A new study led by Dr. Alexander Drilon, member of HLP’s Scientific Advisory Board, finds that adding immunotherapy to chemotherapy doesn’t significantly improve outcomes for RET-positive lung cancer patients.
A new analysis of the phase 3 LIBRETTO-431 trial, led by Dr. Alexander Drilon at Memorial Sloan Kettering Cancer Center (MSKCC), provides important insights into the role of chemotherapy and immunotherapy in people with RET fusion-positive non-small cell lung cancer (NSCLC).
Key Takeaways
Dr. Drilon is a leading expert in RET cancer and has led several important clinical studies in the field. He is also a member of The Happy Lungs Project’s Scientific Advisory Board.
The study, published in the Journal of Thoracic Oncology (Cui et al. 2026) was partially funded by The Happy Lungs Project. It compared outcomes among patients who received platinum-based chemotherapy alone with those who received chemotherapy combined with the immunotherapy drug pembrolizumab.
What did the study find?
Researchers analyzed 102 patients with advanced RET fusion-positive NSCLC who received chemotherapy as part of LIBRETTO-431. Of these, 83 received chemotherapy plus pembrolizumab, while 19 received chemotherapy alone.
The researchers found no statistically significant difference in progression-free survival (PFS) between the two groups. Median PFS was 11.2 months for patients who received chemoimmunotherapy, while median PFS had not yet been reached in the chemotherapy-alone group at the time of analysis. Overall survival was also not significantly different between the groups.
The response rates were relatively similar as well: 53% of patients receiving chemotherapy plus pembrolizumab responded to treatment compared with 42% receiving chemotherapy alone. This difference was not statistically significant.
Importantly, the researchers also found that PD-L1 levels did not significantly predict better outcomes among patients receiving chemoimmunotherapy. his is particularly important because, in clinical practice, PD-L1 expression is commonly used as a biomarker to help predict response to immunotherapy and guide treatment decisions. These findings suggest that, in RET fusion-positive lung cancer, PD-L1 levels may not be a reliable marker for identifying patients who are more likely to benefit from immunotherapy.
Why does this matter for RET patients?
Like several other oncogene-driven lung cancers, RET-positive tumors tend to have a relatively low tumor mutational burden (TMB) and previous studies have also shown limited activity from immunotherapy alone in this population.
This new analysis is important because it provides for the first time prospective clinical data comparing chemotherapy with and without immunotherapy, rather than relying only on retrospective studies.
The results support the idea that RET-positive lung cancers may be less responsive to traditional checkpoint inhibitor immunotherapy than some other types of lung cancer. The authors describe these tumors as “immunologically cold,” meaning that they may have characteristics that make them less susceptible to immune checkpoint blockade.
What does this mean for treatment of RET patients?
The most important takeaway is that selective RET inhibitors remain the preferred first-line treatment for patients with RET fusion-positive NSCLC, based on the overall results of LIBRETTO-431.
For patients who need chemotherapy, this analysis suggests that chemotherapy alone is a reasonable option, and adding pembrolizumab may not provide a significant additional benefit for most RET-positive patients.
The study also highlights an important area for future research. Because conventional checkpoint immunotherapy appears to have limited effectiveness in RET-positive lung cancer, researchers are exploring new approaches to activate the immune system, including vaccines, bispecific therapies, and cellular therapies.
