Targeted Therapy in NSCLC: Molecular Profiling-Based Treatment Recommendations

EGFR Mutations

For patients with EGFR exon 19 deletions or L858R mutations, osimertinib is the preferred first-line therapy, demonstrating superior efficacy and CNS penetration compared to earlier-generation EGFR TKIs 1, 2, 3.

First-line options:
- Osimertinib (preferred, strong recommendation) 1, 2
- Osimertinib plus chemotherapy (weak recommendation) 2
- Alternative: Standard therapy following non-driver alteration guidelines if osimertinib unavailable 1
For uncommon EGFR mutations (G719X, L861Q, S768I):
- Afatinib (strong recommendation) 2
- Osimertinib (weak recommendation) 2
For EGFR exon 20 insertions:
- Chemotherapy plus amivantamab (strong recommendation, first-line) 2
- Amivantamab monotherapy after platinum chemotherapy failure 3
Resistance management:
- If T790M emerges after 1st/2nd-generation TKIs: Switch to osimertinib 1, 4
- After osimertinib progression without T790M: Platinum-based chemotherapy with or without amivantamab 3
- Critical caveat: Anti-PD-(L)1 agents with or without chemotherapy are NOT recommended after EGFR TKI progression (high-quality evidence, strong recommendation) 3

ALK Rearrangements

Alectinib or brigatinib should be offered as first-line therapy for ALK-positive NSCLC, with both demonstrating superior PFS and lower toxicity compared to crizotinib 1.

First-line hierarchy:
- Preferred: Alectinib or brigatinib (high-quality evidence, strong recommendation) 1
- Alternative: Lorlatinib (low-quality evidence, weak recommendation due to neurocognitive/mood toxicities, hypercholesterolemia, hypertriglyceridemia) 1
- If above unavailable: Ceritinib or crizotinib (strong recommendation) 1
CNS involvement: Alectinib, brigatinib, or ceritinib preferred due to superior CNS penetration 4
Second-line after crizotinib: Alectinib, brigatinib, or ceritinib 4, 3
After 2nd-generation ALK TKI progression: Lorlatinib 4, 3

ROS1 Rearrangements

For ROS1-positive NSCLC, crizotinib or entrectinib may be offered first-line, though evidence quality remains moderate 1.

First-line options:
- Crizotinib or entrectinib (moderate recommendation) 1
- Ceritinib or lorlatinib (weak recommendation) 1
- Standard therapy following non-driver guidelines (moderate recommendation) 1
After prior ROS1 TKI: Repotrectinib (moderate-quality evidence, strong recommendation) 2, 3
- Demonstrated 35.7-month median PFS in TKI-naïve patients 2
- 9.0-month median PFS after one prior ROS1 TKI 2

BRAF V600E Mutations

Dabrafenib plus trametinib combination may be offered as first-line therapy for BRAF V600E-mutated NSCLC 1.

First-line options:
- Dabrafenib/trametinib (moderate recommendation) 1
- Encorafenib/binimetinib (alternative combination) 3
- Standard first-line therapy following non-driver guidelines (moderate recommendation) 1
After BRAF/MEK therapy: Standard therapy following non-driver guidelines 3
Non-V600E BRAF alterations: Standard therapy following non-driver guidelines 3

MET Exon 14 Skipping Mutations

For MET exon 14 skipping mutations, capmatinib or tepotinib may be offered as first-line therapy 1.

First-line options:
- Capmatinib or tepotinib (moderate recommendation) 1
- Standard first-line therapy following non-driver guidelines (moderate recommendation) 1
After MET-targeted therapy: Standard therapy following non-driver guidelines 3

RET Rearrangements

Selpercatinib or pralsetinib should be offered for RET-rearranged NSCLC, with both demonstrating clinically meaningful benefit 1, 3.

First-line options:
- Selpercatinib or pralsetinib (weak recommendation, combined from prior separate recommendations) 1
- Standard therapy following non-driver guidelines if RET inhibitors unavailable (moderate recommendation) 1, 3
After RET inhibitor: Standard therapy following non-driver guidelines 3

NTRK Fusions

For NTRK fusion-positive NSCLC, entrectinib or larotrectinib should be offered, with both demonstrating tumor-agnostic efficacy 5, 1, 3.

First-line options:
- Entrectinib or larotrectinib (moderate recommendation) 1, 3
- Standard therapy following non-driver guidelines if unavailable 1
Key considerations:
- NTRK fusions occur in ~0.1-0.3% of NSCLC overall, enriched 10-fold in tumors without other oncogenic drivers 5
- Larotrectinib: 78% ORR, 36.8-month median PFS, 71% intracranial ORR 5
- Entrectinib: 63.5% ORR, 12.9-month median duration of response, 50% intracranial ORR 5
- Mutually exclusive with KRAS, BRAF, NRAS, EGFR alterations 5

KRAS G12C Mutations

Sotorasib or adagrasib may be offered for KRAS G12C-mutated NSCLC after prior chemotherapy and/or anti-PD-(L)1 therapy 3.

Second-line options:
- Sotorasib (moderate-quality evidence, strong recommendation) 3
- Adagrasib (low-quality evidence, strong recommendation) 3
First-line: Standard treatment with immune checkpoint inhibitor and/or chemotherapy following non-driver guidelines 3

HER2 Mutations

Trastuzumab deruxtecan may be offered for HER2-mutated NSCLC 3.

Low-quality evidence, strong recommendation 3
Typically after platinum-based chemotherapy 6

Critical Implementation Principles

Molecular testing imperative: Comprehensive NGS testing should include all 12 NCCN-recommended biomarkers (EGFR, ALK, ROS1, BRAF, MET exon 14, RET, NTRK1/2/3, KRAS, HER2, MET amplification) 2, 7
Mutually exclusive drivers: EGFR, ALK, ROS1, RET fusions typically occur without concurrent KRAS, BRAF, NRAS alterations 5
Resistance monitoring: Re-biopsy or liquid biopsy (ctDNA) at progression to identify targetable resistance mechanisms (e.g., EGFR T790M) 4, 3
Performance status: Most recommendations apply to PS 0-2 patients 1
Sequential therapy: After exhausting targeted options, transition to standard therapy following non-driver alteration guidelines 3

What targeted therapy regimens are recommended for non‑small cell lung cancer (NSCLC) based on molecular profiling of EGFR, ALK, ROS1, BRAF, MET exon‑14, RET, NTRK, and KRAS G12C alterations?

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