Expert answers to your most pressing questions about RET-positive cancer from our scientists and pharmaceutical industry partners.
Each year, our Annual End-of-Year RET Research Webinar brings together leading oncologists, researchers, and pharmaceutical partners to share the latest advances in RET-positive cancer care — and each year, the questions from our community remind us why this work matters so deeply. The 2025 webinar was no exception. Patients, caregivers, and advocates submitted thoughtful, probing questions that touched on everything from managing treatment progression and side effects, to the promise of next-generation RET inhibitors, early-stage treatment options, and emerging immunotherapy approaches. Because every question deserves a careful answer, we have taken the time to review and respond to them thoroughly below, drawing on the expertise of our panelists and the latest available research. Whether you are newly diagnosed, currently on treatment, or supporting a loved one on this journey, we hope this Q&A provides you with valuable information and, above all, a sense of the real momentum building in the RET cancer research community.
Progression with selpercatinib as first-line therapy. How is this situation usually managed? Have there been any advancements in new drugs beyond selpercatinib or similar drugs?
Dr. Carbone kindly addressed this question and highlighted the importance to re-biopsy and sequencing the new tumor lesions whenever possible. Look for acquired, on-target resistance mechanisms, or off-target resistance mechanisms, and then often you can find targetable bypass pathways and try to get insurance coverage for dual tyrosine kinase inhibitors (TKIs). Also look for clinical trials of novel agents that might be active in this setting.
You can find below some related resources from HLP:
We always emphasize the importance of sequencing the new tumor lesions to better guide next treatment options. Tumor sequencing can provide valuable information about the best next steps for treatment.
There has been advances in new drugs for RET cancer. Some of which are effective against acquired RET resistant mutations.
There is a clinical trial of a next-generation RET inhibitor called EP0031 (lunbotinib), developed by Ellipses Pharma. This trial is currently open at several sites across the USA, Spain, France, the UAE and the UK, and very recently they opened new sites in Italy, Germany and Poland. The study includes 1st and 2nd line cohorts that are evaluating EP0031 alone or in combination with chemotherapy, in NSCLC patients that are naïve to or have progressed on selpercatinib or pralsetinib.
https://happylungsproject.org/ellipses-ret-inhibitor-ep0031-advances-to-phase-2-clinical-trials/
EP0031 is also being developed under the name A400 by Kelun Biotech in China and a submission to seek marketing approval has been made recently to the Chinese regulatory authorities, the NMPA.
Other next generation drugs are vepafestinib which has a trial ongoing in Japan and APSO3118, HA121-28, HS-10365, SY-5007, which have ongoing trials in China. Info here.
If progression is due to activation of another pathway, for example nvolving a molecule called MET, there are compounds available that can inhibit MET:
- Telisotuzumab vedotin-tllv, a c-Met-directed antibody and microtubule inhibitor conjugate, approved for adults with locally advanced or metastatic, non-squamous NSCLC with high c-Met protein overexpression, who have received a prior systemic therapy.
- The MET tyrosine kinase inhibitors tepotinib and capmatinib could sometimes be used off-label for MET amplification, but this is not their FDA-approved indication (they are approved for MET exon-14 disease) and the evidence is limited. They have been shown to work better in high-level MET amplification cases.
- Amivantamab, a bispecific antibody that binds to the extracellular domains of EGFR and MET in combination with RET inhibitors, is being studied for patients who progressed on TKI therapies including RET therapies (NCT05845671).
- The cMET-targeting antibody-drug conjugate (ADC) compound called MYTX-011, is also being studied in patients with previously treated, advanced NSCLC (NCT05652868).
- Cabozantinib, a multi-kinase inhibitor targeting RET, MET, and VEGFR2, has shown clinical activity in RET-mutant tumors (NCT01639508).
