Selpercatinib (RETEVMO/RETSEVMO) is a kinase inhibitor used to treat adult patients with metastatic RET fusion-positive NSCLC. Abnormally activated RET can act as an oncogene in NSCLC; RET fusions retaining the kinase domain are drivers of NSCLC. It is the first FDA-approved treatment for people with RET-positive advanced NSCLC. It is given orally to the patients. In China, selpercatinib is approved for adults with LA or metastatic RET fusion-positive NSCLC without restriction on prior therapy, enabling use in both 1L and 2L+ settings.

In the past, RET fusion–positive NSCLC was treated similarly to oncogene-negative disease using chemotherapy and immunotherapy, but the development of selective RET TKIs has shifted management toward a biomarker-driven approach. Despite surgery and adjuvant therapy, many early-stage NSCLC patients still relapse, highlighting a key unmet need, especially in the small (1–2%) RET fusion subgroup with no prior adjuvant targeted option. In this setting, selpercatinib (Retevmo) in the Phase III LIBRETTO-432 trial demonstrated a meaningful reduction in recurrence, progression, or death, reinforcing the importance of RET as an actionable biomarker across disease stages and marking a shift toward targeted therapy in the curative setting. The detailed results are described below:

Key Efficacy Highlights

• Adjuvant selpercatinib significantly improved investigator-assessed event-free survival (EFS) vs. placebo.

• 83% reduction in the risk of disease recurrence or death (HR=0.172; 95% CI: 0.058–0.509; p = 0.0003).

• Median EFS: Not reached with selpercatinib vs. 31.8 months with placebo.

• 24-month EFS rate: 91.5% with selpercatinib vs. 61.1% with placebo.

• Benefit was described as highly statistically significant and clinically meaningful.

• Overall survival data remain immature, although early trends favored selpercatinib.

• Results establish RET fusions alongside EGFR and ALK alterations as actionable biomarkers in early-stage NSCLC.

Key Safety Highlights

• Safety profile was consistent with previous selpercatinib studies, with no new safety signals observed.

• Adverse events were generally consistent with the known safety profile of selpercatinib.

• Known risks remained consistent with the established profile, including QT prolongation, ILD/pneumonitis, hemorrhage, and hypersensitivity reactions.

• Adverse events were reported as manageable with dose modifications and monitoring.

KOL insights

“No adjuvant targeted therapy has been approved for the subset of patients whose tumors harbor RET fusions, leaving an important gap in care for this molecularly defined population. These results have the potential to [establish] adjuvant selpercatinib as a new standard of care for patients with RET fusion–positive NSCLC.” –Expert Opinion

“Selpercatinib has previously been shown to offer superior progression-free survival versus chemotherapy plus pembrolizumab in patients with advanced or metastatic RET fusion–positive NSCLC. Other adjuvant targeted therapies have been established as standards of care for NSCLC harboring different driver mutations, including EGFR and ALK.”–Expert Opinion

Conclusion: 

The market for RET fusion-NSCLC, representing 1–2% of NSCLC cases, has seen significant advancements with the approvals of RETEVMO (selpercatinib) and GAVRETO (pralsetinib) in 2020. 

Six years after its launch as the first targeted therapy for cancers driven by RET alterations, Eli Lilly’s selpercatinib (RETEVMO) continues to build on its clinical impact, with new LIBRETTO-432 Phase III data showing “dramatic” outcomes in early-stage RET fusion–positive NSCLC and reinforcing the importance of routine RET biomarker testing across disease stages. While selpercatinib has already established a broad footprint in RET-altered cancers, including advanced NSCLC and thyroid malignancies, the early-stage patient population had not previously seen major benefit from targeted therapy until this study, which shows a meaningful reduction in recurrence and supports its potential role in curative-intent treatment. In the same therapeutic space, Blueprint Medicines’ pralsetinib (GAVRETO) is also an approved RET inhibitor, and together these two agents represent the current competitive landscape in RET-driven oncology, with selpercatinib generally viewed as the more widely adopted standard in clinical practice due to its broader uptake and stronger overall dataset. These results are expected to form the basis for an upcoming global regulatory label expansion by Lilly, further reinforcing selpercatinib’s position as a cornerstone therapy in RET-driven oncology and highlighting the continued evolution of precision medicine in lung cancer.