TKI is an acronym for Tyrosine Kinase Inhibitor. These types of medications attempt to block enzymes that help cells grow and divide. TKIs are a targeted therapy. Eventually, cells die off and this applies to cancer cells as well. By stopping the replication of (at least some or most of) the cancer cells, the growth can slow and or stop.
Crizotinib was the first ALK TKI approved, and it showed significant activity in ALK-mutated non-small cell lung cancer (NSCLC).
These include ceritinib, alectinib, brigatinib, and ensartinib. They were developed to address resistance to crizotinib and have demonstrated improved efficacy and CNS penetration.
Lorlatinib was designed to be effective against tumors that have stopped responding to first- and second-generation ALK inhibitors, and it has shown promise in the front-line setting.
| ALK TKIs | Generic Name | Brand Name | Manufacturer | FDA Approved |
|---|---|---|---|---|
| First Generation | Crizotinib | Xalkori | Pfizer | Yes |
| Second Generation | Alectinib | Alecensa | Genentech | Yes |
| Brigatinib | Alunbrig | Takeda | Yes | |
| Ceritinib | Zykadia | Novartis | Yes | |
| Ensartinib | Ensacove | Xcovery | Yes (2024-12-18)[1] | |
| Third Generation | Lorlatinib | Lorbrena | Pfizer | Yes |
| Fourth Generation* | NVL-655 (in clinical trial) | Neladalkib | Nuvalent | In clinical trial. Seeking potential approval in 2026[2]. |
Current guidelines recommend alectinib, brigatinib, or lorlatinib as the preferred first-line treatment for ALK-positive advanced or metastatic NSCLC.
While ALK TKIs have revolutionized the treatment of ALK-positive NSCLC, resistance mechanisms can emerge, leading to disease progression. Ongoing research focuses on developing new strategies to overcome resistance, including novel ALK TKIs and combination therapies.
For MET amplification, some MET inhibitors are Capmatinib (brand name: Tabrecta) and Tepotinib (brand name: Tepmetko) can be used in combination with ALK TKIs.