2026 RET Research Update: What the Experts Shared

Mapping RET resistance mutations systematically. In collaboration with Dr. Ralph Kittler’s lab, the team applied a method called LentiMutate, testing every possible single change in the RET gene (millions of mutations) to see which ones make each drug stop working. This builds a lookup library of “which mutation resists which drug” — something that would otherwise take data from thousands of patients a rare cancer doesn’t have. These experiments confirmed that specific fusion partners are associated with distinct drug sensitivities and clinical outcomes, and that secondary RET mutations may confer drug-specific resistance.

Targeting RET drug-tolerant persister cells (DTPCs). Even highly active RET inhibitors eliminate roughly 95–99% of tumor cells, but some residual cells can persist and become the reservoir for relapse — these are called drug-tolerant persister cells (DTPCs). By investigating RET DTPCs, the team identified a cell-surface molecule markedly upregulated in DTPCs and in selpercatinib- and pralsetinib-resistant cells. The team developed CAR T cells directed against this target and showed they could eliminate RET inhibitor-resistant cells and DTPCs in vitro, and also killed osimertinib-resistant EGFR-mutant cells, suggesting activity beyond RET.

An mRNA vaccine trial in the minimal residual disease (MRD) setting. MD Anderson, in partnership with BioNTech, has opened a trial of BNT116, an mRNA vaccine against six tumor-associated antigens, many expressed in RET fusion-positive NSCLC. A new cohort was opened to enroll patients with RET fusions. Patients continue their RET inhibitor while disease is controlled and receive the vaccine in an induction phase. More on the vaccine RET cohort here.

AI-guided “digital twins” to de-risk single-arm clinical trials for RET. Because efficacy is hard to read out without a control arm when a patient has minimal residual disease, the team (led by Drs. Jia Wu, Jianjun Zhang, Natalie Vokes and colleagues) combines radiomics, clinical and molecular data, large language models and agentic AI to predict each patient’s expected trajectory on standard therapy. Applied to a recent single-arm trial of brigatinib in ALK-positive NSCLC, the model’s predictions closely matched outcomes from randomized trials in independent validation sets. A RET-specific predictor is now in development to support interpretation of single-arm studies, such as RET inhibitor plus antibody-drug conjugate (ADC) combinations, and to make RET trials more attractive to industry partners.

Biological rationale. Some RET cancers lose a gene called MTAP. When that happens, drugs called PRMT5 inhibitors can selectively inhibit proliferation of MTAP-deleted cells. In early-phase trials, heavily pretreated oncogene-driven NSCLC patients achieved objective responses, some lasting more than 6 months to over a year, without continuing their targeted therapy.

Prevalence and prognostic signal in RET patients with MTAP loss. MTAP loss appears enriched in oncogene-addicted NSCLC, with the highest frequencies in ALK- and RET-driven disease. At Gustave Roussy, 37% (about 1 in 3 or 4) of RET patients had MTAP loss. In this small, early dataset, MTAP-deleted patients treated with first-line selective RET inhibitors showed a trend toward worse outcomes, suggesting they may need intensified or alternative treatment and should be identified early for trial referral.

Preclinical models and combination strategy to tackle RET tumors with MTAP loss. The team has generated 2 patient-derived xenografts (PDXs) and 2 RET cell models with MTAP loss — one with a co-occurring TP53 mutation and one with MET amplification — both from patients progressing on selpercatinib. With Happy Lungs Project support, these models will be treated with PRMT5 inhibitors alone and combined with RET TKIs. In prior work across 20 MTAP-deleted cell lines with other drivers, the combination of targeted therapy plus a PRMT5 inhibitor increased cell death and reduced proliferation in more than half. The ultimate aim is a phase 1 trial of a RET inhibitor plus a PRMT5 inhibitor.

