Taletrectinib for the treatment of ROS-1 positive non-small cell lung cancer: a drug evaluation of phase I and II data

ABSTRACT

Introduction

While crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC), unmet needs remain. These unmet needs include treatment options for patients with resistance mutations and efficacious options even in the presence of brain metastasis while simultaneously avoiding unwanted neurological side effects.

Areas covered

Taletrectinib was designed to: improve efficacy; overcome resistance to first-generation ROS1 inhibitors; and address central nervous system penetration while conferring fewer neurological adverse events. All of these features are demonstrated and supported by data from the phase I and the regional phase II TRUST-I clinical trial. Here, we describe the preclinical and clinical characteristics of taletrectinib and evaluate the data from phase I and II studies and review the rationale and design of TRUST-II, a global phase II study of taletrectinib, which is enrolling patients in North America, Europe, and Asia.

Expert opinion

Taltrectinib has the potential to improve PFS based on its greater potency against ROS1+ tumors and high CNS penetration. By selectively inhibiting ROS1 wild-type and its resistant mutations over TRKB, taltrectinib has a better safety profile with minimal CNS-related AEs compared to other ROS1+ inhibitors.

KEYWORDS:

• ROS-1 fusions
• targeted therapy
• precision oncology
• CNS penetrant TKI
• TRKB related adverse events

1. Preclinical data

Taletrectinib (previously AB106 or DS-6051b) is a highly potent, selective, orally available next-generation ROS1 inhibitor. Taletrectinib (Box 1) is not only highly potent against tumors with primary fusions in ROS1, but also for those with ROS1 resistance mutations, such as the secondary solvent-front mutation G2032R [1]. Taletrectinib potently inhibited G2032R tumors with IC50 in the subnanomolar range in the presence of 10 μM ATP in the in vitro kinase assay (Table 1). The IC50 of taletrectinib against G2032R is more than 400-times lower than that of the approved ROS1 inhibitors crizotinib and entrectinib.

Table 1. Summary of IC50 (nM) in the kinase assay (in the presence of 10 µM ATP).

Kinase	Taletrectinib	Crizotinib	Entrectinib	Repotrectinib
ROS1	0.07	0.66	0.71	<0.05
ROS1-G2032R	0.20	86.22	88.00	0.09
TRKA	1.26	8.46	1.63	0.53
TRKB	1.47	6.75	0.15	<0.05
TRKC	0.18	0.53	0.19	0.07

Biochemical IC₅₀ data were generated by Reaction Biology Corp, comparing taletrectinib, repotrectinib, entrectinib, and crizotinib side by side at 10 µM ATP concentration.

IC50: Half maximal inhibitory concentration; ROS1: Proto-oncogene tyrosine-protein kinase; TRKA: Tyrosine receptor kinase A; TRKB: Tyrosine receptor kinase B; TRKC: Tyrosine receptor kinase C.

Box 1: Drug Summary Box.

In addition, taletrectinib demonstrated a superior capability to penetrate the central nervous system (CNS). In rats, the brain-to-plasma ratio of taletrectinib ranged from 0.40 to 3.11 following a single dose at 30 mg/kg. Even after 24 h of dosing, the brain concentrations were still measurable at 26 ng/g (Table 2), indicating that taletrectinib sufficiently penetrated into and had sustained concentrations in the CNS. By comparison, repotrectinib, another next-generation ROS1 inhibitor in development, showed significantly weaker CNS penetration, with the brain-to-plasma ratio ranging from 0 to 0.53 and undetectable at 24 h after dosing (Table 2). In an intracranial mouse patient-derived xenograft tumor model of SDC4 ROS1+ NSCLC, seven out of eight mice survived for 60 days when treated with 100 mg/kg of taletrectinib daily starting on day 6 post inoculation, while all eight mice treated with vehicle died on day 25. In contrast, six out of eight mice treated with 15 mg/kg twice a day of repotrectinib died between day 25 and day 60 (Figure 1). The prolonged survival benefit of taletrectinib compared with repotrectinib in mouse studies suggested its better intracranial antitumor activity.

