ASCO 2026 had no shortage of data. But LIBRETTO-432 was the lung cancer result that people were still talking about in the hallways after the session ended.
SurvivorNet was in Chicago when the data were presented and spoke with Dr. Vamsidhar Velcheti, Chief of Hematology and Oncology at Mayo Clinic Florida, who put it plainly: “This selpercatinib adjuvant data is really practice changing. It’s a really incredible benefit that we see with event-free survival.”
Among patients with stage II or IIIA RET fusion–positive non-small cell lung cancer, adjuvant selpercatinib produced an 83% reduction in the risk of disease recurrence, progression, or death compared to placebo — hazard ratio 0.17 (95% CI, 0.06–0.51; p<0.001). Two-year event-free survival was 92% with selpercatinib versus 61% with placebo. Every death during the study period occurred in the placebo group.
The results were published simultaneously in the New England Journal of Medicine.
About LIBRETTO-432
LIBRETTO-432 was a phase 3, multinational, double-blind, placebo-controlled trial. To get in, patients needed histologically confirmed stage IB, II, or IIIA RET fusion–positive NSCLC, and they had to have already completed definitive locoregional therapy with curative intent (meaning surgery in nearly every case), with adjuvant systemic chemotherapy in approximately 75–93% of patients depending on the analysis population.
RET status was confirmed by local molecular testing, comprehensive genomic profiling, or other sponsor-approved assays.
Patients were randomized 1:1 to selpercatinib or placebo for up to three years and a total of 151 patients were enrolled across 65 sites in 22 countries.
The Efficacy Data
- Primary endpoint — stage II/IIIA population:
- Two-year investigator-assessed event-free survival: 92% with selpercatinib vs. 61% with placebo (HR 0.17; 95% CI, 0.06–0.51; p<0.001).
- Disease recurrence occurred in 4 patients (7%) on selpercatinib versus 19 (35%) on placebo. The majority of recurrence events in the placebo group were in patients with stage IIIA disease.
- Overall population (stage IB, II, IIIA): Two-year event-free survival: 94% vs. 70% (HR 0.16; 95% CI, 0.06–0.48; p<0.001).
- Overall survival: Not yet mature. Three deaths occurred during the study period, all in the placebo group.
Dr. Velcheti was direct about what the hazard ratio implies for where OS data will eventually land:
“Given the magnitude of the benefit that we are seeing with the hazard ratio 0.17 for patients receiving selpercatinib for EFS, I think there is a very high possibility that we will eventually see overall survival benefit pan out for this population.”
For context: the ADAURA trial (osimertinib in EGFR-mutant NSCLC) produced the same hazard ratio of 0.17 for disease-free survival and ultimately demonstrated OS benefit. The ALINA trial (alectinib in ALK-positive NSCLC) showed an HR of 0.24. LIBRETTO-432 sits at HR 0.17. The effect size is consistent with what has converted to OS benefit in the EGFR space.
Safety
Grade 3 or higher adverse events occurred in 67% of patients on selpercatinib versus 24% on placebo. The dominant driver was hepatotoxicity: grade ≥3 ALT elevation in 17%, grade ≥3 AST elevation in 19%. Both were manageable with dose modification and the majority of cases resolved.
Permanent discontinuation due to adverse events: 17% in the selpercatinib group versus 1% in the placebo group. Notably, most discontinuations were attributed to grade 1 or 2 events, not grade 3 or 4. The authors note this is consistent with discontinuation rates seen with adjuvant osimertinib, and that tolerability thresholds may be lower in the curative-intent setting than in metastatic disease — an important point when counseling patients who feel well and are being asked to commit to three years of treatment.
Other relevant adverse events: hypertension any grade 31% (grade ≥3: 11%), diarrhea 39% (grade ≥3: 4%), interstitial lung disease in 2 patients (both grade 1, both resolved). No treatment-related deaths occurred.
The median relative dose intensity was 81% with selpercatinib versus 99% with placebo, a meaningful gap that reflects the real management burden in clinical practice.
Where This Sits in the Broader Adjuvant TKI Landscape
Dr. Velcheti was specific about the clinical context: “There’s a lot of data gap for patients with rare oncogenic fusions like RET. We’ve had recent trial readouts from ADAURA, and we also had recent data from the ALINA trial looking at ALK TKIs and EGFR TKIs showing significant improvement in outcomes. But we don’t have the same kind of data for RET — until this trial.”
LIBRETTO-432 now closes that gap. Osimertinib established the adjuvant TKI approach in EGFR-mutant disease. Alectinib did it for ALK. Selpercatinib now does it for RET and the underlying message across all three is the same: immunotherapy doesn’t move the needle in driver-positive early-stage NSCLC. Targeted therapy does.
“Patients with actionable genomic alterations, specifically EGFR, ALK, RET, these patients don’t have a benefit from adjuvant immunotherapy,” Dr. Velcheti said. “So these patients really need an adjuvant tyrosine kinase inhibitor to improve outcomes.”
For community oncologists managing these patients, the clinical decision itself is actually straightforward once the molecular result exists. Stage II–IIIA, RET fusion–positive, post-resection: adjuvant selpercatinib.
The harder problem, the operational one, is whether the molecular result is there at all.
The Testing Problem Is the Real Clinical Problem
RET fusions occur in approximately 1 to 2% of NSCLC, rare enough, that it’s easy to deprioritize testing, common enough that real patients are being missed every day. Comprehensive genomic profiling catches these patients. Hotspot panels often don’t. And in a community practice seeing ten early-stage resected NSCLC patients a year, skipping NGS on even one of them risks missing the patient who would have had a therapy with an HR of 0.17.
NCCN guidelines already recommend comprehensive molecular profiling at all stages of NSCLC. LIBRETTO-432 doesn’t change the recommendation, it makes ignoring it harder to justify.
Dr. Velcheti made this the centerpiece of his comments at ASCO: “If we don’t sequence our patients appropriately, we cannot tailor the adjuvant therapies for our patients appropriately. Now we have three standard of care adjuvant targeted therapy approaches for our patients. And if we don’t do comprehensive genomic profiling for our patients with early stage lung cancer, we fail to offer them the best treatment options to achieve a cure.”
For community oncologists who may not routinely send comprehensive NGS panels on early-stage resected patients, especially those who have already received standard adjuvant chemotherapy and appear disease-free, LIBRETTO-432 changes the calculus. The reflex to defer NGS to the metastatic setting is no longer defensible for EGFR, ALK, or RET. The adjuvant data are here.
