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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
ALK-positive lung cancer is driven by a fused ALK gene and is treated with a pill from the start. The newest inhibitors keep the disease under control for years, with lorlatinib holding six in ten patients progression-free at five years, and two years of alectinib after surgery cuts recurrence by three quarters.
The EML4-ALK fusion was found in lung cancer in Japan in 2007, and crizotinib, a MET inhibitor that happened to block ALK, was approved four years later on the strength of response rates around 60 percent, one of the fastest paths from discovery to approval in oncology. PROFILE 1014 (2014) showed crizotinib beat chemotherapy first line, but most patients progressed within a year, frequently in the brain, which crizotinib penetrates poorly. Ceritinib, alectinib and brigatinib were developed against crizotinib-resistant disease and then moved to the front.
ALEX (2017) showed alectinib beat crizotinib first line, with median progression-free survival of 34.8 versus 10.9 months, brain progression cut from 41 to 9 percent at one year and five-year survival of 62.5 versus 45.5 percent. ALTA-1L (2018) showed the same for brigatinib (24.0 versus 11.1 months), and CROWN (2020) for lorlatinib, a third-generation inhibitor designed to cover every known resistance mutation and to enter the brain: at five years 60 percent of lorlatinib patients were progression-free against 8 percent with crizotinib (hazard ratio 0.19), a result without precedent in metastatic lung cancer, though lorlatinib's cognitive, mood, weight and lipid effects need active management. Resistance to second-generation drugs is dominated by the G1202R solvent-front mutation, which lorlatinib covers; resistance to lorlatinib produces compound mutations that neladalkib (NVL-655, ALKOVE-1) is designed to overcome. Oligoprogression is often treated with local radiotherapy while the inhibitor continues.
| Setting | Approach | Guideline |
|---|---|---|
| Advanced, first line | Alectinib (ALEX), brigatinib (ALTA-1L) or lorlatinib (CROWN); lorlatinib gives the longest control and the best brain protection, with dose adjustment for cognitive, mood and metabolic effects. | not mapped |
| Advanced, after a second-generation inhibitor | Lorlatinib, guided where possible by the resistance mutation; local radiotherapy for oligoprogression; platinum-pemetrexed once inhibitors are exhausted. | not mapped |
| Advanced, after lorlatinib | Neladalkib in trials (ALKOVE-1); chemotherapy; clinical trial. | not mapped |
| Resected stage IB to IIIA | Surgery then two years of adjuvant alectinib (ALINA) in place of platinum chemotherapy. | not mapped |
| Brain metastases | Next-generation inhibitors control most brain metastases without radiotherapy; stereotactic radiosurgery for large or symptomatic lesions; whole-brain radiotherapy avoided. | not mapped |