Figure 1. Survival rates from patient-derived xenograft tumor model of SDC4 ROS1+ NSCLC in mice.

Table 2. Total drug concentrations in the brain and plasma in rat pharmacokinetics study (30 mg/kg PO dosing).

	Taletrectinib			Repotrectinib
Time points (h)	Total Conc. in brain (ng/g)	Total Conc. in plasma (ng/mL)	Brain/plasma ratio	Total Conc. in brain (ng/g)	Total Conc. in plasma (ng/mL)	Brain/plasma ratio
4	220	550	0.40 ± 0.10	32	475	0.07 ± 0.01
10	145	170	0.90 ± 0.19	15	28	0.53 ± 0.15
24	26	8	3.11 ± 1.20	0	2	0

Conc.: Concentration; H: Hour; PO: Per oral.

While entrectinib and repotrectinib do show some intracranial antitumor activity, it comes at a cost of unwanted neurological side effects, likely due to nonselective inhibition of tropomyosin receptor kinase B (TRKB) in the CNS [2,3]. In contrast, taletrectinib was shown to be selective for ROS1 and ROS1 G2032R over TRKB in the kinase assay (Figure 2 & Table 1). The data showed that taletrectinib is 7- to 20-times more selective against ROS1 G2032R, and ROS1 wild-type (i.e., only ROS1+ without other point mutation) over TRKB.

Figure 2. Selectivity graph showing different ratio of TRKB over ROS1 wild type or ROS1 G2032R.

2. Phase I data

Ths US phase I first in human study of taletrectinib enrolled patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/neurotrophic tyrosine kinase receptor (NTRK) rearrangements (NCT02279433). Primary objectives were safety/tolerability, and maximum tolerated dose (MTD) determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity. From a total of 46 patients, the steady-state peak concentration (C_max) and exposure (AUC_0–8) was found to increase dose dependently from 50-mg to 800-mg once-daily doses. Dose limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was determined to be 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1 NSCLC, demonstrating the preliminary efficacy of taletrectinib in this population [4].

Around the same time, Japan was conducting their phase I study of taletrectinib (NCT02675491) and pooled results from the patients with ROS1 NSCLC who enrolled onto either of the phase I study (US or Japan) were subsequently published. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. From a total of 22 patients with ROS1 NSCLC with a median follow-up time of 14.9 months (95% confidence interval [CI]: 4.1–33.8), a total of 18 patients were assessable for response. The confirmed objective response rate (ORR) for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4–87.9) with a disease control rate of 100% (70.1–100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7–70.0) with a disease control rate of 88.3% (95% CI: 443.6–97.0). The median progression-free survival (PFS) for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6–not reached) and 14.2 months (95% CI: 1.5–not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%) [5]. Although the number of patients were small, clinical activity and safety profile appeared to be promising.

3. Phase II data

The current phase II data on taletrectinib comes from the regional phase II trial (TRUST-I, NCT04395677), which is being conducted in China. The study enrolled 40 patients naïve to TKI therapy and 21 patients with prior crizotinib treatment. Given CNS penetration demonstrated in preclinical studies, patients with stable, asymptomatic brain metastases were enrolled. This study excluded patients who received a prior ROS1-TKI other than crizotinib. Participants were treated with taletrectinib 600 mg daily. The interim data showed robust efficacy results with ORRs of 92.5 (95% CI: 83.4–97.5) and 52.6% (95% CI: 35.8–69) in 67 ROS1 TKI-naive patients and 38 ROS1 TKI-pretreated patients, respectively [6]. Among five patients with the ROS1 G2032R resistance mutation, four achieved partial response and one achieved stable disease. In 12 patients with measurable baseline CNS metastases, the intracranial ORR was 91.7% (95% CI: 61.5–99.8).

