A New Treatment Cuts the Risk of Early-Stage Lung Cancer Coming Back by 83% — But Only If Doctors Test for the Right Gene

The trial is called LIBRETTO-432. The drug is selpercatinib (brand name Retevmo). And the results, published simultaneously in the New England Journal of Medicine, showed that patients with early-stage lung cancer who carry a specific gene rearrangement, called a RET fusion, were dramatically less likely to see their cancer come back after surgery when they took selpercatinib as an adjuvant treatment. That means after surgery, not during it. As a pill, taken at home, for up to three years.

At two years, 92% of patients taking selpercatinib were still free from any sign of their cancer returning. In the group that received a placebo instead, that number was 61%.

“In my opinion, this should be the standard of care for these patients,” Dr. Vamsidhar Velcheti, Chief of Hematology and Oncology at Mayo Clinic Florida, told SurvivorNet at ASCO. “It’s incredibly important that we pay attention to the data here.”

The Problem This Drug Is Solving

Here’s the thing about early-stage lung cancer that most patients don’t fully understand when they’re first diagnosed: surgery is the goal, but surgery alone is often not enough.

Up to two-thirds of patients with early-stage non-small cell lung cancer will eventually see their cancer come back, even after a successful operation. It spreads quietly, through cells too small to see on any scan, before they’re ever cut out. By the time surgeons are operating, microscopic disease may already be elsewhere in the body.

That’s why the field has been moving aggressively toward adjuvant therapy (drugs given after surgery), aimed at killing off whatever microscopic disease the surgeon couldn’t see or reach.

The approach is working. Osimertinib after surgery transformed outcomes for patients with another specific mutation (EGFR mutations). Alectinib did the same for ALK rearrangements. RET fusions, affecting roughly 1 to 2% of lung cancer patients, had been the gap. Until now.

“These patients with a RET oncogenic rearrangement with early stage lung cancer have a very high risk for relapse,” Dr. Velcheti explained. “And immunotherapy doesn’t work very well for them. So these patients really need an adjuvant targeted therapy to improve outcomes.”

What the Trial Found

LIBRETTO-432 enrolled 151 patients with stage IB, II, or IIIA RET fusion–positive non-small cell lung cancer across 65 sites in 22 countries. All of them had already undergone surgery or radiation with curative intent. Half received selpercatinib for up to three years. Half received a placebo.

The results were striking. Among patients with stage II or IIIA disease (the higher-risk group) those on selpercatinib had an 83% lower risk of their cancer returning or progressing compared to placebo. At two years, 92% of patients on selpercatinib remained cancer-free, compared to 61% on placebo.

Just as important: all three deaths that occurred during the study happened in the placebo group. No deaths were reported with selpercatinib during the study period; however, follow-up was limited and the cohort included early-stage disease, limiting interpretation of survival outcomes.

Overall survival data (the ultimate measure of whether a drug helps people live longer) are not yet mature, meaning the trial hasn’t been running long enough to draw conclusions. But Dr. Velcheti was direct about what the early numbers imply: “Given the magnitude of the benefit that we are seeing, there is a very high possibility that we will eventually see overall survival benefit pan out for this population.”

The Critical Catch: You Have to Be Tested

None of this matters if a patient doesn’t know they have a RET fusion.

RET fusions are found in roughly 1 to 2% of all lung cancer patients. That’s a small percentage, but lung cancer is one of the most common cancers in the world, which means thousands of people each year have this specific genetic change driving their disease. And right now, not all of them are being tested for it.

“Not everyone gets molecular sequencing,” Dr. Velcheti told SurvivorNet plainly. “Now with three targeted therapy options for patients with early stage lung cancer, it is incredibly important for patients to have comprehensive genomic profiling so that we can offer them the best adjuvant targeted therapy option.”

Comprehensive genomic profiling, sometimes called molecular testing or next-generation sequencing, looks at tumor tissue and can identify dozens of genetic changes at once, RET fusions included. National guidelines already recommend it for all lung cancer patients. It’s not a new test. It’s not experimental. But Dr. Velcheti was blunt with SurvivorNet: it still isn’t being done routinely, particularly outside of major cancer centers.

That gap needs to close. If you or someone you love has been diagnosed with early-stage non-small cell lung cancer and molecular testing hasn’t been discussed, bring it up — directly, by name. Ask: “Has my tumor been sent for comprehensive genomic profiling?” The answer to that question determines whether a drug with this kind of effect size is even an option.

About the Drug and Its Side Effects

Selpercatinib already has FDA approval for advanced or metastatic RET fusion–positive lung cancer, the later-stage setting where it proved itself first. What LIBRETTO-432 changes is the conversation happening much earlier, right after surgery, when a patient’s scans look clear but the statistical odds of recurrence are still significant.

It’s taken as a pill, twice daily, for up to three years.

Side effects are real and worth discussing with your doctor. The most common serious side effects in the trial were elevated liver enzymes, a lab finding that can indicate the liver is under stress. About 17 to 19% of patients on selpercatinib developed grade 3 (significant) elevations in liver markers.  Grade 3 or higher treatment-emergent adverse events occurred in 66.7% of patients.  This sounds alarming, but in almost all cases, these were managed by adjusting the dose, and the abnormalities resolved once the drug was paused or reduced.

Other common side effects included diarrhea, dry mouth, hypertension, and constipation. About 17% of patients on selpercatinib eventually stopped treatment because of side effects, which is a real number. Most of those discontinuations were due to low-grade side effects, and the vast majority of those issues resolved after stopping the drug.

“You don’t have overall survival benefit yet, but given the magnitude of benefit,” Dr. Velcheti said, “this is something that should be the standard of care.”

What This Means for You

That’s the whole reason SurvivorNet goes to ASCO, to find the results patients need to know about before their oncologist brings them up. The LIBRETTO-432 data qualify.

If you’ve been diagnosed with early-stage non-small cell lung cancer:

Ask your doctor whether you’ve had comprehensive molecular testing. Not just a standard biopsy report. Comprehensive genomic profiling that checks for RET fusions, EGFR mutations, ALK rearrangements, and other actionable alterations.

If you haven’t been tested, push for it. You have the right to ask. You have the right to know.

If you do have a RET fusion, ask specifically about selpercatinib as an adjuvant treatment. Tell your doctor you’ve read about LIBRETTO-432. Ask whether you qualify, what the side effect management looks like, and what a three-year course of treatment would mean for your life.

Dr. Velcheti said it about as plainly as any doctor can: “If you have this genetic alteration with an early stage cancer, this is the drug that you should be getting after finishing either surgery or chemotherapy and radiation. It’s a wonderful thing for patients.”

Be pushy. Be your own best advocate. And get tested.

Questions to Ask Your Doctor

• Has my tumor been sent for comprehensive molecular testing or next-generation sequencing?
• Does my lung cancer carry a RET fusion, EGFR mutation, ALK rearrangement, or any other actionable alteration?
• If I have a RET fusion, am I a candidate for adjuvant selpercatinib after surgery?
• What is the expected duration of treatment, and what side effects should I watch for?
• Is this drug available to me, and is it covered by my insurance?

Learn more about SurvivorNet's rigorous medical review process.

---