Taletrectinib Sustains Durable ROS1+ NSCLC Responses at 3-Year Follow-Up

According to updated results from the phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) trials presented at the 2026 World Conference on Lung Cancer (WCLC), taletrectinib (Ibtrozi) continued to produce durable responses in patients with ROS1-positive non–small cell lung cancer (NSCLC), regardless of prior chemotherapy exposure or ROS1 fusion partner, after almost 3 years of follow-up.¹

With a median follow-up of 35.5 months in tyrosine kinase inhibitor (TKI)-naive patients and 35.8 months in TKI-pretreated patients, the confirmed objective response rate (cORR) was 89.8% (95% CI, 84.0%-94.1%) in the TKI-naive population (n = 157) and 55.8% (95% CI, 46.1%-65.1%) in the TKI-pretreated population (n = 113). Median duration of response (DOR) was 49.7 months (95% CI, 38.6-not reached [NR]) and 16.6 months (95% CI, 10.7-24.9), respectively, and median progression-free survival (PFS) was 46.1 months (95% CI, 31.8-NR) and 9.7 months (95% CI, 7.6-12.0).

Long-Term Control Was Expected, Not Surprising

Asked whether anything in the updated poster data surprised him, Jorge J. Nieva, MD, associate professor of clinical medicine and section head of solid tumors at USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, said the durability itself was consistent with the trajectory the field has already seen with ROS1-directed therapy.

"We've known that ROS1 inhibitors have improved tremendously as we've moved from earlier generation agents to later generation agents, and so seeing long-term disease control wasn't surprising," Nieva told Targeted Oncology^TM. "It is delightful, though, every time we see it, and it's just so wonderful to be able to have an oral therapy that we can offer to these patients that we know is going to provide them disease control that's going to last many years for the majority of patients."

Response Rates Held Steady Regardless of Prior Chemotherapy

The poster data showed that efficacy was similar irrespective of prior chemotherapy exposure. Among TKI-naive patients, the cORR was 90.0% (95% CI, 73.5%-97.9%) in those with prior chemotherapy (n = 30) vs 89.8% (95% CI, 83.1%-94.4%) in those without (n = 127). Among TKI-pretreated patients, the cORR was 59.5% (95% CI, 43.3%-74.4%) with prior chemotherapy (n = 42) vs 53.5% (95% CI, 41.3%-65.5%) without (n = 71).

Fusion Partner Did Not Diminish Efficacy

Efficacy also did not vary meaningfully by ROS1 fusion partner. In TKI-naive patients, the cORR was 89.5% (95% CI, 66.9%-98.7%) with a CD74 fusion partner (n = 19) vs 88.9% (95% CI, 65.3%-98.6%) with a non-CD74 partner (n = 18); in TKI-pretreated patients, the cORR was 55.0% (95% CI, 31.5%-76.9%) with CD74 (n = 20) vs 46.2% (95% CI, 19.2%-74.9%) with a non-CD74 partner (n = 13).

"What we see is whether the fusion partner was CD74 or whether it was a different partner, the overall response rate was still around 90% for both, without major differences," Nieva said of the TKI-naive subgroup. "So you can have confidence that, regardless of the fusion partner that your patient has, that this drug is going to be a highly efficacious choice for them."

Longer Survival Raises New Questions About Surveillance Intensity

With patients now remaining on taletrectinib for years, Nieva said the bigger open question is not efficacy but how aggressively to monitor patients who are doing well long-term. "I don't think this really changes what we do in terms of disease monitoring and surveillance. With any cancer, you can have disease progression at any time," he said.

But he noted that as ROS1-positive NSCLC—a disease that disproportionately affects younger patients—becomes a chronic illness measured in years rather than months, patients themselves are pushing back on frequent imaging. "I've had a number of my patients who are long-term survivors on [TKIs] who begin to say things like, 'Can't I just get my CTs every 6 months now instead of every 3?'" Nieva said. "I think we need to do more research as to what is the role of deintensification of imaging. I think we need to do more research into the role of [measurable residual disease (MRD)] testing as a substitute for radiographic assessments, because I think in young patients with cancer, in particular, we do need to keep in mind that radiation exposure can now be a problem as we begin to have patients who are out a decade or more on [TKI] therapy."

Safety Profile Remained Manageable With Longer Follow-Up

In the integrated safety population (N = 363), the most common any-grade treatment-emergent adverse events (TEAEs) were increased aspartate aminotransferase (71.9%), increased alanine transaminase (68.3%), diarrhea (64.5%), nausea (47.9%), and vomiting (45.2%); TEAEs led to dose interruptions in 42.7% of patients, dose reductions in 31.3%, and discontinuations in 8.5%.

Nieva said the monitoring burden has not changed with longer-term data. "The things that we need to do are laboratory monitoring for potential [liver function test] abnormalities, and that's something that's not really any different than what we do routinely with any [TKI]," he said. "I think the most predictable toxicity is the gastrointestinal toxicity, but we're medical oncologists; we do gastrointestinal toxicity all the time, and the management of that is something that can be addressed early on in the course of therapy with dosing modifications, addition of antiemetics, antidiarrheal agents, and other types of supportive care medicines that keep the patient on an optimal dose of treatment, and at the same time making sure that they have a great quality of life, where the gastrointestinal toxicity doesn't burden them and doesn't affect their ability to live the life they want to live."

Sequencing and Intensification Remain Open Questions

Looking ahead, Nieva pointed to unresolved questions about how to combine taletrectinib with other modalities to extend remission. "There's a movement with [TKIs] in general to understand how we should incorporate chemotherapy and radiation therapy for eradication of residual disease after initial induction treatment," he said. "We need to get our patients to have the longest remissions possible, and undoubtedly that's going to involve some strategy towards intensification, whether that be with addition of chemotherapy or consolidation radiotherapy strategies. I think time will tell what the best approach is going to be. But we want our patients to be on oral agents that are tolerable for years and decades, and so trying to maximize the length of time that patients can stay on an oral agent is going to be very important."

REFERENCE

1. Hayashi H, Lin JJ, Choi CM, et al. Taletrectinib across key subgroups in patients with ROS1+ non-small cell lung cancer: results from TRUST-I and TRUST-II. Poster presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, Republic of Korea. Abstract P3.277.