Metastatic NSCLC: Targetable Driver, First-Line: overview
This algorithm maps first-line treatment of metastatic non-small cell lung cancer when broad next-generation sequencing identifies a targetable driver, with each driver forming its own branch. For EGFR exon 19 deletion or L858R, osimertinib is preferred (FLAURA), with chemotherapy plus osimertinib (FLAURA2) or amivantamab plus lazertinib (MARIPOSA) as alternatives. EGFR exon 20 insertions receive amivantamab plus chemotherapy (PAPILLON), and atypical EGFR mutations afatinib or osimertinib. ALK rearrangements are treated with lorlatinib (CROWN), or alectinib (ALEX).
ROS1 fusions are treated with entrectinib or repotrectinib (TRIDENT-1), BRAF V600E with dabrafenib plus trametinib or encorafenib plus binimetinib, MET exon 14 skipping with capmatinib or tepotinib (GEOMETRY), RET fusions with selpercatinib or pralsetinib (LIBRETTO-001), and NTRK fusions with the tumor-agnostic agents larotrectinib or entrectinib (NAVIGATE / STARTRK). Two drivers are addressed with agents used after initial therapy: sotorasib or adagrasib for KRAS G12C (CodeBreaK 200, in previously treated disease) and trastuzumab deruxtecan for HER2 (ERBB2) mutations (DESTINY-Lung02, also in previously treated disease). Agents with notable CNS activity are flagged on the chart.
Trials behind this algorithm
- FLAURA trial Soria J-C et al, NEJM, 2018, PMID: 29151359
- FLAURA2 Jänne PA et al, NEJM, 2025; PMID: 41104938
- MARIPOSA-2 Trial Passaro A et al., Ann Oncol, 2024, PMID: 37879444
- PAPILLON trial Zhou C et al, N Engl J Med, 2023, PMID: 37870976
- CROWN trial Solomon BJ et al., JCO 2024, PMID: 38819031
- Alex trial, alect vs crizo Peters S et al, NEJM, 2017, PMID: 28586279
- TRIDENT-1 Drilon A et al, NEJM, 2024; PMID: 38197815
- GEOMETRY mono-1 Wolf J et al, NEJM, 2020; PMID: 32877583
- LIBRETTO-001 Drilon A et al, NEJM, 2020; PMID: 32846060
- CODEBREAK 200 Johannes de Langen et al, Lancet, 2023, PMID: 36764316
- DESTINY-Lung02 Goto K et al, JCO, 2023; PMID: 37694347
Background reading: NSCLC (Part 2): Stage IV, Targeted and Systemic Therapy board review notes.
Metastatic NSCLC: Targetable Driver, First-Line: the algorithm in words
Starting point: Metastatic NSCLC targetable driver on broad NGS. Full background: NSCLC (Part 2): Stage IV, Targeted and Systemic Therapy notes.
- EGFR ex19 / L858R (first-line): Preferred: Osimertinib (FLAURA); Intensified: Chemo + osimertinib (FLAURA2); Chemo-free: Amivantamab + lazertinib (MARIPOSA).
- EGFR exon 20 ins (first-line): Targeted: Amivantamab + chemo (PAPILLON).
- EGFR atypical (first-line): TKI: Afatinib or osimertinib (context-dependent).
- ALK (first-line): Preferred: Lorlatinib (CROWN); Alternative: Alectinib (ALEX).
- ROS1 (first-line): TKI: Entrectinib / repotrectinib (TRIDENT-1).
- BRAF V600E (first-line): Targeted: Dabrafenib + trametinib (or encorafenib + binimetinib).
- MET exon 14 (first-line): TKI: Capmatinib / tepotinib (GEOMETRY).
- RET fusion (first-line): TKI: Selpercatinib / pralsetinib (LIBRETTO-001).
- NTRK fusion (first-line): Tumor-agnostic: Larotrectinib / entrectinib (NAVIGATE / STARTRK).
- KRAS G12C (second-line): Later-line: Sotorasib / adagrasib (CodeBreaK 200).
- HER2 (ERBB2) (second-line): Later-line: Trastuzumab deruxtecan (DESTINY-Lung02).