TRUST-IV: Bringing targeted therapy to earlier-stage ROS1-positive lung cancer
For many people living with ROS1-positive lung cancer, targeted therapies have transformed what it means to live with advanced or metastatic disease. But what if treatment could begin before the cancer has a chance to metastasize? That's the question researchers hope to answer with the TRUST-IV clinical trial.
For years, one unfortunate reality has shaped the ROS1 community: most patients are diagnosed after their cancer has already spread.
Unlike some cancers that are commonly detected through routine screening, ROS1-positive non-small cell lung cancer (NSCLC) has historically been diagnosed at Stage IV. By the time symptoms appear, the disease has often already metastasized or spread beyond the lungs, leaving patients and their families focused on managing the cancer rather than preventing it.
Fortunately, that landscape is beginning to change.
More patients are undergoing comprehensive molecular testing earlier in their diagnosis and more targeted therapies are becoming available, and researchers are asking an exciting new question:
Can treating early stage ROS1-positive lung cancer with a targeted therapy after curative surgery improve long-term outcomes?
The newly launched TRUST-IV clinical trial is designed to answer exactly that.
Why researchers are studying earlier treatment
The idea of using targeted therapy after curative surgery (called adjuvant therapy) isn't entirely new.
Over the past several years, several other biomarker-driven lung cancers have successfully moved targeted therapies into the adjuvant setting. Patients with early-stage EGFR-positive lung cancer can now receive adjuvant osimertinib following curative surgery, based on the results of the ADAURA trial, while adjuvant alectinib has become an important option for people with early-stage ALK-positive disease also after curative surgery based on the ALINA trial. Earlier this year, encouraging results from the LIBRETTO-432 trial showed that adjuvant selpercatinib significantly improved event-free survival in patients with RET fusion-positive NSCLC after curative surgery, further expanding the role of targeted therapies in early-stage disease.
These advances naturally raised the next question:
Could the same strategy benefit people with ROS1-positive lung cancer?
Researchers believe taletrectinib is a strong candidate to explore because of its demonstrated activity in advanced ROS1-positive disease and its manageable safety profile observed in the TRUST-I and TRUST-II clinical trials.
Unlike patients living with advanced or metastatic disease, individuals who have undergone successful surgery often feel healthy. Their willingness to accept side effects from taking therapy long-term is understandably different, making safety an especially important consideration when designing an adjuvant trial.
What is the TRUST-IV trial?
TRUST-IV is an international Phase 3 clinical trial evaluating whether taletrectinib can reduce the risk of cancer returning after curative surgery in people with early-stage ROS1-positive NSCLC.
The study is enrolling adults with:
Stage IB, II, or IIIA ROS1-positive non-small cell lung cancer
Who have had complete surgical removal of their tumor and are recovered from surgery
Confirmation of a ROS1 fusion
Patients may have already completed standard adjuvant chemotherapy if recommended by their oncology team before enrolling.
In today's standard treatment approach, surgery remains the primary treatment for most patients diagnosed with resectable early-stage lung cancer, with chemotherapy after surgery recommended for some individuals depending on their pathology and overall risk of recurrence.
Timing matters
One interesting aspect of TRUST-IV is that enrollment timing depends on whether patients receive chemotherapy.
Patients who do not receive adjuvant chemotherapy generally enroll within approximately 16 weeks after surgery. Those who complete chemotherapy have a longer enrollment window—up to 30 weeks after surgery—allowing them to recover before beginning study treatment.
Understanding the trial design
Clinical trials can sometimes sound intimidating, especially when terms like "randomized" and "placebo" are involved.
TRUST-IV is a randomized, double-blind study. Participants are assigned in a 2:1 ratio, meaning approximately two-thirds will receive taletrectinib while one-third will receive placebo.
For some patients, the idea of receiving placebo may initially seem discouraging. However, it's important to understand why this design was chosen.
For patients who have completed surgery—and adjuvant chemotherapy if appropriate—the current standard of care is often careful observation with regular imaging. In other words, participants who are randomized to receive placebo are generally receiving today's standard of care treatment; patients randomized to placebo are not being denied an established targeted therapy.
Researchers explained that this type of comparison is essential to determine whether taletrectinib truly reduces the likelihood of recurrence beyond current standard practice.
What are researchers measuring?
The primary goal of TRUST-IV is to determine whether taletrectinib can extend disease-free survival, the amount of time patients remain free of detectable cancer after treatment.
Researchers will monitor participants for several years, evaluating outcomes through both local investigators and independent central review to ensure consistent assessment across study sites. Long-term follow-up will help determine whether earlier treatment translates into a lasting benefit.
Why earlier testing matters more than ever
Perhaps the strongest message that emerged during our conversation had very little to do with taletrectinib itself.
It was about testing.
Historically, many patients weren't tested for ROS1 until after developing advanced or metastatic disease. Even today, comprehensive genomic profiling is not consistently performed for every patient with early-stage lung cancer.
Researchers emphasized that broader molecular testing will become increasingly important if targeted therapies continue moving into earlier stages of disease.
Finding a ROS1 fusion early is the first step toward identifying patients who may benefit from studies like TRUST-IV, and potentially future approved therapies.
Another challenge is how testing is performed.
Single-gene tests may identify common biomarkers but can miss rare gene fusions like ROS1.
Comprehensive next-generation sequencing (NGS) panels provide a much broader evaluation, helping ensure patients are matched with the most appropriate treatment or clinical trial. Insurance coverage for comprehensive testing remains inconsistent in some settings, but advocacy efforts continue to push for broader access.
Could TRUST-IV change the future of ROS1 care?
It's too early to know whether TRUST-IV will ultimately change clinical practice.
That's exactly why the trial is being conducted.
However, if taletrectinib demonstrates that treating patients after surgery significantly delays, or even prevents, recurrence, it could represent a major shift in how ROS1-positive lung cancer is managed.
Just as EGFR, ALK, and RET therapies have expanded beyond advanced or metastatic disease into earlier stages, ROS1 could eventually follow a similar path.
Importantly, such a change would not only offer another treatment option, it could also encourage more routine molecular testing after diagnosis, allowing more patients to learn about their tumor's biology before making treatment decisions.
What this means for patients today
For individuals currently living with advanced ROS1-positive lung cancer, TRUST-IV does not change today's treatment recommendations. Taletrectinib is approved in many regions for advanced disease, based on its activity demonstrated in the TRUST-I and TRUST-II trials, with additional regulatory reviews pending around the world.
For patients diagnosed with earlier-stage ROS1-positive lung cancer, however, TRUST-IV represents an encouraging step toward answering a question that has long remained out of reach:
Can targeted therapy help keep cancer from returning after curative surgery in early-stage ROS1-positive lung cancer?
While we won't know the answer until the study is completed, the trial itself reflects how much progress the ROS1 community has made. Not long ago, most patients were diagnosed only after their cancer had spread. Today, earlier diagnosis, broader molecular testing, and increasingly personalized treatment strategies are opening new possibilities that simply didn't exist a decade ago.
For the ROS1 community, that's a meaningful reason for optimism.
