Taletrectinib's Sustained Efficacy in Advanced ROS1-Positive NSCLC

Updated results from the pivotal phase 2 TRUST-II study of taletrectinib (Ibtrozi) in adult patients with locally advanced or metastatic ROS1-positive (ROS1+) non–small cell lung cancer (NSCLC) demonstrate sustained durability of responses, impressive progression-free survival (PFS), and a favorable, manageable safety profile.¹ These findings were presented at the IASLC 2025 World Conference on Lung Cancer (WCLC). The drug, recently approved by the FDA,² represents an important new treatment option for patients with ROS1+ NSCLC regardless of prior tyrosine kinase inhibitor (TKI) exposure. The studies represent one of the largest global clinical trial programs in ROS1+ NSCLC to date, enrolling over 300 patients.

Geoffrey Liu, MD, medical oncologist at Princess Margaret Cancer Center, University of Toronto, and primary investigator of the TRUST-II study, discusses the findings and implications for community oncologists.

What role does taletrectinib play in the treatment landscape?

Taletrectinib is a ROS1 fusion inhibitor designed for ROS1 fusion metastatic [or locally advanced] non–small cell lung cancer. It fits in the area of other drugs that have been approved in the US, including crizotinib [Xalkori], entrectinib [Rozlytrek], and repotrectinib [Augtyro]. Taletrectinib offers improved efficacy and safety.

What were the objectives of TRUST-II?

TRUST-I evaluated taletrectinib in a Chinese population. TRUST-II is the global version of the study, which includes non-Asians and Asians globally in this particular setting. The study has 2 main cohorts. One is newly diagnosed or treatment-naive patients with a ROS1-fusion metastatic lung cancer, and the second cohort is those who have been pretreated with 1 prior line of a tyrosine kinase inhibitor, which in this case could be either crizotinib or entrectinib. Both of these are major areas in which we're looking for improved efficacy, safety, or both.

Would you summarize your findings presented at WCLC?

Last year, I had presented the initial data on TRUST-II. This year, the updated data includes 5 more months of follow-up in both cohorts. For the first time ever, time-to-event data is being presented this year because we finally have a long enough follow-up to consider that.

The efficacy outcomes for taletrectinib are very impressive. In the treatment-naïve or newly diagnosed patients, we ended up having a confirmed objective response rate of 85% in this cohort, and with 20 months of median follow-up time, neither the duration of response nor the progression-free survival medians have been reached. What it's starting to look like is that the TRUST-II data is starting to look like both the pooled TRUST-I and TRUST-II data that was sent to the FDA for approval of the drug, as well as looking very similar to the TRUST-I data, which has close to 40 months of follow-up in the treatment-naive group.

In the pretreated group, the objective response rate was 61.7%. The median progression-free survival is 11.8 months. But the median duration of response is actually an impressive 19.4 months in this particular setting.

In terms of safety, there are no new safety events compared [with] what was presented last year. Specifically, the things that community oncologists would be interested in would be the fact that most of the [adverse] effects are related to the GI [gastrointestinal] system, and they include nausea, vomiting, and diarrhea. However, it's important to note that these [adverse] effects are extremely transient. They occur within the first, oftentimes, couple of days but last a really short period of time and tend to be really low grade and very manageable. The other [notable adverse] effect is that of elevated liver enzymes, which we see in other drugs such as crizotinib as well. It’s managed very similarly. If it gets to a grade 3 or higher, there is a dose interruption and then often a dose reduction, and that usually handles that particular issue.

The big key thing is the fact that unlike the 2 prior drugs, entrectinib and repotrectinib, that are approved in the US, taletrectinib has significantly fewer [adverse] effects. These are neurologic [adverse] effects, such as dysgeusia, which sit at around 15% at grade 1 and 4% at grade 2, and dizziness, which is actually quite debilitating in some patients treated with these other drugs. [With taletrectinib], it is sitting mostly a grade 1 at 15% and only 2.3% at grade 2. And when you treat patients using all of these drugs, this is actually a significantly improved safety profile, in my opinion.

Both efficacy- and safety-wise, this drug seems to be dominating.

Based on these updated findings, what questions do you still have? Where do you see this research going?

I think the realistic answer is that we still want to see the TRUST-II data mature. When you have a median follow-up of 20 months, but you have the pooled data showing progression-free survival in the 40-something–month range and beyond, you do need a longer follow-up to make sure that the global data are similar and will read out the same way. But so far, it's been looking very similar. That is very promising.

Safety-wise, I think one of the big questions will be the fact that there are [GI adverse] effects. They're well noted to occur with this drug, but they're really self-limiting. More data, I think, [will] demonstrate how easy it is to manage this and how self-limited this often is—very short periods of just a couple of days of symptoms, and then the symptoms dissipate at that point. I think gathering a little more data showing that would be very useful.

There's no data to show potential drug-drug interactions, which is what is important with a lot of these new drugs. That data is being reported out as well.

What would your main takeaways be?

I think if there's a message to community oncologists, it is the fact that this drug, both in efficacy and safety profiles, dominates over the existing drugs. Especially if they've had experience with some of the other drugs, they may find this one so much easier for themselves and also for their patients.

This article was generated with assistance from NotebookLM. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCES:

1. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. FDA. June 11, 2025. Accessed September 8, 2025. https://tinyurl.com/4v5bkvfh

2. Nuvation Bio announces new data from pivotal clinical studies of Ibtrozi (taletrectinib) in advanced ROS1-positive non-small cell lung cancer at 2025 World Conference on Lung Cancer. News release. Nuvation Bio. September 7, 2025. Accessed September 8, 2025. https://tinyurl.com/vb6up9vm