Taletrectinib Shows Positive Efficacy and Toxicity in ROS1+ NSCLC

In the phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) trials, taletrectinib (Ibtrozi) demonstrated positive toxicity and an acceptable safety profile in patients with ROS1-positive non–small cell lung cancer (NSCLC). Based on these results, the agent was approved in the aforementioned indication.1

During a conversation with CancerNetwork®, Jorge Nieva, MD, stated that taletrectinib demonstrated improved efficacy relating to the response rate, duration of response (DOR), and progression-free survival (PFS) in those who are treatment-naïve. He also spoke about the “high” intracranial response rates, as well as the good central nervous system (CNS) penetration that is seen with taletrectinib.2,3

Regarding toxicities, most were associated with the gastrointestinal tract. Nausea and diarrhea were 2 of the most prominent adverse effects that he mentioned. Despite this, he also stated that nausea and diarrhea are common in oncology, so the means to treat them are available.

Nieva is an associate professor of clinical medicine at the Keck School of Medicine of the University of Southern California and was an investigator on the phase 2 TRUST-II trial (NCT04919811) that evaluated taletrectinib in this population.

Transcript:

In all things in oncology, the outcomes are always best when drugs are used in the first line compared with the second line. When looking at the results of the TRUST-I and TRUST-II studies on which taletrectinib is based, we see that patients who are newly diagnosed have a higher response rate—89% compared with 56%—we see a DOR that’s significantly longer—44 months compared with 17 months—and a PFS which is also much longer—46 months vs 10 months.

We see very high intracranial response rates with taletrectinib, repotrectinib [Augtyro], and entrectinib [Rozlytek], and these are all much higher than the drug that sort of started it all, crizotinib [Xalkori]. I don’t think there are many people in the US who are still using crizotinib as first-line therapy for ROS1 disease, with the newer generation agents commanding the majority of market share for what most practitioners are doing these days. The good news for patients is that all the newer generation agents have very good CNS penetration, and we can expect that patients who have CNS disease will have reductions in their tumor size in the majority of cases. This means that there will be fewer patients who need to receive CNS radiation, which is something that many people want to try to avoid.

The majority of toxicities for this drug center around the gastrointestinal tract, so nausea and diarrhea are the mainstays of therapy. The good news is, we’re oncologists, and we’re good at treating nausea and diarrhea. We’ve done it for a long time. The [5-HT-receptor] agonists are good choices for the nausea because the [5-HT-receptor] antagonists tend to [cause constipation]…. The combination of those features seems to help this patient population. We also have drugs that work on gastrointestinal opiate receptors, like loperamide [Imodium], and those work quite well for diarrhea. From the standpoint of toxicity management, we have a lot of good drugs available for that.

Reference

1. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. News release. FDA. June 11, 2025. Accessed June 23, 2025. https://tinyurl.com/yc4f379m
2. Nagasaka M, Ohe Y, Zhou C, et al. TRUST-II: a global phase II study of taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors. Future Oncology, 19(2), 123–135. doi:10.2217/fon-2022-1059
3. Pérol M, Li W, Pennell NA, et al. Taletrectinib in ROS1+ non-small cell lung cancer: TRUST. J Clin Oncol. Published online April 3, 2025. doi:10.1200/JCO-25-00275