Access to RET drugs across borders. Two patient cases illustrated the unmet needs some RET patients face around access to treatment. A patient in France with an acquired RET G810C solvent-front mutation lacks access to next-generation RET inhibitors. A patient in Belgium with MET amplification (and MTAP loss) after selpercatinib could not receive a RET plus MET inhibitor combination. Dr. Aldea called for treatment access “without borders.” Closing the webinar, Executive Director Kelli Beyer Patel acknowledged the panelists for raising these access issues and said The Happy Lungs Project is keenly aware of them and working behind the scenes to improve access, noting that far too many patients still cannot reach therapies that are already working for others.

Engineered T cells can overcome some of the hurdles of TIL therapy. TIL therapy takes the T cells already inside a tumor and assumes they can see and kill it, but only 10–15% of them actually can. CAR T cells are built to recognize one specific target, but they can only grab proteins on the surface of the tumor cell — as Dr. Reuben put it, the vast majority of proteins are found within the cell. TCR engineering inserts a new gene that gives these cells the ability to see tumors they weren’t previously able to see, including targets deep inside the cell and in its nucleus. The catch: you have to know which protein you are going after, and it has to match the patient’s immune type (HLA).

A validated discovery pipeline. Over the past 6–7 years, Dr. Reuben’s lab has refined a pipeline for identifying therapeutically relevant T cells and their receptors, yielding 21 validated TCRs, each a candidate therapeutic for a distinct patient population, primarily in lung cancer.

FOXM1 as a RET-relevant target. FOXM1 is a nuclear transcription factor, inaccessible to CAR T cells but targetable by TCR engineering. Expression is very low across normal lung, kidney, liver, brain and heart tissue, indicating a therapeutic window — and among oncogenic driver subgroups, RET-driven tumors showed the highest FOXM1 expression. Engineered T cells did not recognize or kill normal-tissue cell lines but did kill lung cancer cells, including a RET fusion patient-derived line generated in Dr. Heymach’s lab. In vivo, treated mice showed substantially reduced tumor growth and significantly prolonged survival versus controls. The program is moving toward clinical translation, including in RET-driven lung cancer. Find more details of this study here.

Where vaccines fit. A vaccine boosts an immune response the patient already has, while TCR engineering gives them one they never had, so the two likely suit different patients and may work well together. A vaccine needs a target (an overexpressed protein like FOXM1, or a tumor mutation), a format such as mRNA, and an adjuvant — a danger signal that tells the immune system this protein is a threat rather than something to tolerate. Once injected, immune cells carry the target to the lymph nodes, show it to T cells, and those primed T cells go hunting for tumor cells carrying it.

Supporting clinical evidence Dr. Reuben highlighted:
• An MD Anderson analysis found that patients receiving a COVID-19 mRNA vaccine prior to immunotherapy had significantly prolonged survival, consistent with broad immune reactivation rather than antigen-specific effects.
• In resected pancreatic cancer (Memorial Sloan Kettering with BioNTech), patients who mounted a vaccine-induced immune response had markedly improved overall and relapse-free survival.
• In melanoma, recently reported Merck/Moderna data showed that adding an individualized mRNA vaccine to PD-1 blockade reduced the risk of recurrence and death, with reductions of 42% and 58% cited at 6 months.

The RET cohort of the BNT116 trial has slots reserved for RET fusion-positive patients at MDACC and Johns Hopkins. More info here.

Efficacy:

This corresponds to approximately an 83% reduction in the risk of recurrence or death.

Safety. Individual adverse events, severe and serious toxicities, and rates of dose reduction or interruption were comparable to the metastatic experience. The exception was discontinuation due to adverse events, roughly double the 8–10% typically seen in metastatic trials. Dr. Barker attributed this to a lower tolerance threshold among patients who are disease-free after resection, and noted the rate is expected to decline in routine practice.

Implications for genomic testing in the RET early-stage setting. With RET joining EGFR and ALK as actionable targets in the early-stage setting, he argued the case for comprehensive biomarker testing over sequential single-gene assays has strengthened considerably.

More info here.

