Taletrectinib Approved for ROS1-Positive NSCLC

Today’s approval of taletrectinib (Ibtrozi; Nuvation Bio Inc) by the FDA for ROS1-positive locally advanced or metastatic non–small cell lung cancer (NSCLC) comes on the heels of the January approval of this next-generation tyrosine kinase inhibitor (TKI) by China’s National Medical Products Administration, but incorporating data from the phase 2 TRUST-II (NCT04919811) trial in addition to TRUST-I (NCT04395677).^1,2

In treatment-naïve patients, data from the trials confirm the major efficacy outcomes of 90% (95% CI, 83%-95%) and 85% (95% CI, 73%-93%) overall response rate (ORR, the primary end point) in TRUST-I and TRUST-II, respectively, and corresponding durations of response (DOR, a secondary end point) for 12 months or more of 72% and 63%. Results trended similarly for pretreated patients, albeit at somewhat lower but still promising rates of 52% (95% CI, 39%-64%) and 62% (95% CI, 46%-75%) for ORR in TRUST-I and TRUST-II, respectively, while 74% and 83% exhibited DORs of 6 months or more.

These ongoing multicenter, single-arm, open-label clinical analyses are investigating ORR and DOR in both treatment-naïve patients (103 in TRUST-I and 54 in TRUST-II) and treatment-experienced patients (at least 1 prior ROS1 TKI; 66 in TRUST-I and 47 in TRUST-II) who received taletrectinib as monotherapy.

In TRUST-I, patients received either 400 mg or 600 mg daily in stage 1, until the optimal clinical dose was determined, and in stage 2, the efficacy and safety of that dose was evaluated; patients in cohort 1 were treatment naïve and those in cohort 2 had progressed on crizotinib (Xalkori; Pfizer).^3,4 In TRUST-II, patients again received either 400 mg or 600 mg daily, but in 21-day cycles, with one of the patient groups also receiving intravenous carboplatin and pemetrexed in 21-day cycles for 4 cycles; again, cohort 1 was treatment naïve and cohort 2 had disease progression following treatment with either crizotinib or entrectinib (Rozlytrek; Genentech).^4,5 In both trials, patients were treated over 21-day cycles until disease progression, intolerable toxicity, withdrawal, or death.^4,6

This next-generation ROS1 tyrosine kinase inhibitor previously received breakthrough therapy and orphan drug designations for the same patient population. | Image Credit: wladimir1804-stock.adobe.com

ROS1-positive NSCLC is a rare, aggressive form of lung cancer harboring rearrangements in the ROS1 gene.⁷ These mutations are present in just 1% to 2% of all cases of NSCLC. An oncogene, ROS1 can become cancerous in the presence of a mutation, and these patients are less likely to benefit from immunotherapy, are younger at diagnosis, and are more likely to be female, compared with other patients who have lung cancer, according to the Lung Cancer Foundation of America. Treatment options include other targeted therapies, surgery, radiation, chemotherapy, and immunotherapy.

Earlier this year, pooled data from these trials demonstrated high rates of response that were also durable, and favorable outcomes for the other secondary end points of progression-free survival (PFS), intracranial ORR, and safety.⁴ Combining the efficacy populations from both trials (N = 273 patients) resulted in an ORR of 88.8% and an intracranial ORR of 76.5% in treatment-naïve patients (n = 160). Pretreated patients (n = 113) exhibited an ORR of 55.8% and an intracranial ORR of 65.6%. Median DOR and PFS were 44.2 months and 45.6 months among the treatment-naïve group but 16.6 months and 9.7 months in the pretreated group. These data were previously presented at the 2024 European Society for Medical Oncology.⁸

With this approval—which comes almost 2 weeks ahead of the original June 23 Prescription Drug User Fee Act date—the recommended once-daily dose is 600 mg orally, no food being allowed for the 2 hours before or after. Taletrectinib previously received priority review, a breakthrough therapy designation, and an orphan drug designation for this same indication.

“The FDA approval of Ibtrozi marks a major milestone in the evolution of targeted therapy for advanced ROS1-positive NSCLC,” said David Hung, MD, founder, president, and CEO of Nuvation Bio, in a statement.⁹ “We believe one of the greatest threats to ROS1-positive lung cancer patients is disease progression, especially in the first-line setting. In pivotal trials, Ibtrozi delivered high response rates with sustained durability—truly meaningful benefits for patients. With its clinically proven efficacy and safety profile, we believe Ibtrozi has the potential to become a new standard for what targeted therapies can achieve in this type of lung cancer. With approvals for Ibtrozi now in the US and China, and additional global filings underway, we remain committed to delivering innovative therapies that help patients stay ahead of their disease.”

References

1. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. News release. FDA. June 11, 2025. Accessed June 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-taletrectinib-ros1-positive-non-small-cell-lung-cancer
2. Nuvation Bio receives approval from China’s National Medical Products Administration. News release. Nuvation Bio. January 6, 2025. Accessed June 11, 2025. https://investors.nuvationbio.com/news/news-details/2025/Nuvation-Bio-Receives-Approval-from-Chinas-National-Medical-Products-Administration-for-Taletrectinib-for-Patients-with-Advanced-ROS1-positive-Non-Small-Cell-Lung-Cancer/
3. A study of AB-106 in subjects with advanced NSCLC harboring ROS1 fusion gene. ClinicalTrials.gov. Updated October 30, 2023. Accessed June 11, 2025. https://clinicaltrials.gov/study/NCT04395677
4. Pérol M, Li W, Pennell NA. Taletrectinib in ROS1+ non–small cell lung cancer: TRUST. J Clin Oncol. 2025;43(16):1920-1929. doi:10.1200/JCO-25-00275
5. Taletrectinib phase 2 global study in ROS1 positive NSCLC (TRUST-II). ClinicalTrials.gov. Updated November 21, 2024. Accessed June 11, 2025. https://clinicaltrials.gov/study/NCT04919811
6. Davenport LA. Talecrectinib provides “prolonged disease control” in ROS1+ NSCLC. Cancer Therapy Advisor. April 14, 2025. Accessed June 11, 2025. https://www.cancertherapyadvisor.com/news/taletrectinib-prolonged-disease-control-ros1-nsclc/
7. ROS1. Lung Cancer Foundation of America. Accessed June 11, 2025. https://lcfamerica.org/about-lung-cancer/diagnosis/biomarkers/ros1/
8. Efficacy of taletrectinib in patients with advanced ROS1 fusion-positive NSCLC. ESMO. April 18, 2025. Accessed June 11, 2025. https://www.esmo.org/oncology-news/efficacy-of-taletrectinib-in-patients-with-advanced-ros1-fusion-positive-nsclc
9. US Food and Drug Administration approved Nuvation Bio’s Ibtrozi (taletrectinib), a next-generation oral treatment for advanced ROS-1 positive non–small cell lung cancer. June 11, 2025. Accessed June 11, 2025. https://investors.nuvationbio.com/news/news-details/2025/U-S--Food-and-Drug-Administration-Approves-Nuvation-Bios-IBTROZI-taletrectinib-a-Next-Generation-Oral-Treatment-for-Advanced-ROS1-Positive-Non-Small-Cell-Lung-Cancer/default.aspx