Other alterations:
- TROP2 overexpression
There is now a bispecific antibody that targets TROP2 called Dato-DXd, currently being evaluated across different types of lung cancer, including RET. Early results look encouraging. Although the Dato-DXd Tropion Lung5 clinical trial is not currently recruiting patients (as of Sept 2025) a phase III trial of Dato-DXd compared to platinum-based chemotherapy in patients with actionable genomic alterations with disease progression on targeted therapies is expected.
- MTAP Loss
Another possible mechanism of resistance that has been recently described is MTAP loss, which occurs in a subset of RET-positive lung cancer patients. Two phase I/II clinical trials are available: a selective PRMT5 inhibitor, TNG462-C101 study (NCT05732831) and the MTRX 1719 study
More resources and information related to drug resistance:
For more information about this and research on new RET treatment options:
https://happylungsproject.org/2025-ret-cancer-research-update/
Side effects with RET drugs including pain or gastric side effects. How do clinicians find out about updated side effects of RET targeted drugs as these drugs are used longer now? Should we, as patients make sure our symptoms are reported and if so, to whom? Is it possible to reduce the dose in order to lessen the side effects?
Selpercatinib and pralsetinib studies continue to report side effects even after these drugs were approved. The final data from the pralsetinib study, published last year, included updated information on side effects, and the same is true for selpercatinib studies. Please find below a summary of the pralsetinib study here and here and the selpercatinib study here.
When it comes to reporting side effects, we strongly encourage RET patients to speak with your care team, especially if you are experiencing side effects. They keep the records updated and send the reports of the side effects to the regulatory agencies. Also, if needed they are able to offer treatments or other supportive measures to help ease how you are feeling. In some situations, if side effects are particularly challenging, adjusting the dose or even temporarily stopping treatment may be considered. Because these decisions can influence how well the therapy works, it is important that they are made together with your doctor and care team, who know your medical history and current condition best.
Gastric side effects with selpercatinib? Secondary lymphangiatasia? Is research being conducted to find help for those that developed this?
Dr. Jaime Rubio-Perez from MSKCC presented an abstract on the Targeted Therapies in Lung Cancer meeting this year titled: Intestinal Lymphangiectasia with RET Tyrosine Kinase Inhibitor Therapy. Find the abstract here. Please visit the TTLC2026 blog post on HLP web for more information on this presentation.
Have there been a reporting (in the studies or in practice) of seizures as an adverse event?
Seizures are not a common side effect of RET drugs. If you as a patient are experiencing seizures it is very important to contact your doctor right away, as it may be related to the cancer, the medication or another medical issue. It may also be a good idea to schedule a brain MRI for peace of mind. Patients with RET lung cancer that has spread to the brain can have a higher risk of seizures because of the cancer itself, not necessarily the medication. When it comes to side effects, we strongly encourage you to speak with your care team, especially if any symptoms are becoming difficult to manage. Your healthcare team can monitor you closely for any neurological symptoms and help manage them if they occur.
Can you comment on the use/success of any combined targeted drugs with RET and MET mutations?
There is one study testing combinations of MET and RET inhibitors but there has been no reported data as of yet: Amivantamab is a drug that targets both EGFR and MET. It is being studied in combination with RET inhibitors for patients whose cancer has progressed after treatment with targeted therapies, including RET inhibitors (clinical trial NCT05845671). This study is led by Dr. Tejas Patil at the University of Colorado.
Do we have enough data now to project updated survival rates for RET positive lung cancer patients? Can you update us on what PFS and overall survival you are seeing now that you are further along?
The final data from the pralsetinib study (ARROW) was presented this year at ASCO. Please find the ASCO abstract here and a summary in our website here.
For selpercatinib (LIBRETTO-001), among patients who had previously received platinum-based chemotherapy, the median overall survival was approximately 47.6 months in pretreated patients. In treatment-naïve patients, the median overall survival was not reached at the time of analysis, meaning that more than half of the patients were still alive at the follow-up point. Median progression-free survival (PFS) was 26.2 months for pretreated and 22.0 months for treatment-naïve patients.
What’s the data on RET inhibitors for stage IIIA or less patients?