Taletrectinib was well tolerated. The most common treatment-emergent adverse events (TEAEs) of any grade reported in a total of 178 patients from the taletrectinib 600 mg safety population (with incidences ≥15%) were increased aspartate aminotransferase (70.8%), increased alanine aminotransferase (64.0%), diarrhea (61.2%), vomiting (43.3%), nausea (42.1%), anemia (35.4%), decreased white blood cell count (22.5%), abnormal hepatic function (20.8%) and dizziness (20.8%). Outside of 4 patients (2.2%) with grade 4 decreased white blood cells, no other grade 4 or 5 events were reported for these common TEAEs. The only grade 3 treatment-related adverse events (AEs) to occur in >5% of patients were increased aspartate aminotransferase (6.7%), increased alanine aminotransferase (7.3%) and abnormal hepatic function (6.7%). Out of 178 patients, one patient (0.6%) reported grade 3 dizziness. In all, 36 patients (20.2%) had TEAEs requiring dose reduction, and nine (5.1%) had TEAEs requiring discontinuation of taletrectinib [6].

Inhibition of TRKB in the brain is one of the potential reasons for the high incidence of unwanted CNS-related AEs associated with entrectinib. An ideal next-generation ROS1 TKI should be able to cross the BBB and exert its intracranial antitumor activity while sparing TRKB in the CNS. By comparing the relationship between intracranial objective response and one of the CNS-related AEs, dizziness, among four different ROS1 TKIs (Figure 3), we found that taletrectinib demonstrated a unique balance of excellent intracranial antitumor activity and low CNS AEs [5,6].

Figure 3. Graph on any grade dizziness versus intracranial ORR.

Based on the clinical data accumulated to date, taletrectinib has been granted breakthrough therapy designation by the US FDA for the treatment of adult patients with advanced or metastatic ROS1+ NSCLC who are either TKI treatment naive or previously treated with crizotinib.

4. Ongoing global phase II study

The differentiating property of taletrectinib demonstrated by in vivo and in vitro studies and promising clinical data from the regional study TRUST-I warrant further investigation of taletrectinib in a more diverse patient population, and the global phase II study (TRUST-II, NCT04919811) is ongoing.

The TRUST-II trial is a global, multicenter, open-label, single-arm, phase II study to evaluate the efficacy and safety of taletrectinib in the treatment of patients with advanced or metastatic NSCLC and other solid tumors harboring ROS1+. An overview of the study design is provided in Figure 4. This study will be conducted at approximately 80 investigational sites in countries in Asia, Europe, and North America, including but not limited to Canada, China, France, Italy, Japan, Korea, Poland, Spain, and the U.S.A.

Figure 4. Study schema for TRUST-II.

A total of 119 patients will be enrolled in this study, and the study population will consist of four cohorts:

• Cohort 1: systemic chemotherapy naive or pretreated with one prior line of chemotherapy, but never treated with any ROS1 TKI in ROS1+ NSCLC;

• Cohort 2: prior treatment with one ROS1 TKI (crizotinib or entrectinib) and disease progression. The subject could be either chemotherapy naive or have received one line of platinum- and/or pemetrexed-based chemotherapy for the locally advanced or metastatic NSCLC;

• Cohort 3: prior treatment with two or more ROS1 TKIs and disease progression. The patient could be either chemotherapy naive or have received two or more lines of platinum- and/or pemetrexed-based chemotherapy for the locally advanced or metastatic NSCLC;

• Cohort 4: systemic chemotherapy naive or pretreated with two or more prior lines of chemotherapy, but never treated with any ROS1 TKI. ROS1+ solid tumor types other than NSCLC will be enrolled.

