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Selpercatinib in Early-Stage RET Fusion-Positive Non-Small-Cell Lung Cancer
Yi-Long Wu1, Maximilian Hochmair2, Yi Yang3
1Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
Background:
Selpercatinib, a highly selective, potent, and central nervous system-penetrant RET inhibitor, is approved for RET fusion-positive advanced or metastatic non-small-cell lung cancer (NSCLC). The efficacy and safety of selpercatinib in early-stage NSCLC are unknown.
Methods:
We conducted a phase 3, double-blind trial involving patients with RET fusion-positive NSCLC who had received definitive therapy with curative intent (surgery or radiotherapy with adjuvant systemic anticancer therapy, if applicable). Patients were randomly assigned to receive adjuvant selpercatinib or placebo for up to 3 years. The primary end point was investigator-assessed event-free survival in patients with stage II or IIIA disease. Secondary end points were investigator-assessed event-free survival in patients with stage IB, II, or IIIA disease; event-free survival as assessed by blinded independent central review; overall survival; and safety.
Results:
A total of 151 patients were assigned to receive selpercatinib (75 patients) or placebo (76 patients). Median follow-up was 24 months and 27 months in the respective groups. Among 109 patients with stage II or IIIA disease, 2-year investigator-assessed event-free survival was 92% with selpercatinib and 61% with placebo (hazard ratio for disease recurrence, progression, or death, 0.17; 95% confidence interval [CI], 0.06 to 0.51; P<0.001). Event-free survival as assessed by blinded independent central review was consistent with investigator-assessed event-free survival. Among the 151 patients with stage IB, II, or IIIA NSCLC, investigator-assessed event-free survival at 2 years was 94% with selpercatinib and 70% with placebo (hazard ratio for disease recurrence, progression, or death, 0.16; 95% CI, 0.06 to 0.48; P<0.001). The most common adverse events during the treatment period were increased levels of alanine aminotransferase and aspartate aminotransferase (grade ≥3 in 17% and 19% of patients, respectively, in the selpercatinib group). Three deaths occurred, all in the placebo group, owing to disease progression.
Conclusions:
Among patients with stage II or IIIA RET fusion-positive NSCLC, event-free survival was significantly longer with adjuvant selpercatinib than with placebo. (Funded by Lilly; LIBRETTO-432 ClinicalTrials.gov number, NCT04819100.).
Insights
Adjuvant selpercatinib significantly improved event-free survival in patients with RET fusion-positive non-small-cell lung cancer (NSCLC). This targeted therapy offers a promising new option for early-stage NSCLC patients following definitive treatment.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Selpercatinib is an approved RET inhibitor for advanced RET fusion-positive non-small-cell lung cancer (NSCLC).
- The efficacy and safety of selpercatinib in early-stage NSCLC remained unknown prior to this study.
Purpose of the Study:
- To evaluate the efficacy and safety of adjuvant selpercatinib in patients with RET fusion-positive NSCLC after definitive therapy.
- To assess event-free survival (EFS) as the primary endpoint in patients with stage II or IIIA disease.
Main Methods:
- A phase 3, double-blind, randomized trial (LIBRETTO-432) was conducted.
- Patients with RET fusion-positive NSCLC received adjuvant selpercatinib or placebo for up to 3 years.
- Key endpoints included investigator-assessed EFS, blinded independent central review EFS, overall survival, and safety.
Main Results:
- In patients with stage II or IIIA disease, 2-year EFS was 92% with selpercatinib vs. 61% with placebo (HR 0.17, P<0.001).
- For patients with stage IB-IIIA disease, 2-year EFS was 94% with selpercatinib vs. 70% with placebo (HR 0.17, P<0.001).
- Common adverse events included elevated liver enzymes; three deaths occurred in the placebo group due to disease progression.
Conclusions:
- Adjuvant selpercatinib demonstrated a significant improvement in event-free survival for patients with stage II or IIIA RET fusion-positive NSCLC.
- Selpercatinib represents a potential new standard of care for adjuvant therapy in this patient population.
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