RET gene fusions occur in approximately 1–2% of NSCLC (predominantly adenocarcinoma) and function as potent, mutually exclusive oncogenic drivers, associated with younger age, never/light smokers, low tumor mutational burden, and a high propensity for brain metastases.
The two highly selective RET inhibitors selpercatinib and pralsetinib are the preferred targeted therapies, and RET fusion-positive tumors respond poorly to immune checkpoint inhibitors given their low TMB.
First-line:selpercatinib or pralsetinib. If the fusion is discovered during first-line systemic therapy, interrupt current therapy and start a RET inhibitor
Subsequent therapy (after progression on a RET inhibitor): standard systemic therapy per the NSCLC systemic therapy principles, or cabozantinib.
Selpercatinib (LIBRETTO-431, phase 3, first-line): significantly longer median PFS vs platinum-based chemotherapy ± pembrolizumab (24.8 vs 11.2 months and ORR 84% vs 65%, with notable intracranial activity.
This established selpercatinib as standard of care.
Selpercatinib (LIBRETTO-001, final data): ORR 83% treatment-naïve and 62% pretreated; median PFS 22.0 and 26.2 months, respectively; CNS-ORR 85%.
Pralsetinib (ARROW, final data): ORR 78% treatment-naïve and 63% pretreated; median OS 44.3 months overall.
ASCO guidelines recommend selpercatinib first-line (strong), and either selpercatinib or pralsetinib for patients who have not received a RET inhibitor in the second-line setting.
Early-stage/adjuvant disease
NCCN now lists adjuvant selpercatinib for resected stage IB–IIIA RET fusion-positive NSCLC.
This follows LIBRETTO-432, in which adjuvant selpercatinib significantly improved 2-year event-free survival vs placebo in stage II–IIIA disease (92% vs 61%).
NCCN recommends RET testing as part of multigene panel testing for advanced non-squamous NSCLC.
RNA-based NGS is preferred over DNA-based NGS for fusion detection; FISH break-apart probes and targeted RT-PCR may under-detect fusions with novel partners.
Common fusion partners are KIF5B, CCDC6, and NCOA4, and responsiveness to RET TKIs is independent of the fusion partner.
Emerging evidence presented at the 2026 ASCO Annual Meeting suggests first-line pralsetinib significantly improved median PFS versus platinum-based standard of care (18.7 vs 9.0 months0mand ORR (65.5% vs 41.6%), though a higher rate of infections—including pneumonia and opportunistic infections—was observed with pralsetinib.
Among patients with stage II or IIIA RET fusion positive NSCLC, event free, survival was significantly longer with adjuvant selpercatinib than with placebo.