The Food and Drug Administration (FDA) has approved a supplemental new drug application for taletrectinib (Ibtrozi), incorporating longer follow-up and duration-of-response over four years from the phase 2 TRUST-I and TRUST-II studies into the prescribing information. The action does not expand the indication, but adds more evidence supporting taletrectinib as a preferred treatment option for ROS1-positive non-small cell lung cancer (NSCLC).

Taletrectinib remains approved at 600 mg orally once daily for adults with locally advanced or metastatic ROS1-positive NSCLC, without a line-of-therapy restriction in the label.

The original full approval, granted June 11, 2025, was supported by 270 patients in two multicenter, open-label, single-arm trials. Patients had measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and either no prior ROS1 tyrosine kinase inhibitor or one prior ROS1 inhibitor. TRUST-I enrolled in China; TRUST-II was global. ORR and DOR were assessed by blinded independent central review.

The main revision concerns the 103 TKI-naive patients in TRUST-I. At original approval, ORR was 90%, and median DOR was not reached (lower 95% confidence limit, 30.4 months).

With 51 months of median follow-up, the revised label reports a 49.7-month median DOR (95% CI, 41.3 to not reached); 59% of responders had a DOR of at least 24 months. In TRUST-II, ORR was 87% among 54 TKI-naive patients, and median DOR remained not reached.

Separate from the label’s new DOR estimate, the long-term TRUST-I publication reported a median progression-free survival of 49.6 months.

“The label update to the approval of taletrectinib includes new long-term follow-up data that solidified it as a preferred treatment for ROS1-positive advanced NSCLC in the first-line setting,” Dr. Jyoti Malhotra, a thoracic medical oncologist at Yale Cancer Center, tells SurvivorNet Connect. “Updated data from the TRUST-I trial reported a median PFS of more than 4 years (49.6 months), which is the longest ever reported response time with an FDA-approved ROS1 inhibitor.”

The term “preferred” reflects clinical or guideline positioning, not an FDA ranking of available drugs.

Activity after one prior ROS1 inhibitor remains clinically relevant. In TRUST-I, ORR was 52% among 66 pretreated patients and median DOR was 13.2 months. In TRUST-II, ORR was 62% among 47 pretreated patients; median DOR was not reported in the label. Intracranial responses occurred in 11 of 15 evaluable TKI-naive patients and 15 of 24 evaluable pretreated patients with measurable central nervous system disease and no recent brain radiotherapy. Among 15 patients with resistance mutations after prior TKI therapy, eight responded, all with ROS1 G2032R.

Taletrectinib’s Safety Profile

“It’s reassuring that no additional safety warnings were added to this label update,” Dr. Malhotra adds. “This drug is unique in having low rates of neurological side effects, which are usually quite common with this class of drugs. This update will hopefully make it easier for patients to get access to this drug now that long-term data highlighting its durability, tolerability, and CNS activity has been provided.”

In the pooled NSCLC safety population of 337 patients:

• Serious adverse reactions occurred in 31%
• Fatal adverse reactions in 5%
• Discontinuation in 7%
• Dose interruption in 41%
• Dose reduction in 29%
• Grade 3 or 4 alanine and aspartate aminotransferase elevations occurred in 13% and 10%, respectively

Warnings include hepatotoxicity, interstitial lung disease or pneumonitis, QTc prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, fractures, and embryo-fetal toxicity. No safety sections changed.

Dr. Misako Nagasaka, a hematologist/oncologist with UCI Health, agrees that taletrectinib is an appealing option.

“Taletrectinib is a next-generation ROS1 inhibitor with good activity against resistant mutations that earlier-generation drugs couldn’t cover. It also has excellent penetration to the brain to treat and prevent cancer spread there,” Dr. Nagasaka tells SurvivorNet Connect. “The relatively gentle side effect profile of mild nausea, diarrhea, and liver enzyme abnormalities makes it an appealing option for patients with ROS1-positive non-small cell lung cancer.”

For sequencing, taletrectinib must be considered alongside crizotinib, entrectinib, repotrectinib, and zidesamtinib, which is approved after a prior ROS1 inhibitor. CNS disease, prior agent, resistance genotype, toxicity, and access may guide selection.

DOR is not an overall-survival result. No randomized head-to-head evidence establishes taletrectinib as superior, and cross-trial comparisons of response durability are unreliable. Randomized comparative data and additional evidence after newer-generation ROS1 inhibitors remain needed.