Actionable Genetic Alterations in Cancer and the Current List of FDA-Approved Drugs
In this article
Targeted therapiesshape treatment decisions by decoding cancer genetics. The FDA's list of "molecularly matched" drugs now extends beyond a few genes, laying the foundation for a tumor-agnostic era. New approvals in 2024–2025 for genes such as HER2, ROS1, KRAS, and NRG1 again highlight focusing on "what a tumor is, rather than where it comes from" in oncology.
A. Actionable Genetic Alterations (Tumor-Type-Specific)
| Gene | Genetic Alteration | FDA-Approved Treatment (Year) |
|---|---|---|
| AKT1 | Mutation |
|
| ALK | Fusion |
|
| BCR-ABL1 | Fusion |
|
| BRAF | Mutation (V600E/K) |
|
| BRCA1/2 | Mutation |
|
| EGFR | Mutation |
|
| ERBB2 (HER2) | Amplification / Overexpression |
|
| ESR1 | Mutation |
|
| FGFR2/3 | Fusion / Mutation |
|
| KRAS | Mutation |
|
| MET | Fusion / Mutation |
|
| MET (IHC+) | High protein expression |
|
| NRG1 | Fusion |
|
| NTRK | Fusion |
|
| RET | Fusion / Mutation |
|
| ROS1 | Fusion |
|
| VHL | Germline mutation |
|
🧬 B. Tumor/Tissue-Agnostic Biomarkers and FDA-Approved Treatments
| Biomarker | Definition | FDA-Approved Treatment (Year) | Note |
|---|---|---|---|
| MSI-H / dMMR | Microsatellite instability or DNA repair deficiency |
|
All solid tumors |
| TMB-H | ≥10 mutations/Mb |
|
All solid tumors |
| NTRK fusion | ETV6-NTRK and other fusions |
|
All solid tumors |
| RET fusion | RET rearrangement |
|
All solid tumors |
| HER2 IHC 3+ | Protein overexpression |
|
All solid tumors |
| BRAF V600E | Activating V600E mutation |
|
Excluding colorectal cancer |
What Does It Mean in Clinical Practice?
Modern NGS panels now need to include HER2, NRG1, RET, FGFR2, KRAS G12C, and KMT2A targets. Matched drugs significantly extend survival, particularly in tumor-agnostic indications , increasing the value of early molecular diagnosis.
Looking Ahead
Over the next 2 years, menin inhibitors, dual PI3K-AKT blockade and tissue-agnostic ADCs will form the next approval wave. As with every update, revising ESMO and FDA tables every 3 months is critical for clinical accuracy.
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