.0%).

Most patients experienced low-grade TEAEs, although 12% of patients did report a serious AE. The majority of neurologic TEAEs were similarly low grade and less frequently observed. However, 13% of patients experienced dizziness. Dose reductions due to TEAEs occurred in 34% of patients, the most common reason for which was increased liver enzymes (23%). Treatment discontinuation due to TEAEs was observed in 2% of patients, and no drug-related deaths were reported.

“We're seeing a much better safety profile [with taletrectinib] because you're not inhibiting TRK or some of these other kinases. Early data suggest that the safety profile looks pretty good,” said Alexander Drilon, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York. “It's good to hear that there are other options coming down the pike for patients with 

Christine Bestvina, MD, assistant professor of medicine, hematology, and oncology (cancer), University of Chicago Medicine Comprehensive Cancer Center added that taletrectinib does have “some impressive response rates from what we’ve seen early on, and it looks like it has significant CNS efficacy. The side effects are [also] a little bit different than what we've seen with some of the prior TKIs. I'm not quite sure where taletrectinib is going to fit in [to the paradigm in light of] the approval of repotrectinib [Augtyro]. There's always going to be a balance of toxicity and efficacy, so I think [its role is] still to be determined.”

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

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 2023, 2022. 

https://www.anhearttherapeutics.com/news/press-releases/080322/

Innovent and AnHeart Therapeutics announce the National Medical Products Administration of China has granted taletrectinib (ROS1 Inhibitor) priority review designation. News Release. PRNewswire. December 18, 2023. Accessed December 20, 2023. https://www.prnewswire.com/news-releases/innovent-and-anheart-therapeutics-announce-the-national-medical-products-administration-of-china-has-granted-taletrectinib-ros1-inhibitor-priority-review-designation-302017538.html#:~:text=In%20March%202022%2C%20taletrectinib%20was,TKIs%20(TKI%2Dna%C3%AFve). 

Li W, Yang N, Li K, et al. Updated efficacy and safety of taletrectinib in patients with ROS1+ non–small cell lung cancer. 

. 2023;18(4):S47-S48. doi:10.1016/S1556-0864(23)00268-X

Articles

Clinicians discuss data on the ROS1 TKI taletrectinib in patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer.

Taletrectinib Continues to Demonstrate High Clinical Activity in Advanced ROS1+ NSCLC

The Potential Benefit of Taletrectinib in ROS1+ NSCLC

Dr Drilon on the Potential Benefit of Taletrectinib in ROS1+ NSCLC

Alexander Drilon, MD, thoracic oncologist, chief, early drug development service, Memorial Sloan Kettering Cancer Center, discusses the potential benefit of taletrectinib (AB-106) in patients with 

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

Repotrectinib (Augtyro) is currently one of the only 

 for patients who are refractory to prior ROS1 TKIs. This approval was granted in November 2023 based on findings from the phase 1/2 TRIDENT-1 study (NCT03093116). However, repotrectinib is not the only next-generation ROS1 inhibitor that is being evaluated for this patient population, Drilon begins. 

The next-generation TKI taletrectinib has shown efficacy in patients post progression on a previous ROS1 TKI, he states. The agent is currently being investigated in the international, multicenter, open-label, single-arm, phase 2 TRUST-II trial (NCT04919811). Findings from this trial presented at the 

 demonstrated robust and durable tumor responses with taletrectinib in evaluable patients with 

-mutated NSCLC. The agent produced a confirmed overall response rate of 92.0% (95% CI, 74.0%-99.0%) in patients who were ROS1 TKI naive, and 57.1% (95% CI, 34.0%-78.2%) in those who were pretreated with a ROS1 TKI.

Beyond taletrectinib, the novel ROS1 inhibitor NVL-520 has also shown early benefit for patients within this patient population, Drilon adds.

The body of evidence in support of taletrectinib, including previously reported findings from the TRUST-I study (NCT04395677) in China, has expanded with data from TRUST-II, he states. Drilon explains that the agent may receive regulatory approval for both ROS1 TKI-pretreated and ROS1 TKI-naive patients. Notably, taletrectinib has shown clinical proof of principle, emphasizing its role as an active drug in this treatment space, he states.

