RET fusion–positive NSCLC: evolving adjuvant and metastatic targeted therapies

Authored by Open Medicine, published on 2026-05-27 01:26:53.0

The metastatic portion is broadly aligned with current standards: comprehensive RET fusion testing at diagnosis and first-line selective RET inhibition (selpercatinib or pralsetinib) is guideline-concordant and supported by phase 3 and robust phase 1/2 evidence. The post-progression approach (re-biopsy/ctDNA, CNS assessment, local therapy for oligoprogression, and platinum/pemetrexed chemotherapy) reflects common contemporary practice but is supported more by consensus and extrapolation than RET-specific randomized data. The adjuvant selpercatinib component is plausible but remains evolving and should be treated as investigational/pending until full phase 3 data and regulatory/guideline integration are available.

  1. Test for RET Fusion at diagnosis (Broad DNA/RNA NGS preferred)
    Guidelines for NSCLC biomarker testing recommend broad molecular profiling at diagnosis of advanced non-squamous NSCLC and endorse RNA-based NGS or combined DNA/RNA approaches to optimize fusion detection (including RET). These sources directly support the testing strategy and timing.
    • Resected / definitive stage IB-IIIA disease
      • Complete definitive local therapy (surgery ± adjuvant platinum chemotherapy as indicated)
        Surgery ± adjuvant platinum chemotherapy Definitive radiation/chemoradiation ± consolidation therapy, where appropriate
        • Adjuvant selpercatinib (up to 3 years)
          Selpercatinib for up to 3 years New adjuvant option based on LIBRETTO-432 (Phase 3): significant and clinically meaningful EFS benefit vs placebo. PENDING FULL ASCO 2026 DATA / REGULATORY-LABEL INTEGRATION
          • Surveillance / follow-up
            Per guideline-recommended schedule
    • Advanced / metastatic disease
      (UNRESECTABLE LOCALLY ADVANCED OR METASTATIC)
      • Selective RET inhibitor (selpercatinib or pralsetinib)
        RET inhibitors are preferred first line for RET fusion–positive metastatic NSCLC Selpercatinib has phase 3 evidence (LIBRETTO-431) showing superior PFS vs platinum chemotherapy ± pembrolizumab Pralsetinib has phase 3 evidence (AcceleRET) showing improved PFS vs platinum-based chemotherapy ± pembrolizumab NCCN 2026: selpercatinib or pralsetinib preferred.
        • At progression on RET inhibitor (re-biopsy, resistance mechanisms, assess CNS involvement)
          Re-biopsy / plasma NGS if feasible Treat based on resistance pattern, clinical tempo, and site of progression Consider local CNS therapy for isolated CNS progression
          • Oligoprogression (local therapy ± continue RET inhibitor)
            Local therapy (surgery or RT) + continue RET inhibitor
            • Clinical trial participation (preferred when available)
              Clinical trial preferred when available
          • Systemic progression → systemic therapy and/or clinical trial
            Platinum / pemetrexed-based chemotherapy (± immunotherapy as appropriate)
            • Clinical trial participation (preferred when available)
              Clinical trial preferred when available
  2. IMPORTANT
    Phase 3 studies (LIBRETTO-432, LIBRETTO-431 and AcceleRET) support selective RET inhibition across early-stage and advanced RET+ NSCLC. Selective RET inhibitors demonstrate meaningful intracranial activity. Clinical adoption should follow full data presentation at ASCO 2026, regulatory guidance and local practice standards.
tosprivacyAcceleRET Lung: A phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLCLIBRETTO-432, a phase III study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive non-small-cell lung cancer