What are the commonly used oncogene‑targeted agents for specific genetic alterations (e.g., EGFR‑mutated non‑small cell lung cancer, ALK‑rearranged non‑small cell lung cancer, BRAF V600E‑mutated melanoma or non‑small cell lung cancer, HER2‑positive breast cancer, KRAS G12C‑mutated non‑small cell lung cancer, PI3K‑α mutated or PIK3CA‑amplified breast cancer) and their typical adult dosing?

Oncogene-Targeted Agents for Specific Genetic Alterations

For patients with oncogene-driven cancers, targeted therapies matched to specific molecular alterations provide superior survival and quality of life compared to conventional chemotherapy, making comprehensive molecular testing mandatory before initiating treatment. 1, 2

EGFR-Mutated Non-Small Cell Lung Cancer

Osimertinib is the preferred first-line agent for EGFR-mutated metastatic NSCLC due to superior CNS penetration and efficacy, particularly in patients with brain metastases. 2

• Standard dosing: Osimertinib 80 mg orally once daily until disease progression or unacceptable toxicity 2
• Complete sequencing of EGFR exons 18-21 by NGS is strongly recommended to identify all sensitizing mutations, including uncommon variants in exon 18 that may respond differently 1
• For T790M resistance mutation after first- or second-generation EGFR TKIs, osimertinib demonstrates median PFS of 9.6 months 2
• Critical pitfall: Avoid PD-1/PD-L1 monotherapy in EGFR-positive NSCLC as it shows inferior efficacy; EGFR TKI + immunotherapy combinations increase risk of severe pneumonitis 2

ALK-Rearranged Non-Small Cell Lung Cancer

Alectinib or lorlatinib should be used as first-line therapy, with lorlatinib preferred for patients with brain metastases due to superior intracranial control. 2

• Alectinib dosing: 600 mg orally twice daily with food 2
• Lorlatinib dosing: 100 mg orally once daily 2
• Crizotinib is not recommended as first-line therapy due to inferior CNS penetration, though it may be considered for second-line therapy 2
• ALK IHC with appropriately validated assay may be used to prescribe ALK inhibitors, though molecular confirmation is preferred 1
• TP53 comutations may be associated with lower efficacy of ALK TKIs, making NGS panel testing important 1

BRAF V600E-Mutated Melanoma and Non-Small Cell Lung Cancer

Dabrafenib plus trametinib combination is recommended for BRAF V600E-mutated NSCLC, demonstrating response rates of 60% and clinically significant survival improvement over single-agent therapy or conventional chemotherapy. 1, 2

• Dabrafenib dosing: 150 mg orally twice daily 1
• Trametinib dosing: 2 mg orally once daily 1
• In pretreated patients, median OS was 18.2 months (4-year survival: 34%; 5-year survival: 22%) 1
• In treatment-naive patients, median OS was 17.3 months (4-year survival: 26%; 5-year survival: 19%) 1
• Single-agent ICI shows poor outcomes in BRAF-mutated population (ORR 24%, mPFS 3.1 months) 1

HER2-Positive Breast Cancer

Trastuzumab-based regimens remain the standard of care for HER2-positive breast cancer, with the specific agent selected based on line of therapy and prior treatments. 3, 4

• Trastuzumab demonstrates synergistic or additive effects with classical chemotherapy, though single-agent response rates are low 3
• For HER2 exon 20 mutations in NSCLC: Trastuzumab deruxtecan is recommended following prior first-line therapy 2, 5
• HER2 amplification represents an oncogene involved at later stages of transformation, requiring combination approaches for optimal efficacy 3

KRAS G12C-Mutated Non-Small Cell Lung Cancer

Sotorasib or adagrasib should be used as subsequent therapy after progression on first-line immunotherapy-based treatment for KRAS G12C-mutated NSCLC. 2, 5, 6

• Sotorasib dosing: 960 mg orally once daily 5, 6
• Adagrasib dosing: Specific dosing per FDA approval, used after at least one prior course of chemotherapy and/or immunotherapy 5
• KRAS G12C comprises approximately 44% of KRAS mutations in NSCLC, present in ~13% of all lung adenocarcinomas 6
• Adagrasib in first-line combination with pembrolizumab shows greater benefit, especially in patients with high PD-L1 expression 5
• KRAS mutations are typically mutually exclusive with EGFR and ALK alterations 7

PIK3CA-Mutated or PIK3CA-Amplified Breast Cancer

For PIK3CA-altered breast cancer, PI3K inhibitors are used in combination with endocrine therapy in hormone receptor-positive, HER2-negative disease. 4

• PI3K pathway alterations contribute to tumor progression and endocrine resistance 4
• Combination approaches with endocrine therapy are required due to pathway redundancy 4

Additional Actionable Oncogenic Drivers

RET Fusions (NSCLC)

Selpercatinib or pralsetinib is recommended for RET fusion-positive NSCLC, with both agents demonstrating high intracranial response rates. 1

• Selpercatinib: ORR 64% in platinum-pretreated patients, 85% in treatment-naive patients; median DoR 17.5 months 1
• Pralsetinib: ORR 59% in platinum-pretreated patients, 72% in treatment-naive patients; median DoR not reached in treatment-naive, 22.3 months in pretreated 1
• EMA indication is for patients not previously treated with a RET inhibitor 1

MET Exon 14 Skipping Mutations

Capmatinib or tepotinib should be used for MET exon 14 skipping mutations in first or second line. 1, 2, 5

• FDA approved but not EMA approved in first line 1
• RNA-based NGS may identify additional cases missed by DNA sequencing 1
• MET amplification is an important resistance mechanism to EGFR and ALK inhibitors 1

EGFR Exon 20 Insertion Mutations

Amivantamab is the preferred treatment for EGFR exon 20 insertion-mutated NSCLC after prior therapy. 2, 5

• Approved for progression after platinum-based chemotherapy 5
• Distinct from classical EGFR activating mutations and requires different therapeutic approach 5

ROS1 Rearrangements

Crizotinib or entrectinib should be used first-line for ROS1-rearranged NSCLC, with entrectinib preferred in patients with brain metastases. 2

• ROS1 or NTRK IHC must be confirmed by molecular method 1
• TP53 comutations may reduce efficacy 1

NTRK Gene Fusions

Larotrectinib or entrectinib should be used for NTRK gene fusion-positive cancers when no satisfactory treatment options exist. 2

• Tumor-agnostic indication across multiple cancer types 2
• RNA-based NGS is preferred for identifying fusion genes 1

Critical Testing and Management Principles

Comprehensive molecular testing with NGS is mandatory before initiating any treatment for advanced NSCLC to identify all actionable mutations. 1, 2, 8

• Testing should include: EGFR (exons 18-21), ALK, ROS1, BRAF, KRAS, MET exon 14 skipping, RET, NTRK, HER2, and emerging biomarkers 1, 2, 8, 6
• RNA-based NGS is preferred for fusion detection 1
• PD-L1 expression testing is required to guide immunotherapy decisions 8
• Re-biopsy at progression should be discussed with patients who may benefit from genotyping to identify resistance mechanisms 2
• For oligometastatic progression during targeted therapy, continue TKI and add local treatment (surgery or radiotherapy) 2