For studies regarding stage IIIA RET patients, there were 2 clinical studies looking at the use of RET-targeted inhibitors in earlier-stage (including stage IIIA) RET-positive lung cancer. One of these studies, called NAUTIKA1, tested a RET-targeted drug called pralsetinib in patients whose cancer could be removed with surgery.
Another study, called LIBRETTO-432, was testing selpercatinib in patients with stage IB–IIIA RET-positive lung cancer. Positive results were recently released from this study. Selpercatinib showed a statistically significant improvement in event-free survival (EFS) as adjuvant therapy in patients with early-stage RET fusion-positive NSCLC. Overall survival trended positively (data immature), and safety was consistent with prior trials. Detailed results will be shared at an upcoming medical meeting. Info here.
Experience from other oncogene-driven lung cancers, such as EGFR- or ALK-positive NSCLC, supports this approach in stage IIIA RET patients. Early treatment with targeted tyrosine kinase inhibitors has demonstrated significant and durable benefit in these populations, as shown in the ADAURA and LAURA trials for EGFR-mutated disease and the ALINAtrial for ALK-positive disease.
A case study has been published showing that neoadjuvant treatment with selpercatinib was successful in a patient with stage IIIA RET fusion-positive lung adenocarcinoma.
Why is pralsetinib not approved in Germany?
In 2023, Roche made the decision to terminate its global collaboration agreement with Blueprint Medicines to develop and commercialize Gavreto® (pralsetinib). Steps were then initiated to deregister Gavreto in most territories where it was initially approved outside of the United States and greater China – As a result Gavreto is no longer available in Germany – Rigel Pharmaceuticals only acquired US commercial rights for the drug and doesn’t have any licensing rights outside of the USA.
Discuss the use of tartatamab (DLL3/CD3 bispecific T-cell engager (BiTE) for RET survivors.
Dr. Heymach kindly responded that tarlatamab is approved for SCLC and would be considered if the RET tumor underwent SCLC transformation. His team has done this for EGFR mutants that have undergone SCLC transformation.
I am interested in my “digital twin” approach.
During the Q&A, Dr. Heymach 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.
Is there any new information on heredity and RET + lung cancer?
During the RET webinar, Dr. Caitlin Nichols of Troper Wojcicki Philanthropies kindly shared an update on the Lung Cancer Genetics Study, a national research effort created in partnership with the 23andMe Research Institute and more than 20 lung cancer advocacy organizations, including The Happy Lungs Project.
The goal for this study is to understand more about how our genetics influence lung cancer so that we can work to improve detection, risk reduction, and care. Ultimately, we want to help advance research toward finding a cure. 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, and patients are involved in reviewing research proposals to help shape future research.
Early data shows strong representation of women and younger patients, and about 400 participants reported having a tumor biomarker. Sixteen patients with RET lung cancer have joined the study. Anyone who has been diagnosed with lung cancer, lives within the United States, and is 18 years or older is eligible to participate. Eligible participants will get a 23andMe Health + Ancestry Service kit at no cost. More than 1,300 people have already enrolled, with a goal of reaching 10,000 participants.
We need your help to reach our goal of 10,000 participants. If you know someone who may be interested in the study, tell them to learn more here.
Noticed on the Rigel presentation mentioning of immunotherapy being provided to patients. My understanding was that immunotherapy did not provide the response or benefits to RET+ mutations as it does for other types?
On the Rigel presentation, Dr. Villarimo highlighted the past and current challenges in biomarker testing, including long turnaround times of 2 or 3 weeks. Such delays may lead to patients receiving chemotherapy or immunotherapy in cases where RET-targeted therapy would be the more appropriate treatment choice per National Comprehensive Cancer Network (NCCN) guidelines recommendations.
Dr. Carbone kindly added that there is no data that PD-1 pathway immunotherapy benefits RET fusion positive patients so he would not give it.