ARROW trial, with extended follow-up. The registrational ARROW study was an open-label, single-arm phase 1/2 trial without a comparator, enrolling 281 patients with RET fusion-positive metastatic NSCLC, split into platinum-pretreated and treatment-naive cohorts, at a recommended dose of 400 mg daily. Primary measures were overall response rate and duration of response. Parallel cohorts covered RET-mutant medullary thyroid cancer, RET fusion-positive thyroid cancer and other RET-altered solid tumors, though only lung and thyroid led to approvals. The extended follow-up, published in the Journal of Clinical Oncology in March 2026, showed durable responses with no new safety signals.

AcceleRET-Lung: randomized phase 3, first line. This trial directly compared pralsetinib with investigator’s choice of platinum/pemetrexed chemotherapy with or without pembrolizumab.
• Planned enrollment 226 patients, randomized 1:1, stratified by history of brain metastases, ECOG performance status (0–1) and intended pembrolizumab use.
• No prior systemic therapy; asymptomatic CNS metastases permitted on stable corticosteroid doses.
• Optional crossover at progression.
• Primary endpoint: investigator-assessed progression-free survival per RECIST v1.1. Secondary endpoints included overall response rate, duration of response, overall survival, clinical benefit rate, disease control rate and safety.

Results, presented in an oral session at ASCO 2026, showed greater tumor shrinkage and longer disease control with pralsetinib than chemotherapy. The toxicity profiles differed: less nausea and fatigue with pralsetinib, but more infections, including serious and fatal events, which informed the boxed warning mentioned above. More info here.

Guidelines. NCCN lists pralsetinib as a category 2A preferred first-line option for RET fusion-positive metastatic NSCLC, reflecting panel consensus (over 85%) despite the phase 2 basis of approval. Her central message to patients: there is enough data out there, across targeted therapies, that when an actionable mutation is found, the data shows the benefit of switching to a targeted therapy appropriate for your mutation — in this case a RET fusion, if you are RET fusion positive. She stressed this point because, as she put it, sometimes this can be missed.

New RET trials on the pipeline. A protocol is being finalized with Dr. Heymach and the MD Anderson team testing pralsetinib plus carboplatin and pemetrexed beyond progression on a prior selective RET inhibitor. The rationale is that continued RET inhibition suppresses persistent RET-dependent clones while chemotherapy addresses heterogeneous resistant populations. Rigel has also flagged potential interest in RET-altered pancreatic and colorectal cancers based on activity in the early solid-tumor cohorts. Patient access, coverage and financial assistance resources are at rigelonecare.com.

Data released this year for the APS RET inhibitor showed deep responses in treatment-naive patients and meaningful shrinkage or stabilization in patients previously treated with selpercatinib or pralsetinib, supporting sequential RET inhibition in selected cases.

EP0031 monotherapy data (from China). Turning to the Ellipses drug, Dr. Drilon presented results from China in which EP0031 has been tested in two groups of patients: those starting treatment for advanced disease and those who had already had chemotherapy.
• Treatment-naive patients: the majority achieved substantial tumor shrinkage, and median progression-free survival has not yet been reached.
• Patients previously treated with chemotherapy: median progression-free survival of nearly 28 months.
• Safety: liver function and blood counts are monitored, and roughly 1 in 4 patients developed inflammation of a layer of the eye, warranting close ophthalmologic follow-up. Overall tolerability was reasonable. More info here.

The rationale for combinations. Secondary RET mutations explain resistance in fewer than 1 in 10 cases across pooled datasets, implying that most RET-positive cancers acquire dependence on pathways beyond RET. In EGFR-mutant NSCLC, FLAURA2 showed osimertinib plus chemotherapy outperforms osimertinib alone, and preclinical data show EP0031 plus chemotherapy outperforms either single agent. Ellipses is testing the combination: the cohort for patients previously treated with selpercatinib has completed accrual, and the cohort for patients with no prior therapy for advanced disease remains open. The open question Dr. Drilon posed is whether, as in EGFR, combinations will ultimately move into the first-line setting.