Overall, the treatment armamentarium for patients with 

-positive NSCLC reflects the increased focus on precision medicine, Drilon continues. This paradigm extends beyond TKIs and small molecules to novel antibody-drug conjugates, he says. This diversified armamentarium may provide patients with innovative treatment options, Drilon explains.

Videos

Alexander Drilon, MD, discusses the potential benefit of taletrectinib in patients with ROS1-positive non–small cell lung cancer.

Dr Porter on the Potential Role for Taletrectinib in ROS1+ NSCLC

Jason Porter, MD, medical oncologist, hematologist, director, Lung Cancer Disease Research Group, West Cancer Center and Research Institute, discusses the potential role of the next-generation TKI taletrectinib (AB-106) in patients with 

-positive non–small cell lung cancer (NSCLC), according to data from the phase 2 TRUST-II trial (NCT04919811).

Interim results from the international, multicenter, open-label, single-arm TRUST-II trial were presented at the 

, and showed that taletrectinib demonstrated robust and durable tumor responses. Confirmed overall response rates with the agent were 92.0% (95% CI, 74.0%-99.0%) and 57.1% (95% CI, 34.0%-78.2%) in evaluable patients who were TKI naive and TKI pretreated, respectively.

Furthermore, the intracranial overall response rates in patients with measurable brain metastases were 80% (95% CI, 28.4%-99.5%) in the TKI-naive population and 62.5% (95% CI, 24.5%-91.5%) in the TKI-pretreated population.

These data have clinical implications for reshaping treatment approaches in 

-positive disease, Porter begins, adding that the agent’s impact may be comparable to that of crizotinib (Xalkori) in 

-positive NSCLC. Taletrectinib exhibits notable activity against 

 mutations, which are associated with resistance to crizotinib and earlier ROS1 inhibitors, Porter explains. This extends the potential applicability of taletrectinib to patients who have previously progressed on crizotinib, he says.

Notably, another key feature of taletrectinib is its efficacy against central nervous system (CNS) involvement, which has the potential to address unmet needs associated with crizotinib, Porter adds. Although crizotinib demonstrates CNS activity, recent ALK inhibitors have showcased improved efficacy in the CNS, he details. Taletrectinib shows similarly improved activity in patients with 

-mutant disease, potentially becoming a preferred choice for its enhanced CNS penetration, Porter states.

 resistance mutation combined with increased CNS efficacy positions taletrectinib as a promising candidate for patients with 

 mutations who are at a higher risk of CNS disease, Porter emphasizes. These observed benefits could position taletrectinib as a prospective first-line agent for patients with 

In addition to taletrectinib's promising efficacy, it is important to consider potential toxicities associated with this agent, particularly neurotoxicity or CNS toxicity, Porter continues. However, taletrectinib was developed, in part, to overcome some of the CNS toxicity observed with crizotinib and entrectinib (Rozlytrek), he notes. Despite originating in a small patient population, the encouraging data from TRUST-II underscore the value of taletrectinib as a potential option for patients with 

-positive NSCLC in need of an effective and safe treatment, Porter concludes.

Jason Porter, MD, discusses the potential role of the next-generation TKI taletrectinib in patients with ROS1-positive non–small cell lung cancer, according to data from the phase 2 TRUST-II trial.

Heather Wakelee, MD, FASCO, discusses early data on the use of taletrectinib (AB-106) in patients with ROS1-positive NSCLC from the phase 2 TRUST-II trial.

  Dr Wakelee on the Implications of the TRUST-II Trial of Taletrectinib in ROS1+ NSCLC

Heather Wakelee, MD, FASCO, professor, medicine, chief, Division of Oncology, Stanford University School of Medicine, deputy director, division chief, Medical Oncology, Stanford Cancer Institute, president, International Association for the Study of Lung Cancer, discusses the significance of early data on the use of taletrectinib (AB-106) in patients with 

-positive non–small cell lung cancer (NSCLC) from the phase 2 TRUST-II trial (NCT04919811).