Immunotherapy based on checkpoint blockade inhibitors such as anti-PD-1/PD-L1 have shown limited activity in RET lung cancer patients. Other therapeutic strategies should be considered before administering immunotherapy alone for the treatment of patients with RET alterations. For more information on this please visit our web here.
Do you think there will be place in the future for specific RET inhibitors in adjuvant or neoadjuvant setting for RET patients?
As a note, adjuvant therapy is when the drug is given after surgery (± chemoradiation) with the goal of eradicating residual microscopic disease and reducing the risk of recurrence. This approach is better established and supported by stronger data, especially in EGFR- and ALK-driven cancers. Neoadjuvant therapy is when the drug is given before definitive treatment (usually surgery, sometimes radiation). The goals are to shrink the tumor, improve resectability, and treat micro metastatic disease early. However, in oncogene-driven cancers, neoadjuvant targeted therapy is more controversial because it may delay curative surgery and can raise safety concerns, particularly perioperative risks (e.g., wound healing or bleeding issues with agents that have VEGF inhibition like some RET drugs).
The panel discussed the use of targeted kinase inhibitors (TKIs) in the adjuvant setting for RET-driven cancers, noting that current practice largely extrapolates from strong evidence in EGFR- and ALK-mutant disease. While adjuvant TKIs after surgery or chemoradiation are now standard of care for EGFR and ALK, similar data for RET are not yet available. Panelists emphasized that TKIs dramatically outperform immunotherapy in oncogene-driven cancers, reducing recurrence risk by 75–80% in EGFR and ALK compared with more modest benefits from immunotherapy. Ongoing clinical trials, including adjuvant selpercatinib studies (LIBRETTO-432, are expected to provide prospective data, though the group highlighted the challenge of long trial durations and the need for more efficient endpoints and regulatory flexibility to accelerate progress in this setting. More info here, here, and here.
Though experts consider adjuvant use a reasonable hypothesis, the neoadjuvant preoperative or pre-radiation use remains more controversial due to safety concerns, including VEGF-related perioperative risks. Neoadjuvant RET inhibitor therapy for NSCLC remains unexplored but there is some data from other oncogene driven NSCLC including EGFR and ALK and medullary thyroid cancer (MTC) that indicates that neoadjuvant SRI therapy is effective and well tolerated in patients with early-stage NSCLC.
In this study of MTC, authors present a consecutive case series of four patients with RET-mutated MTC treated with neoadjuvant selpercatinib followed by surgical resection. This study reports outcomes related to treatment response, surgical morbidity, and locoregional disease control, offering early evidence to support this novel treatment strategy.
I am a RET+ poorly differentiated thyroid cancer patient and it would be great for the panelists to mention where any info they are presenting crosses over to thyroid cancer patients.
Many of the therapeutic strategies being investigated for lung cancer may also be applicable to thyroid cancers. Selpercatinib has been approved for advanced or metastatic RET-mutant medullary thyroid cancer, and advanced RET fusion–positive thyroid cancers (papillary or other types) refractory to radioactive iodine. Pralsetinib has already been approved for adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). Second-generation agents, such as EP0031 also include patients with thyroid cancer in their trials.
It is true that in RET-positive lung cancer and papillary thyroid carcinoma, RET fusions are more prevalent, whereas point mutations are more common in medullary thyroid cancer. However, investigators are actively studying a wide range of RET alterations in the laboratory, including both fusions and point mutations. As a result, many of these findings should be readily translatable to thyroid cancers.
Another example is the TCR-based immunotherapies being developed by Dr. Reuben, which could also be applicable to patients with RET-driven thyroid cancers. Here you can find the 2024 annual webinar and other resources in which he discusses these findings:
https://happylungsproject.org/2024-ret-cancer-research-update/
https://happylungsproject.org/research/
https://www.retpositive.org/pages/ret-altered-cancers-recent-research-overview
Will there be new Ellipses sites opening? When will this be FDA approved?
