Taletrectinib Demonstrates Durable Efficacy in ROS1-Positive NSCLC

High, enduring response rates were observed with taletrectinib (Ibtrozi) among patients with ROS1-positive non–small cell lung cancer (NSCLC) who received no prior tyrosine kinase inhibitors (TKIs), according to a pooled analysis of the phase 2 TRUST-I (NCT04395677) and TRUST-II trials (NCT04919811) presented in a poster session at the 2026 American Association for Cancer Research (AACR) Annual Meeting.¹

Lead study investigator Lyudmila Bazhenova, MD, FASCO, spoke with CancerNetwork® to break down the design, efficacy findings, and updated safety data related to the pooled analysis she presented at the meeting. In addition to detailing outcomes such as overall response rate (ORR) and progression-free survival (PFS) across the trials, she discussed the potential next steps for research dedicated to unveiling mechanisms of resistance to taletrectinib. Overall, she noted that the findings presented at AACR reflect the importance of conducting molecular testing to identify targeted therapeutic strategies for patients.

Bazhenova is a board-certified medical oncologist and a professor of medicine at UC San Diego Moores Cancer Center.

CancerNetwork: What was the background for the TRUST-I and TRUST-II trials assessing taletrectinib among patients with ROS1-positive NSCLC?

Bazhenova: About 1% to 2% of patients with lung cancer will have a ROS rearrangement. Currently, we have several medications approved for patients with ROS-rearranged lung cancer. The analysis that we [performed] on taletrectinib concentrated on the efficacy of taletrectinib in patients who were TKI naive. There was a separate presentation at AACR looking at the TKI-pretreated patients as well.² What we are reporting are data with an extra 10 months of follow-up, therefore giving us more a durable view on the efficacy of taletrectinib in patients with TKI-naive ROS1-rearranged NSCLC.

What did the updated results from these trials show regarding the clinical efficacy of taletrectinib among this patient population?

Between the TRUST-I and TRUST-II trials, we had 157 patients in the efficacy populations. In the safety populations, we looked at 363 patients across both trials with taletrectinib. What we saw was a very high confirmed overall response rate of almost 90%. We also saw high intracranial efficacy, with an intracranial confirmed ORR of 76.5%. Responses appeared to be very durable. The median duration of response for the TKI-naive patients across TRUST-I and TRUST-II was 49.7 months; very durable numbers. Then, we also saw a very durable median PFS of 46.1 months.

While then median overall survival had not been reached in this patient population, at 48 months, 58% of the patients were still alive.

Have any new safety signals emerged with taletrectinib in this updated analysis? What are some best practices for mitigating any toxicities that may occur?

We didn’t see any new safety signals with longer follow-up. What we saw is what we expected with taletrectinib. There was an elevation in aspartate aminotransferase and alanine aminotransferase. A majority of those elevations were early grade. There was a little bit of nausea and diarrhea—also very early grade. It is very important to highlight the fact that taletrectinib does not have a lot of neurologic adverse events, which could be seen with other oral TKIs. For example, in this trial, grade 1 dizziness was seen in 18.5% of the patients, and 2.8% had grade 2 dizziness. For dysgeusia, 13.2% had grade 1 [events], and 2.2% had grade 2 [events]. The management of adverse events with taletrectinib is standard; dose reductions or dose interruptions are appropriate based on our package insert.

What are the next steps for optimizing outcomes among patients with ROS1-mutated lung cancer across different treatment settings?

There are lots of questions we can still answer. Borrowing from the EGFR space, for example, where we use intensification of therapy by layering on third-generation EGFR-TKIs and some additional treatment modalities, this can certainly be looked at in taletrectinib. We also need to learn a little bit more about the mechanism of resistance to taletrectinib and the most appropriate way of managing resistance to taletrectinib. An important next question is, what would be the role of ROS inhibition in patients with early-stage lung cancer who have received surgery? We now have 3 settings where adjuvant TKIs make a difference. This is in EGFR classical mutations; ALK-rearranged lung cancer; and, most recently, RET-rearranged lung cancer. I hope that we will eventually be able to do a trial in early-stage patients who have ROS1 mutations and underwent surgery.

What do you hope colleagues take away from this presentation?

You cannot administer the medication unless you test [for alterations]. No. 1, [it’s] very important to make sure that you do molecular testing for your patients with lung cancer in stage IV. Another thing, which is very important, is to make sure you understand what type of testing is necessary. ROS1 fusions can be easily missed on a DNA testing. Even though I’m not highlighting the molecular testing in my presentation, it is important to make sure that we all understand that it is important. Currently, our penetration of molecular testing in the US is not at 100%, so there’s room for improvement.

The second [takeaway] is taletrectinib is a very effective oral TKI that should be considered for patients with ROS1-rearranged NSCLC.

References

1. Bazhenova L, Nieva J, Nagasaka M, et al. Taletrectinib in tyrosine kinase inhibitor (TKI)-naïve patients with ROS1+ non-small cell lung cancer (NSCLC): updated data from TRUST-I and TRUST-II. Presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract CT300.
2. Liu G, Nieva J, Bazhenova L, et al. Taletrectinib in tyrosine kinase inhibitor (TKI)-pretreated patients with ROS1+ non-small cell lung cancer (NSCLC): updated data from TRUST-I and TRUST-II. Presented at the 2026 American Association for Cancer Research (AACR) Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract CT244.