Education

IASLC Podcast: RET-Positive Lung Cancer with Dr. Aldea

By October 19, 2026November 3rd, 2026No Comments

Dr. Aldea explains what people with RET-positive lung cancer should know about treatment, testing, and the questions to ask their care team.

If you or someone you love has RET-positive lung cancer, here is what to know

A RET-positive lung cancer is driven by a change in a gene called RET. Treatment for this type has changed a lot in recent years, and there are specific things worth knowing and asking your care team about. In this conversation with the IASLC, Dr. Aldea shares what matters most.

The short version:

Each section below explains the science and gives you questions to bring to your next appointment. You don’t need to read it all at once. Start with whichever topic fits where you are right now.

1

For advanced RET-positive NSCLC, targeted therapy should generally come first

The fact: Selective RET inhibitors have changed the treatment paradigm for RET-positive lung cancer. In the phase 3 LIBRETTO-431 trial, first-line selpercatinib produced a median progression-free survival of 24.8 months with selpercatinib versus 11.2 months with platinum-based chemotherapy with or without pembrolizumab.

Make sure that you are receiving a selective RET inhibitor as the first treatment option and ask your doctor, “now that my tumor has tested positive for a RET fusion…”

  • Which RET fusion do I have?
  • What exactly is my cancer stage?
  • Could I benefit from a second opinion?
  • Which selective RET inhibitor do you recommend for me, and why?
  • What are the expected side effects, and how can they be managed?
  • How will we monitor whether I am responding to treatment?
  • Would you recommend local therapy, such as stereotactic body radiation therapy (SBRT) while continuing on the specific RET inhibitor?
  • What happens if the treatment stops working?

2

Immunotherapy may not be the best starting point — and treatment order can matter

The fact: RET-positive lung cancers generally derive less benefit from immunotherapy than cancers without an actionable driver, while RET-targeted therapy has demonstrated substantially greater efficacy. Selective RET inhibitors remain the preferred first-line treatment for patients with RET fusion-positive NSCLC, based on the overall results of LIBRETTO-431 where patients receiving chemotherapy, adding pembrolizumab did not significantly improve progression-free survival or overall survival compared with chemotherapy alone. Evidence also suggests that patients who receive immune checkpoint inhibitors before selpercatinib are more likely to experience hypersensitivity reactions once they start selpercatinib. In LIBRETTO-001, most patients who developed these reactions had previously received immunotherapy.

Make sure that you are receiving a selective RET inhibitor as first treatment option and ask your doctor:

  • Because my cancer has a RET fusion, how does that affect whether immunotherapy should be part of my treatment later on if I progress on a RET inhibitor?

3

Your tumor can change under treatment — so a new biopsy at progression may reveal what to do next

The fact: RET inhibitors can control cancer for a long time, but tumors can eventually develop resistance. That resistance is not the same in every patient. Some tumors acquire changes in RET itself; others develop entirely different “bypass” pathways that allow the cancer to grow despite RET inhibition. Understanding why a therapy stopped working can therefore influence the next treatment choice or identify a clinical trial. Experts specifically recommend repeat tissue biopsy with molecular profiling at progression whenever feasible.

Ask your doctor:

  • If my cancer progresses, can we biopsy it again and do comprehensive genomic profiling before deciding on my next treatment so we can understand how it has changed and what is driving the resistance?
  • Can we make sure we test for MET amplification?
  • If a tissue biopsy isn’t possible, could a liquid biopsy (blood-based ctDNA test) provide useful information?
  • If we identify the mechanism of resistance, are there clinical trials or targeted treatments specifically designed to address it?

4

Molecular testing shouldn’t necessarily be a one-time event — and comprehensive testing can include both DNA and RNA

The fact: The genomic profile found at diagnosis isn’t necessarily the end of the story. Repeat next-generation sequencing at progression can uncover new resistance mechanisms and potential treatment options. For lung cancers driven by gene fusions such as RET, RNA-based next generation sequencing (NGS) is particularly valuable because it is better suited to detecting and characterizing fusion events, while DNA sequencing can identify mutations, amplifications and other genomic alterations. Current ASCO guidance says comprehensive NGS should ideally incorporate RNA-based testing, and tissue has the additional advantage of allowing the tumor’s histology to be reassessed.

Ask your doctor:

  • When we repeat molecular testing, will the testing be comprehensive enough to look for both RET-related and other resistance mechanisms?
  • Does the panel include both DNA- and RNA-based NGS, or is there a reason one isn’t needed in my case?
  • Can we make sure we test for MET amplification?

5

RET-positive lung cancer has a meaningful risk of brain metastases — but RET-targeted therapies can work very well in the brain

The fact: Brain metastases occur in a meaningful proportion of people with RET-positive NSCLC. Importantly, selective RET inhibitors such as selpercatinib have substantial activity in the central nervous system. In LIBRETTO-431, among patients with measurable brain metastases at baseline, 82% had an intracranial response to selpercatinib, and the drug substantially reduced the risk of CNS progression compared with chemotherapy with or without pembrolizumab.

Ask your doctor:

  • If my cancer has spread to my brain, could my RET-targeted therapy treat those tumors effectively?
  • Do I need local treatment such as radiation as well, or is it reasonable in my situation to start targeted therapy and closely monitor the response?

6

RET-positive lung cancer can involve the lining around the lungs or heart, causing fluid to accumulate

The fact: RET-positive NSCLC commonly spreads within the chest, including to the pleura—the tissue surrounding the lungs. Some patients develop pleural effusions, an abnormal buildup of fluid around the lungs, or pericardial effusions, fluid around the heart. Large effusions can cause symptoms and sometimes require drainage. In the podcast, Dr. Aldea specifically calls pleural and pericardial effusions an important clinical feature she sees in RET-positive disease.

Ask your doctor:

  • Does my imaging show any fluid around my lungs or heart?
  • What symptoms could indicate that an effusion is developing or getting worse, and when should I contact you?

7

RET-positive lung cancer may carry a higher risk of blood clots and stroke

The fact: A 2023 JAMA Oncology study led by Dr. Aldea examined 66 patients with advanced RET fusion-positive NSCLC. Nearly half experienced at least one thromboembolic event: 24% developed deep-vein thrombosis, 29% pulmonary embolism, and 15% ischemic stroke. Importantly, this was a relatively small, retrospective, single-center cohort, and most events occurred before or without effective RET-targeted therapy—so these percentages should not be interpreted as the expected risk for every patient receiving treatment today.

Ask your doctor:

  • Does having RET-positive lung cancer affect my risk for blood clots or stroke? Are there symptoms I should watch for, and does my personal history suggest that I need any additional monitoring?
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