Ellipses kindly responded that new sites will soon be initiated in Ohio, Miami and Florida (all current US sites are on clinicaltrials.gov). New sites are currently opening in Italy, Germany and Poland too. No other countries are planned to open in the EP0031-101 study. EP0031 is in Phase 2 development. Ellipses cannot speculate at this time as to when EP0031 will be approved by FDA.
Is it possible to access second-generation targeted drugs on an experimental basis in Italy?
Ellipses Pharma has recently opened 2 new sites in Italy for the EP0031 trial: Fondazione Policlinico Universitario Agostino Gemelli IRCCS with Dr Gennaro Daniele and Centro di Riferimento Oncologico di Aviano with Dr Alessandra Bearz. They expect to open a site in Bologna this month, and further sites in Rome, Milan, and Turin in the next few months.
Question to Ellipses Pharma: Will inclusion criteria change with stage 3 trials? Will stage 3 be trial drug only or trial drug + chemo?
Ellipses: EP0031 is still under evaluation in a Phase 2 trial. Ellipses cannot speculate about the design of future trials at this time.
Question to Ellipses Pharma: if/when they might be considering an expanded access/compassionate use for EP0031 for those that do not qualify for the clinical study?
Ellipses: Currently, Ellipses Pharma is unable to offer an expanded access program. We believe that access to our investigational product candidates should be limited to controlled clinical trials until such time as their safety, tolerability and effectiveness have been determined and confirmed by regulatory authorities.
Question to Ellipses Pharma: I believe once phase III is completed, there will be just one more (phase IV). What could be a realistic date when the trial is finished, and drug could be available to all patients (such as selpercatinib)?
Ellipses: EP0031 is currently in a Phase 2 clinical trial. Phase IV trials are trials performed subsequent to first marketing approval. Ellipses cannot speculate currently about when first marketing approval will be attained for EP0031.
Question to Ellipses Pharma: does the RET fusion SQSTM1 eligible for the EP0031 trial?
Ellipses: yes – all RET fusions are eligible.
I have been seeing a lot of blogs about mRNA vaccines for various cancers. What is the status of these and would they apply to RET+ lung cancer patients? Any progress with RET on TIL therapy and car-t therapy?
Although the field is moving to include oncogene-driven lung cancer groups in vaccine trials, as Dr. Carbone kindly mentioned, there are not specific RET vaccines at the moment. We are hopeful to see progress in this area within the coming year.
As for T cell immunotherapies, Dr. Carbone shared that developments have been made in targeting RET with immunotherapies based on T cell therapies in which a novel protein structure within a cell is generated, and a T cell can recognize and attack it. He pointed out that this approach has already been proven successful for P53, for KRAS, and for other neoantigens that are present in the tumor, but not in normal cells.
More resources about cancer vaccines here and about Dr. Reuben’s work on T cell based immunotherapies for RET hereand here.
Can you please explain more about using antibody drug conjugates (ADC)-based combinations with targeted therapies in RET.
Dr. Mihaela Aldea kindly responded that the field is leading toward combinations in the development of ADCs and shared the examples of EGFR and ALK. We know that pursuing targeted therapy beyond progression improves survival outcomes and also decreases the probably of progression in the brain. She pointed out that it would be very interesting to have combinations between TKI and an anti-MET, antibody drug conjugate, or TKI plus anti-TROP2 ADCs. With sufficient funding, this is what she would like to see in future development and patient clinics.
How can we as a community inspire researchers to work on RET-positive lung cancer, or to try to keep pushing this field forward? How can we inspire researchers to walk down the RET path?
Dr. Heymach and Dr. Carbone kindly shared that the most effective way to inspire RET research and researchers is to provide the funds for the research. This is particularly important at this time because it is very difficult to secure federal funding for rare diseases such as RET positive non small-cell lung cancer. Dr. Heymach further shared that collaboration between researchers is highly accessible, and that research that has been found successful with other oncogenes can be used as a foundation for transformational RET research; however, in order to get treatments to patients in an expedited manner, we need the funds to support dedicated and on-going RET research and researchers.
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