Taletrectinib Recommended in NCCN Guidelines for ROS1-Positive NSCLC

Taletrectinib (Ibtrozi; Nuvation Bio) was added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Non-Small Cell Lung Cancers (NSCLC) as a preferred option for the first-line and subsequent treatment of patients with advanced ROS1-positive NSCLC.1

A highly selective, next-generation oral ROS1 tyrosine kinase inhibitor (TKI), taletrectinib was approved on June 11, 2025, based on positive outcomes in the phase 2 TRUST-II (NCT04919811) trial and TRUST-I (NCT04395677).2 The agent was subsequently added to the NCCN Guidelines in version 5.2025,3 which was updated on June 20, 2025.1

ROS1-positive NSCLC is aggressive and rare, with approximately 3000 new diagnoses of advanced disease in the US each year. | Image credit: appledesign - stock.adobe.com

The update recommends taletrectinib as a preferred first-line therapy in patients with NSCLC and ROS1 rearrangement discovered prior to or during first-line systemic therapy.3 As a subsequent therapy, it was added as an option for asymptomatic, symptomatic, or systemic disease with limited progression, or asymptomatic, symptomatic, or systemic disease with multiple lesions if not previously given. Notably, taletrectinib also joined entrectinib and repotrectinib as a preferred option for patients with brain metastases in the first line and joined repotrectinib as a preferred subsequent therapy option for those with symptomatic brain metastases.

Taletrectinib was also added to the NCCN Guidelines as an option for patients with resistant NSCLC mutations, such as ROS1 G2032R, in subsequent lines of therapy, with repotrectinib also noted as an option in this patient population.3 

“We are very pleased the NCCN acted with such urgency to review and update the NCCN Guidelines to include taletrectinib (Ibtrozi) as a preferred option for advanced ROS1-positive NSCLC across treatment lines, with particular recognition of benefit for patients with brain metastases and those with acquired resistance after first-line therapy,” David Hung, MD, founder, president, and CEO of Nuvation Bio, said in a statement.1 “These updates address critical needs for patients across their treatment journeys, especially with the prevalence of CNS involvement for those living with ROS1+ NSCLC. Additionally, this version builds further upon a previous guideline update that importantly highlights preferred utilization of ROS1-targeted agents instead of immunotherapy and chemotherapy for these patients.”

The ongoing multicenter, single-arm, open-label TRUST-I and TRUST-II trials are evaluating overall response rate (ORR) as a primary end point and duration of response (DOR) as a secondary end point. Among treatment-naive patients, the ORRs in TRUST-I and TRUST-II were 90% (95% CI, 83%-95%) and 85% (95% CI, 73%-93%), respectively.2 Regarding DOR, 72% and 63% of participants experienced DOR of 12 months or more in TRUST-I and TRUST-II, respectively.

Outcomes were also promising in pretreated patients, with ORR rates of 52% (95% CI, 39%-64%) and 62% (95% CI, 46%-75%) in TRUST-I and TRUST-II, respectively. In 74% and 83% of untreated patients, respectively, DORs were 6 months or more.

Early in 2025, version 1.2025 of the NCCN Guidelines in Oncology for NSCLC included updates to the use of immunotherapy in NSCLC.3 The recommendations were modified to note that active or previously documented autoimmune disease; current use of immunosuppressive agents; and some oncogenic drivers—including EGFR exon 19 deletion or L858R, as well as ALK, RET, or ROS1 rearrangements—may be contraindications for treatment with PD-1/PD-L1 inhibitors. These contraindications have been associated with less benefit from PD-1/PD-L1 inhibitors, the guidelines noted.

ROS1-positive NSCLC is aggressive and rare, with approximately 3000 new diagnoses of advanced disease in the US each year.1 It often occurs in never smokers, and the median age at diagnosis is 50 years. A leading cause of disease progression and death in ROS1-positive NSCLC is the occurrence of brain metastases.

References

1. Nuvation Bio announces National Comprehensive Cancer Network adds taletrectinib (Ibtrozi) as preferred option to clinical practice guidelines in oncology for advanced ROS1+ non-small cell lung cancers. News release. Nuvation Bio Inc. June 24, 2025. Accessed July 31, 2025. https://investors.nuvationbio.com/news/news-details/2025/Nuvation-Bio-Announces-National-Comprehensive-Cancer-Network-Adds-Taletrectinib-IBTROZI-as-Preferred-Option-to-Clinical-Practice-Guidelines-in-Oncology-for-Advanced-ROS1-Non-Small-Cell-Lung-Cancers/default.aspx

2. Shaw M. Taletrectinib approved for ROS1-positive NSCLC. AJMC®. June 11, 2025. Accessed July 21, 2025. https://www.ajmc.com/view/taletrectinib-approved-for-ros1-positive-nsclc

3. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2025. Accessed July 31, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf