In the 4th Annual End-of-Year RET Research Webinar, industry partners and leading researchers shared the latest insights into RET biology, treatment resistance, and emerging strategies aimed at improving outcomes for patients with RET-driven cancers.

We are deeply grateful to all of the presenters for sharing their insightful and compelling perspectives on RET-positive cancer research and future directions. We also thank our sponsors – Lilly, Ellipses, and Rigel – and the nearly 130 participants and members of the broader RET lung cancer community who joined us for the 2025 RET Research Update.

Your continued support of The Happy Lungs Project is helping drive meaningful research progress. We invite you to watch the webinar recording and read the recap below.

Research Presentations:

Rigel Pharmaceuticals:

Dr. Cynthia Villarimo from Rigel Pharmaceuticals, shared updates on Rigel’s RET research pipeline, highlighting pralsetinib (Gavreto) and ongoing efforts to improve outcomes for patients with RET fusion–positive cancers. Rigel is a fully integrated biopharmaceutical company with three FDA-approved therapies across hematology and oncology, including Gavreto, for RET fusion–positive metastatic non-small cell lung cancer (NSCLC) and RET positive thyroid cancer. Approval of pralsetinib was supported by results from the ARROW trial, which demonstrated durable responses across RET-positive solid tumors.

Dr. Villarimo shared Rigel’s ongoing research that focuses on overcoming resistance through combination strategies, evaluating intracranial efficacy, and exploring RET fusions in additional tumor types, including pancreatic and colorectal cancers. Dr. Villarimo also highlighted challenges in biomarker testing, including long turnaround times of 2 or 3 weeks. These delays may contribute to some patients receiving chemotherapy instead of targeted therapy.

To support timely access, Rigel offers patient assistance programs, copay support, and free drug supply coordination. More information is available at RigelOneCare.com.

Ellipses Pharma:

On behalf of Ellipses Pharma, Dr. Alex Drilon, Medical Oncologist at Memorial Sloan Kettering Cancer Center, presented an overview of the evolving treatment landscape for RET fusion–driven cancers, with a focus on lunbotinib (EP0031), a next-generation RET inhibitor currently in global clinical development by Ellipses Pharma.

For patients with RET fusion–positive NSCLC, first-line treatment typically involves selective RET inhibitors such as pralsetinib or selpercatinib, which provide durable benefit for many patients. However, once resistance develops, treatment options are limited and often shift to non-targeted chemotherapy. This unmet need has driven the development of newer RET inhibitors designed to extend benefit and overcome resistance.

Dr. Drilon emphasized that not all investigational RET inhibitors are truly next generation. Key differentiators include the activity against RET resistance mutations, particularly the RET G810, improved brain penetration, and clinical activity in patients previously treated with selective RET inhibitors

Dr. Drilon mentioned that while many RET inhibitors are in development globally, particularly in Asia, few demonstrate these features. Lunbotinib is currently the only next-generation RET inhibitor in active clinical development across Asia, Europe, and the United States, with more than 500 patients treated worldwide. Early-phase studies have shown:

• Meaningful tumor responses in RET fusion–positive lung and thyroid cancers
• Activity in the brain, an important consideration for RET-driven NSCLC
• Clinical responses in patients who previously progressed on pralsetinib or selpercatinib
• Activity against the challenging RET G810 resistance mutation

The objective response rates exceeded 40%, with disease control observed in over 80% of patients, and side effects were generally mild to moderate.

Beyond monotherapy, Dr. Drillon mentioned that lunbotinib is now being studied in combination with chemotherapy, both in patients new to RET inhibitors and in those previously treated. This approach is supported by the lessons learned from EGFR-positive lung cancer, where combining EGFR targeted therapy (osimertinib) with chemotherapy improves outcomes compared with targeted therapy alone.

Lilly:

Dr. Aimee Lin and Dr. Jennifer Wright from Lilly shared updates on the RET inhibitor selpercatinib, focusing on a major formulation change designed to improve patient experience. While selpercatinib continues to show strong clinical benefit across RET-driven cancers, Lilly recently transitioned the drug from capsules to smaller, easier-to-swallow tablets.

Approved by the FDA in April 2024, the tablet formulation offers fewer pills per dose, more flexible dosing, and improved usability, which is especially important for pediatric patients. Feedback from patients notes that the change makes daily treatment feel “less of a thing,” underscoring Lilly’s commitment to patient-centered innovation.

Troper Wojcicki Philanthropies:

Dr. Caitlin Nichols of Troper Wojcicki Philanthropies shared an update on the Lung Cancer Genetics Study, a national research effort created in partnership with 23andMe Research Institute and more than 20 lung cancer advocacy organizations, including The Happy Lungs Project.

The study’s goal is to better understand how genetics, environment, and lifestyle factors influence lung cancer risk, early detection, and treatment. Participants provide a saliva sample for genetic analysis and complete surveys about diagnosis, biomarker testing, treatments, exposures, and family history. De-identified data are securely shared with qualified researchers, with patients involved in reviewing research proposals to ensure studies reflect community priorities.

Dr. Nichols shared that 23andMe has transitioned to the 23andMe Research Institute, a nonprofit organization dedicated to advancing medical research.

The study is open to any U.S. adult who has ever been diagnosed with lung cancer, at no cost to participants. More than 1,300 people have already enrolled, with a goal of reaching 10,000 participants. Early data show strong representation of women and younger patients. Sixteen patients with RET lung cancer have joined the study, and about 400 participants reported they had a tumor biomarker.

Dr. Nichols noted that by growing this study, researchers hope to identify genetic risk factors, improve screening strategies, and ultimately support the development of more personalized treatments. Community participation and advocacy partnerships remain central to the study’s success. Those interested in learning more or enrolling can visit 23andMe.com/lung-cancer.

Dr. John Heymach, MD Anderson Cancer Center:

Dr. John Heymach, Professor and Chair of Thoracic Head and Neck Medical Oncology at MD Anderson Cancer Center, shared new research advances from his team that were made possible through funding from The Happy Lungs Project.

A central focus of Dr. Heymach’s work is the idea that not all RET fusions are the same. While RET-positive lung cancers are often treated as a single group, Dr. Heymach’s team showed that different RET fusions, such as KIF5B and CCDC6, can behave differently and respond differently to treatment. Using RET cell lines engineered in the lab to carry different RET fusions and mutations, the researchers found meaningful differences in drug sensitivity, even among patients treated with the same RET inhibitors.

These laboratory findings are supported by clinical data. Patients with CCDC6-RET fusions showed longer progression-free survival and overall survival compared with those with KIF5B-RET fusions. This suggests that fusion type may influence outcomes and could eventually help guide treatment decisions.

The team is also uncovering important differences in how RET fusions arise in different settings. For example, KIF5B-RET fusions are more common at initial diagnosis, while CCDC6-RET and other fusions are more often seen as resistance mechanisms in patients with EGFR-mutant lung cancer, pointing to distinct biological contexts.

Another major focus of the research is RET drug resistance. Using an innovative approach called Lentimutate developed by Dr. Ralf Kittler (UT Southwestern), the team can rapidly generate and study all possible resistance mutations in RET, rather than waiting for them to emerge in patients. This has revealed that resistance patterns differ not only by drug (such as selpercatinib vs. pralsetinib), but also by fusion partner. This knowledge has already helped guide switching between RET inhibitors when resistance develops.

Beyond mutations in RET itself, the researchers are exploring alternative resistance pathways, including signaling through EGFR, HER3, and MET. Preclinical studies suggest that combining RET inhibitors with newer therapies, such as EGFR/HER3–targeted antibody-drug conjugates, may help overcome resistance.

Looking ahead, Dr. Heymach’s team is identifying new cell-surface targets that appear in drug-resistant or drug-tolerant cancer cells. These discoveries are already being used to develop experimental CAR-T therapies and T-cell engagers, offering potential new strategies for patients whose cancers no longer respond to current RET inhibitors. The group is also exploring AI-driven “digital twin” models to better predict treatment response and accelerate clinical research.

During the Q&A, Dr. Heymach further explained how researchers are using a new tool called “digital twins” to help test new cancer treatments faster and more accurately. Traditional clinical trials, especially large randomized trials, are very expensive and can take many years to complete. Because of this, companies are sometimes hesitant to run them. A digital twin is a computer-generated model of a patient, which is created using large amounts of real patient data. It includes information such as tumor size and how the cancer typically changes over time. Researchers use artificial intelligence to predict how a patient would be expected to do on today’s standard treatment. The goal of this approach is to speed up drug development, identify promising treatments sooner, and help bring effective new therapies to patients more quickly.

Dr. Mihaela Aldea, Institut Gustave Roussy:

Dr. Mihaela Aldea, Medical Oncologist at Institut Gustave Roussy, presented emerging research focused on treatment strategies after progression on selective RET inhibitors in RET fusion–positive NSCLC. Her work builds on a global RET registry launched in 2021 (RET-MAP), which now includes data from more than 500 patients across 48 centers worldwide, enabling detailed study of resistance and new therapeutic opportunities.

Dr. Aldea pointed out that while selective RET inhibitors have transformed care for patients with RET fusions, progression eventually occurs for many patients. At that point, treatment options are limited, as RET-positive tumors tend to respond poorly to immunotherapy, highlighting the need for new targeted approaches.

Dr. Aldea’s research focuses on identifying cell-surface targets that could be exploited by antibody drug conjugates (ADCs) or bispecific antibodies. By analyzing tumor samples from 93 RET-positive patients across 12 European institutions her team evaluated expression of targets including MET, HER2, EGFR, HER3, and TROP2 using immunohistochemistry and gene-expression profiling.

The findings revealed that TROP2 is commonly expressed in RET-positive lung cancers, consistent with other lung adenocarcinomas. More notably, MET expression was significantly higher in RET-positive tumors compared with RET-negative ones, and MET levels often increased after progression on RET inhibitors. Importantly, multiple targets were frequently co-expressed, suggesting that dual-target or bispecific therapies may be effective.

Another key discovery involved angiogenesis, the process by which tumors form new blood vessels. RET-positive tumors showed a stronger angiogenic gene-expression signature and this signature appeared to be further enriched after resistance to RET inhibitors. Laboratory models confirmed that resistant cancer cells could form vessel-like networks, a phenomenon known as vasculogenic mimicry.

Building on these findings, Dr. Aldea’s team tested bevacizumab, an anti-angiogenic drug, in combination with chemotherapy in preclinical models. The combination disrupted vessel-like structures, reduced tumor cell migration, and increased cancer cell death. Retrospective clinical data also suggested a signal of benefit for bevacizumab plus chemotherapy, including in first line treatment, although patient numbers were small, and results require confirmation in prospective studies.

Dr. Aldea concluded that MET and TROP2 are promising targets for future ADC development in RET-positive lung cancer, particularly at progression. Anti-angiogenic strategies, either with bevacizumab or newer VEGF and immune-targeting combinations, may offer additional options, especially in regions where selective RET inhibitors are not yet widely available. She pointed out that further prospective trials will be essential to determine how best to integrate these approaches into clinical care.

Dr. David Carbone, The Ohio State University Cancer Center:

Dr. David Carbone, Professor and Director of the James Oncology Center at The Ohio State University, discussed strategies to improve outcomes for patients with RET fusion positive lung cancer beyond current RET targeted therapies. While selective RET inhibitors have significantly advanced care, Dr. Carbone emphasized that drug resistance remains inevitable, highlighting the need for complementary approaches.

Dr. Carbone shared the  plans for the creation of a multi-institution RET research consortium, coordinated through MD Anderson, to accelerate progress through shared resources, patient samples, and collaborative projects. This model would allow researchers to test new strategies, such as locally ablative therapies, antibody-drug conjugates (ADCs), and bispecific antibodies, more efficiently across institutions.

Dr. Carbone also outlined ongoing research aimed at identifying novel cell-surface protein targets specific to RET-driven tumors and to drug-tolerant “persister” cells that survive after initial treatment. Using advanced cell-surface proteomic techniques, his team has already identified promising new targets in other fusion-driven cancers (ALK), with plans to extend this work to RET fusions.

Together, these efforts aim to move beyond incremental improvements in TKIs and toward next-generation therapies that could delay resistance, improve durability of response, and ultimately enhance long-term outcomes for patients with RET-positive lung cancer.