Metastatic NSCLC — EGFR-mutant

Sequencing for EGFR-mutant metastatic non-small cell lung cancer, branching on mutation subtype (classical vs exon 20 insertion), ECOG performance status, and acquired-resistance mechanism after frontline osimertinib.

EGFR mutation subtype?

• Exon 19 deletion / L858R (classical) → ECOG performance status?
• Exon 20 insertion → Amivantamab + carboplatin/pemetrexed

ECOG performance status?

• ECOG 0-1 → Osimertinib (preferred) — consider osimertinib + platinum/pemetrexed or amivantamab + lazertinib
• ECOG 2 → Osimertinib monotherapy
• ECOG 3-4 → Best supportive care ± single-agent osimertinib if organ function permits

1L: Osimertinib (preferred) — consider osimertinib + platinum/pemetrexed or amivantamab + lazertinib

Osimertinib is preferred single-agent 1L. Add platinum/pemetrexed (FLAURA2) or use amivantamab+lazertinib (MARIPOSA) for higher disease burden or CNS involvement. Monitor QTc, LVEF, and rare ILD/pneumonitis.

Evidence: FLAURA · FLAURA2 · MARIPOSA

• Progression → Acquired-resistance mechanism on osimertinib?

1L: Osimertinib monotherapy

Favorable single-agent toxicity profile makes osimertinib appropriate for ECOG 2.

Evidence: FLAURA

• Progression → Acquired-resistance mechanism on osimertinib?

1L: Best supportive care ± single-agent osimertinib if organ function permits

Palliative focus for ECOG 3-4; consider a TKI trial only if reversible decline is plausible.

1L: Amivantamab + carboplatin/pemetrexed

Exon 20 insertions are insensitive to classical EGFR TKIs including osimertinib. Amivantamab-based therapy is preferred frontline.

Evidence: PAPILLON

Acquired-resistance mechanism on osimertinib?

• MET amplification → Amivantamab-based therapy or osimertinib + MET inhibitor
• SCLC transformation → Platinum + etoposide
• No targetable resistance · ECOG 0-1 → Platinum/pemetrexed ± amivantamab
• No targetable resistance · ECOG 2 → Single-agent pemetrexed or attenuated doublet

2L: Amivantamab-based therapy or osimertinib + MET inhibitor

MET amplification is a common bypass mechanism — see the MET biomarker page for targeted options.

• Progression → Later-line option?

2L: Platinum + etoposide

Small-cell histologic transformation requires SCLC-directed chemotherapy; re-biopsy at progression is essential to detect it.

2L: Platinum/pemetrexed ± amivantamab

ECOG 0-1 with no targetable resistance: platinum doublet, with amivantamab added per MARIPOSA-2.

Evidence: MARIPOSA-2

• Progression → Later-line option?

2L: Single-agent pemetrexed or attenuated doublet

ECOG 2: dose-attenuated or single-agent chemotherapy to balance efficacy and tolerability.

• Progression → Later-line option?

Later-line option?

• Chemotherapy → Docetaxel ± ramucirumab
• Antibody-drug conjugate → Antibody-drug conjugate (datopotamab deruxtecan or patritumab deruxtecan)
• Clinical trial → Clinical trial referral

3L+: Docetaxel ± ramucirumab

Monitor for cytopenias, neuropathy, and (with ramucirumab) hypertension/bleeding.

3L+: Antibody-drug conjugate (datopotamab deruxtecan or patritumab deruxtecan)

Emerging ADC options after chemotherapy; watch for interstitial lung disease.

3L+: Clinical trial referral

Strongly consider enrollment on a biomarker-matched trial at each progression.