The primary objective of this study is to evaluate the efficacy of taletrectinib, as evidenced by confirmed ORR according to Response Evaluation Criteria In Solid Tumors v. 1.1 (RECIST 1.1), assessed by an independent radiology review committee (IRC) in patients with advanced or metastatic ROS1+ NSCLC (cohorts 1 and 2). The secondary objectives are: to evaluate the efficacy by duration of response (DOR), PFS, time to failure and time to response, as assessed by IRC; to evaluate the efficacy by ORR, DOR and PFS, as assessed by the investigators; to assess the intracranial activity, as evidenced by confirmed intracranial ORR, intracranial DOR, intracranial PFS and time to intracranial progression according to RECIST 1.1 and assessed by IRC; to evaluate overall survival for patients enrolled in cohorts 1 and 2; to assess safety and tolerability of taletrectinib for all cohorts; and to characterize the pharmacokinetic profile of taletrectinib. The exploratory objectives include: to assess intracranial efficacy per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria by IRC (cohorts 1 and 2); to assess the efficacy in cohort 2 patients with specific ROS1 secondary mutations; to assess the efficacy of taletrectinib in patients previously treated with two or more TKIs (cohort 3) and patients with non-NSCLC solid tumors (cohort 4); and to evaluate biomarkers of sensitivity or resistance to taletrectinib in tumor tissue and/or peripheral blood.

All patients will be treated with 600 mg taletrectinib, administered orally, once daily (q.d.) at approximately the same hour every day according to the dosing schedule, at least 2 h before a meal or at least 2 h after a meal. Because the MTD of taletrectinib identified in patients enrolled from the U.S.A. in the phase I study DS6051-A-U101 (NCT02279433) was 800 mg q.d., which was higher than 600 mg q.d., the MTD identified in patients enrolled from Japan in phase I study DS6051-A-J102 (NCT02675491) was used to further optimize the dose that can be used in patients enrolled in western countries [5]. The study allows intra-patient dose escalation for the patients in cohorts 2 and 3 (excluding patients in Asian countries): the dose of taletrectinib can be increased from 600 to 800 mg q.d. on the condition that the patient has completed at least one cycle of initial treatment of taletrectinib 600 mg q.d. with good tolerability (no AEs > grade 2) in the clinical judgment of the investigator. Taletrectinib will be administered in 21-day cycles. The study treatment will continue until disease progression as per RECIST 1.1 (determined by IRC), unacceptable toxicity, death, or consent withdrawal.

ROS1+ status will be validated by next-generation sequencing on pre-treatment tumor tissue. Central ROS1+ confirmation is not required. Tumor tissue should be obtained at time of disease progression if possible to identify alterations associated with resistance to taletrectinib. Blood samples will be taken from approximately 10 patients to analyze pharmacokinetics. Samples will be collected at the following timepoints: 0 (pre-dose), 1 (±15 min), 2 (±15 min), 4 (±24 min), 6 (±36 min), 8 (±48 min) and 24 h (±2 h) post-dose on C1D1 and C1D15; and pre-dose on C1D8 and C2D1. Whole blood will also be collected at screening and once per cycle during the first 8 cycles for exploratory biomarker studies.

The trial was opened for enrollment in September 2021, and it is estimated that final data analysis for the primary outcome measure will likely occur in June 2024 with two planned interim analyses.

The first interim analysis of 18 ROS1 TKI-naïve patients and 22 patients after 1 prior ROS1 TKI was recently reported [7] Perol 2023 Ann Oncol]. Within the first two cohorts, 39% and 59% of patients had brain metastases, respectively. The ORR is 94% (95% CI 73–100) in ROS1 TKI-naïve and 55% (95% CI 32–76) with prior TKI. The DCR was 100% and 91%, respectively. Treatment-related adverse events were reported in 90% of participants, most commonly increased ALT (61%), increased AST (61%), and nausea (38%). Although there were no adverse events resulting in treatment discontinuation or death, dose reductions occurred in 24%.

5. Expert opinion

The TRUST-II study was designed in 2020 and began enrolling patients in September 2021. During that time, crizotinib and entrectinib were approved by the FDA and utilized across the globe as treatment options for patients with ROS1+ NSCLC. However, crizotinib has limited penetration to the brain and is ineffective against tumors with ROS1 secondary resistance mutations [8–10]. While entrectinib has improved CNS penetration, it is often ineffective against tumors with ROS1 secondary resistance mutations and is intolerable by many patients, as manifested by its high dose-reduction rate of 29% and high incidence of CNS-related AEs such as dysgeusia, dizziness, and paresthesia [2,11].