Increased understanding of driver mutations in NSCLC has prompted ongoing efforts to refine the efficacy of existing treatments and expand the current armamentarium, Wakelee begins. Although 

 mutations are considered rare, patients with disease harboring this alteration tend to experience good prognosis, Wakelee says. Accordingly, the development of novel therapies targeting 

 mutations is of significance interest, despite the availability of established ROS1–targeted agents, such as entrectinib (Rozlytrek) and crizotinib (Xalkori), she explains.

Interim findings from the international TRUST-II trial were presented at the 2023 ESMO Congress. Although caution should be exercised when interpreting the trial’s findings because of its limited patient population, initial results underscore the agent's high and durable clinical activity, Wakelee reports. Taletrectinib elicited a confirmed overall response rate (cORR) of 92.0% in evaluable patients who were TKI naive (n = 25). Additionally, the agent produced a cORR of 57.1% in patients who had been previously treated with a ROS1 TKI (n = 21). Encouraging intracranial responses were also observed in the TKI-naive population (80.0%; 95% CI, 28.4%-99.5%) and in the TKI-pretreated population (62.5%; 95% CI, 24.5%-91.5%).

Taletrectinib is associated with abnormal liver function test results, although these lab abnormalities may not necessarily manifest as toxicities experienced by patients, Wakelee details. Continued investigation of taletrectinib in an expanded patient population will further elucidate the antitumor activity, duration of response, and overall tolerability achieved with the agent, she says.

Ultimately, the continued investigation of taletrectinib in patients with 

-mutated NSCLC represents the importance of ongoing research efforts to target 

, and various other driver mutations, Wakelee states. The exploration of such novel agents holds promise for advancing personalized medicine within NSCLC, Wakelee concludes.

Heather Wakelee, MD, FASCO, discusses the significance of early data on the use of taletrectinib in patients with ROS1-positive non–small cell lung cancer from the phase 2 TRUST-II trial.

Dr Wakelee on the Implications of the TRUST-II Trial of Taletrectinib in ROS1+ NSCLC

Stephen V. Liu, MD, associate professor, medicine, Georgetown University, director, Thoracic Oncology, head, Developmental Therapeutics, Georgetown Lombardi Comprehensive Cancer Center, discusses the interim analysis of the phase 2 TRUST-II trial (NCT04919811), which is investigating the use of taletrectinib (AB-106) in patients with 

At the 2023 ESMO Congress, Liu expanded on data from the international trial, which indicated that in evaluable patients (n = 154), taletrectinib induced robust and durable tumor responses, with a confirmed overall response rate (cORR) of 92.0% in patients who were TKI naïve and 57.1% in patients who were TKI pretreated. Moreover, intracranial responses proved to be robust, at 80.0% and 62.5% in patients who were TKI naïve and TKI pretreated, respectively.

These data are beneficial, specifically within the TKI-naïve patient population, where ORRs consistently surpass 90%, Liu begins. Taletrectinib is generating exceptionally high efficacy, even when compared with the efficacy seen with TKIs such as crizotinib (Xalkori) or entrectinib (Rozlytrek), he emphasizes. Notably, these data continue to impress investigators, as both the median duration of response and the median progression-free survival (PFS) have not yet been reached, Liu states.

Investigators continue to witness robust activity of taletrectinib within the central nervous system, a domain of importance, he expands. For patients who have not received prior treatment, particularly those with non-irradiated tumors and measurable brain metastases, the intracranial response rate stands at 80%, Liu says. Every patient treated in TRUST-II has exhibited some degree of reduction in their brain lesions. This neurological effectiveness is an important criterion for any drug used in patients with brain metastases, as the utility of these agents hinges on their ability to act decisively within the brain, Liu emphasizes. 

