NCCN Adds Taletrectinib to ROS1+ NSCLC Recommendations

The NCCN now recommends taletrectinib for treatment of ROS1-positive NSCLC in all lines of therapy.

The National Comprehensive Cancer Network (NCCN) has updated its guidelines to recommend taletrectinib (Ibtrozi) as the preferred treatment for patients with ROS1-positive non–small cell lung cancer (NSCLC) as of June 20, according to a press release from Nuvation Bio, the developer of the drug.¹

This NCCN update follows the approval of taletrectinib for ROS1-positive NSCLC on June 11. The recommendation applies to all lines of therapy and includes those with brain metastases and acquired resistance mutations.

“We are very pleased the NCCN acted with such urgency to review and update the NCCN Guidelines to include taletrectinib 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,” said David Hung, MD, the founder, president, and CEO of Nuvation Bio in the release. “These updates address critical needs for patients across their treatment journeys, especially with the prevalence of [central nervous system] involvement for those living with ROS1-positive 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.”

How does the NCCN recommend sequencing taletrectinib?

Taletrectinib now joins entrectinib and repotrectinib as a preferred therapy in the first line of treatment for patients with or without brain metastases whose ROS1 mutation was discovered before initiating therapy and whose ECOG status is 0 to 4.² Crizotinib (Xalkori) is also recommended in this setting for those without brain metastases.

For patients whose ROS1 mutation is discovered during the first line of systemic therapy, the NCCN recommends that therapy be interrupted in favor of treatment with entrectinib (Rozlytrek), repotrectinib (Augtyro), or taletrectinib in patients with or without brain metastases, or with crizotinib for patients without brain metastases.

The NCCN also recommends that taletrectinib or repotrectinib be given in the second line to patients with asymptomatic progression, including those with ROS1 G2032R and similar mutations resistant to therapy. Further, taletrectinib is recommended for use in the second line of therapy for patients with symptomatic brain or systemic progression.

Taletrectinib’s FDA approval

Taletrectinib was approved for use in patients with NSCLC harboring ROS1 mutations based on data from the open-label, multicenter, single-arm phase 1 TRUST-1 (NCT04395677) and phase 2 TRUST-II (NCT04919811) trials, with dual primary end points of overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review.³

The ORR for treatment-naive patients in TRUST-I and TRUST-II were 90% (95% CI, 83%-95%) and 85% (95% CI, 73%-93%), respectively. The DOR at 12 months or longer was 72% and 63%, respectively, for patients in those studies who had not received ROS1-targeted TKI treatment.

Moreover, in patients with prior TKI treatment, the ORR was 52% (95% CI, 39%-64%) for patients in TRUST-I and 62% (95% CI, 46%-75%) for those in TRUST-II. In those respective studies, 74% and 83% of participants had a DOR of at least 6 months.

In both trials, patients with advanced disease were allowed to have had prior chemotherapy. TRUST-I enrolled 103 patients who had not received a prior ROS1-targeted TKI and 66 who had, while TRUST-II enrolled 54 patients who had not received prior ROS1-targeted TKI therapy and 47 who had.

Safety data for taletrectinib

With regard to taletrectinib’s safety profile, the adverse effects (AEs) most commonly associated with the oral, potent, central nervous system-active ROS1 inhibitor include diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%). Each occurred in at least 20% of patients.¹

Additionally, its label includes warnings for hepatoxicity, interstitial lung disease and pneumonitis, QTc interval prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, skeletal fractures, and embryo-fetal toxicity.

Taletrectinib should not be used concurrently with strong or moderate CYP3A inhibitors or CYP3A inducers as well as drugs that prolong the QTc interval. Simultaneous treatment with acid-reducing agents such as PPIs and H2 receptor antagonists should also not be administered. In the case that avoidance is not possible, patients should receive locally active antacids 2 hours prior to or following treatment with taletrectinib.

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. June 24, 2025. Accessed June 26, 2025. https://www.businesswire.com/news/home/20250624605890/en/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
2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 5.2025. Accessed June 26, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
3. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. FDA. News release. 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