FDA approves taletrectinib for ROS1-positive non-small cell lung cancer
What is the potential role for taletrectinib in the treatment of metastatic non-small cell lung cancer?
- Taletrectinib is a ROS1 tyrosine kinase inhibitor (TKI), as well as an inhibitor of tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 domains can drive tumorigenesis through hyperactivation of downstream cellular signaling pathways leading to uncontrolled cellular proliferation.1
- Taletrectinib is approved for metastatic non-small cell lung cancer (mNSCLC) with ROS1 rearrangements.1
- Taletrectinib enters a crowded market, competing with crizotinib, entrectinib, and repotrectinib for ROS1 mNSCLC.2
- Taletrectinib was approved based on the results of the TRUST trial.3
- TRUST evaluated the safety and efficacy of taletrectinib as a pooled analysis of the TRUST-1 and TRUST-2 trials. Both were single arm, open label, nonrandomized, multicenter trials performed in China.
- Patients enrolled into the TKI naïve cohort if they had not received any prior ROS1 TKI, and if they had received prior crizotinib or entrectinib the TKI-pretreated cohort.
- Efficacy cohorts included 160 TKI-naïve patients, and 113 ROS1 TKI-pretreated patients
- The safety cohort included all 352 patients from both trials.
- The primary outcome was confirmed objective response rate (ORR)
- In the TKI naïve cohort, 88.8% of patients had an objective response. In the TKI pretreated cohort, 55.8% of patients had an objective response.
- The response rates were primarily driven by partial responses, which was 83.8% for the TKI naïve and 51.3% pretreated cohorts.
- Secondary outcomes: TKI naïve vs. TKI pretreated cohort
- Intracranial objective response rate (ORR): 76.5% and 65.6%
- Progression free survival (PFS): 45.6 months and 9.7 months
- Duration of response: 44.2 months and 16.6 months
- Overall survival (OS): not reached; however, the 36-month estimate was 66.3% for the TKI naïve cohort, and 12-month OS for the TKI pretreated cohort was 77.5%
- Time to response was short, with a median of 1.4 months in both cohorts.
- Safety:
- The most common treatment related adverse events were LFT elevations (70%), diarrhea (61%), and nausea (44%)
- Most adverse events were grade 1, with grade ≥ 3 occurring in only 33% of patients
- Adverse events leading to dose reductions or treatment discontinuation were low
- Other available agents in this include crizotinib, entrectinib, and repotrectinib.2
- All of the mentioned ROS1 inhibitors are utilized in the first line setting.
- Taletrectinib and repotrectinib can be used for progression on a different ROS1 TKI.
- Lorlatinib is also able to be used for patients who progress on a ROS1 TKI, though it is an ALK targeted TKI and not FDA-approved for ROS1.
- When comparing these medications, one major factor to help guide selection is adverse effects and central nervous system (CNS) penetration.2, 3, 4, 5, 6
- Taletrectinib, entrectinib, and repotrectinib demonstrate CNS response.
- Entrectinib has high rates of adverse events such as rash, dizziness, ocular toxicities, hepatotoxicity, and fatigue, with 41% of patients having any grade ≥ 3 adverse events.
- Repotrectinib adverse effects include rash, metabolic as well as electrolyte disturbances, hepatotoxicity, diarrhea, and cytopenia. Grade ≥ 3 adverse events occurred in 29% of patients receiving repotrectinib.
- Taletrectinib adverse effects include hepatotoxicity, diarrhea, nausea, and cytopenia, with 33% of patients in trials having grade ≥ 3 adverse effects.
- Crizotinib does not have CNS penetration and is not used in the second line setting for patients with disease which progressed on any previous ROS1 inhibitors.
What role can the pharmacist play in the management of patients on taletrectinib?
- Pharmacists play an integral role when navigating multiple medications within the same class with similar efficacy but slightly different toxicity profiles.
- TKI naïve patients:
- Similar efficacy between the ROS1 inhibitors2, 3, 4, 5, 6
- Crizotinib does not have CNS penetration4
- TKI pretreated patients:
- Repotrectinib and taletrectinib are preferred options, especially with symptomatic brain metastases2
- Entrectinib should only be used if the patient had progressed through first line crizotinib2
- Drug interactions:1
- Avoid concomitant use with strong and moderate CYP3A4 inhibitors and inducers
- QT prolonging agents
- Gastric acid reducing agents can lower absorption
- TKI naïve patients:
- Counseling on administration
- Taletrectinib should be taken without food: No food intake for at least 2 hours before and after taking taletrectinib.
- Taletrectinib is supplied as 200 mg tablets. Dosing is three 200 mg capsules once daily.
- Nausea/vomiting: Prophylactic therapy with ondansetron 8 mg, 30 minutes prior to administration.
- Avoid concomitant use with a proton pump inhibitor or H2 receptor antagonists. If acid-suppressing therapy is necessary, administer taletrectinib 2 hours before or after a locally acting antacid to maintain absorption.
- Navigating adverse events of taletrectinib1
- Hepatotoxicity:
- Monitor LFTs prior to initiating, every 2 weeks during the first 2 months of treatment, then monthly thereafter as clinically indicated
- Interstitial lung disease/pneumonitis:
- Monitor for new or worsening pulmonary symptoms
- QTc prolongation:
- Monitor ECG and electrolytes prior to initiating and periodically during treatment
- Avoid concomitant use of drugs that prolong the QTc interval
- Diarrhea:
- Anti-diarrheal agents such as loperamide or Lomotil (diphenoxylate and atropine)
- Fluid and electrolyte replacement
- Nutrition counseling
- Metabolic derangements:
- Hyperuricemia: Monitor uric acid prior to initiating and periodically throughout treatment
- Creatinine phosphokinase (CPK) elevations: Monitor serum CPK levels during treatment in patients reporting unexplained muscle pain, tenderness, or weakness
- Skeletal fractures: Promptly evaluate patients with signs or symptoms of fractures
- Hepatotoxicity:
Clinical Pearls1
- After holding taletrectinib for most toxicities, taletrectinib can be rechallenged at the same dose if the adverse effect has resolved or recovered within 6 weeks.
- Safe handling and storage
- Store at controlled room temperature (20-25ºC), excursions permitted to 15-30ºC.
- Embryo-fetal toxicity: can cause fetal harm, effective contraception should be used and new mothers should not breastfeed while taking this medication and for 3 weeks after the last dose. Counsel pregnant family members on the risks of touching this medication, as fetal abnormalities were seen at 0.1 times the human exposure based on AUC.
- Patient counseling
- LFT elevations are a very common side effect. All grade was 87% for AST and 85% for ALT, and grade ≥ 3 was 10% for AST and 13% for ALT.
- Diarrhea is a common side effect with grade 1-2 occurring in 60% of patient and grade ≥ 3 in 3% patients.
- Dysgeusia occurs in 15% of patients.
- Minimize sun exposure during treatment and for at least 5 days after the last dose of taletrectinib due to photosensitivity.
- Patient access
- Nuvation Connect offers a quick start program for certain payer related coverage delays, a free 30-day supply to trial the drug, copayment assistance, bridge programs through coverage changes, and a patient assistance program for inadequate insurance coverage or those who are uninsured.7
References
1.Ibtrozi. Package insert. Nuvation Bio Inc; 2025 https://ibtrozi-pi.com/IBTROZI_taletrectinib-prescribing-information.pdf
2.Ou SHI, Hagopian GG, Zhang SS, Misako Nagasaka. Comprehensive Review of ROS1 Tyrosine Kinase Inhibitors-Classified by Structural Designs and Mutation Spectrum. Journal of Thoracic Oncology. 2023;19(5):706-718. https://doi.org/10.1016/j.jtho.2023.12.008
3.Pérol M, Li W, Pennell NA, et al. Taletrectinib in ROS1 + Non–Small Cell Lung Cancer: TRUST. Journal of Clinical Oncology. Published online April 3, 2025. https://doi.org/10.1200/jco-25-00275
4.Shaw AT, Ou SHI, Bang YJ, et al. Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2014;371(21):1963-1971. https://doi.org/10.1056/nejmoa1406766
5.Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials. The Lancet Oncology. 2020;21(2):261-270. https://doi.org/10.1016/S1470-2045(19)30690-4
6.Drilon A, D. Ross Camidge, Lin JJ, et al. Repotrectinib in ROS1 Fusion–Positive Non–Small-Cell Lung Cancer. The New England Journal of Medicine. 2024;390(2):118-131. https://doi.org/10.1056/nejmoa2302299
7.Patient Support & Access. IBTROZITM (taletrectinib). Ibtrozihcp.com. Published 2025. https://www.ibtrozihcp.com/support-and-access/. Accessed October 2, 2025.