Although established agents in the NSCLC treatment paradigm, such as crizotinib or entrectinib, are initially effective, the median PFS elicited with these drugs typically hovers around 1.5 years and may be lower in real-world scenarios, depending on various co-variables, Liu continues. Although this 1.5-year median PFS represents a significant improvement over the PFS obtained with chemotherapy and immunotherapy options, this number should be increased, he states. The next generation of TKIs holds promise and may lead to longer PFS akin to those seen with ALK inhibitors, Liu concludes.

Stephen V. Liu, MD, discusses the interim analysis of the phase 2 TRUST-II trial, which is investigating the use of taletrectinib in patients with ROS1-positive non–small cell lung cancer.


Dr Liu on the Utility of Taletrectinib in ROS1+ NSCLC

D. Ross Camidge, MD, PhD, director, Thoracic Oncology Clinical Program, director, Thoracic Oncology Clinical Research Program, University of Colorado Health Lung Cancer Clinic – Anschutz Medical Campus, discusses the rationale for the ongoing phase 2 TRUST-II trial (NCT04919811) of taletrectinib (AB-106) in patients with non–small cell lung cancer (NSCLC) harboring 

Taletrectinib is a second-generation ROS1 inhibitor in the same class as repotrectinib, Camidge says. The phase 1/2 TRIDENT-1 trial (NCT03093116) showed an overall response rate (ORR) of 79% (95% CI, 68%-88%) with repotrectinib in TKI-naïve patients with 

-positive NSCLC. Additionally, in TKI-pretreated patients with baseline 

 G2032R mutations, the ORR was 59% (95% CI, 33%-82%). Based on these data, 

repotrectinib was granted priority review by the FDA

The TRUST-I trial (NCT04395677), which was conducted in China, showed similar efficacy data with taletrectinib in this population. The agent elicited an ORR of 92.5% (95% CI, 83.4%-97.5%) in patients who were ROS1 TKI–naive and 50.0% (95% CI, 33.4%-66.6%) in those with ROS1 TKI–pretreated disease. In 12 patients with measurable central nervous system metastases at baseline, the intracranial ORR was 91.7% (95% CI, 61.5%-99.8%). Furthermore, among 5 patients with 

 G2032R mutations, 4 achieved a partial response and 1 achieved stable disease, Camidge notes. Based on these data, 

the FDA granted breakthrough therapy designation to taletrectinib

-positive NSCLC in 2022. The ongoing TRUST-II trial aims to validate the findings from TRUST-I in a global population, Camidge emphasizes.

The rate of neurological toxicities with taletrectinib in TRUST-1 was low and needs verification in a global trial, according to Camidge. At the 2023 IASLC World Conference on Lung Cancer, findings from a phase 2 study (NCT03909971) of lorlatinib (Lorbrena) in Chinese patients with previously treated, 

-positive NSCLC were presented. Although lorlatinib is associated with an approximately 60% rate of neurological toxicities in Western populations, investigators reported no neurological adverse effects (AEs) with the agent in this study, Camidge says.

One potential explanation for this disparity between the data is that Chinese patients are more resistant to these AEs. because Additionally, the management of these AEs may require nuanced conversations between oncologists and patients that clinics in other parts of the world may approach differently, thereby garnering different results, Camidge explains. Similarly, 1 aim of the TRUST-II trial will be to determine how the safety profile of taletrectinib in a global population compares to that seen in the Chinese population in TRUST-I, Camidge concludes.

D. Ross Camidge, MD, PhD, discusses the rationale for the ongoing phase 2 TRUST-II trial of taletrectinib in patients with non–small cell lung cancer harboring ROS1 mutations. 

Advances in Precision Medicine in Lung Cancer | Supplements and Featured Publications

Taletrectinib Continues to Demonstrate High Clinical Activity in Advanced ROS1+ NSCLC

Dr Drilon on the Potential Benefit of Taletrectinib in ROS1+ NSCLC

Dr Porter on the Potential Role for Taletrectinib in ROS1+ NSCLC

Dr Wakelee on the Implications of the TRUST-II Trial of Taletrectinib in ROS1+ NSCLC

Dr Liu on the Utility of Taletrectinib in ROS1+ NSCLC

Dr Camidge on the Rationale for the TRUST-II Trial in ROS1+ NSCLC