Taletrectinib has shown clinically meaningful efficacy and a favorable safety profile in the phase I [4,5] and regional phase II studies and has the potential to improve PFS based on its greater potency against tumors with ROS1 fusions and its broad in vitro coverage against those with known crizotinib-resistant mutations [6]. Additionally, taletrectinib has high CNS penetration [5,6]. Furthermore, taletrectinib selectively inhibits ROS1 wild-type and its resistant mutations over TRKB, which greatly improves its safety profile with minimal CNS-related AEs. While repotrectnib is also a next generation ROS inhibitor, CNS-related AEs due to TRK inhibition have been reported [3].

The ongoing TRUST-II study is actively enrolling patients globally. Cohorts 1 and 2 are the main cohorts with registrational intention. Cohorts 3 and 4 are exploratory in nature. For NSCLC, cohort 1 (TRUST-II TKI-naïve cohort) includes patients who are either chemotherapy naïve or received one prior line of chemotherapy, whereas cohort 2 allows for one prior TKI and cohort 3 allows prior use of two or more TKIs. By allowing enrollment of patients with different scenarios, the study strives to mimic the ‘real-world’ patient population where more patients may be eligible for this study. Furthermore, some investigators have shown that sequencing of chemotherapy and TKI does not significantly impact PFS [12]. Additionally, not waiting for central confirmation of ROS1 prior to treatment initiation on study is thought to be ‘patient friendly,’ as given the rarity of ROS1+ NSCLC and the life-threatening nature of advanced metastatic NSCLC, the current study was designed to expedite the development and regulatory approval of, and timely patient access to, a potential effective treatment option. If protocol amendments are being considered, the authors suggest the consideration of a new safety cohort where compassionate access of taletrectinib is offered to patients who otherwise do not qualify for the current study (i.e. lack of target lesions, etc).

Given treatment duration with TKIs is frequently limited by acquired resistance mechanisms, the ongoing TRUST-II study will analyze tumor tissue at the time of progression to identify resistance mutations specific to treatment with taletrectinib. Additional therapeutics to prevent these resistance mutations or treat patients upon progression are critical to improving outcomes in the emerging era of targeted therapeutics.

Unfortunately, the current study does not mandate patients without brain metastasis at baseline to follow regular brain imaging. Thus, an accurate cumulative incidence rate of CNS progression would be difficult to capture. Nevertheless, the result of the TRUST-II study, if positive, may reshape the treatment paradigm for ROS1+ NSCLC regardless of treatment-naive patients or those post-first-generation TKIs.

Finally, as we await for the successful read-out of TRUST II, the authors caution regulatory agencies on mandating randomized phase 3 studies for full approval. Clinicians may not feel ethically comfortable in randomizing patients knowing the potency of the ‘investigational’ agent (and also knowing that the ‘standard’ agent may be inferior in some way). This will inevitably slow down the accrual rates, especially in a rare population such as ROS1 where the patient panel is limited and may deter pharmaceutical companies from attempting to develop such drugs. While data may be limited to even a smaller cohort of patients, we also encourage the consideration of tumor agnostic approvals in rare molecular alterations such as ROS1.

Declaration of interests

M Nagasaka is on the advisory board for AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Pfizer, Eli Lilly and Company, Regeneron and Genentech; consultant for Caris Life Sciences (virtual tumor board); speaker for Blueprint Medicines, Janssen, Mirati and Takeda; and reports travel support from AnHeart Therapeutics. SI Ou has stock ownership and was on the scientific advisory board of Turning Point Therapeutics Inc (until 28 February 2019), is a member of the SAB of Elevation Oncology, and has received speaker honorarium from Merck, Roche/Genentech, Astra Zeneca, Takeda/ARIAD and Pfizer; has received advisory fees from Roche/Genentech, Astra Zeneca, Takeda/ARIAD, Pfizer, Foundation Medicine Inc, Spectrum, Daiichi Sankyo, Jassen/JNJ, and X-Covery. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.