BCR-ABL, EGFR & ALK/ROS1 Kinase Inhibitors

Generation-by-generation resistance, mutation targets, and class toxicities

BCR-ABL Inhibitor Generations

1st Gen

Imatinib

ATP site, inactive conformation. Inhibits KIT and PDGFR. Edema, nausea, muscle cramps.

2nd Gen

Dasatinib · Nilotinib · Bosutinib

Overcomes most P-loop/contact site mutations. Not active vs T315I.

3rd Gen

Ponatinib

Pan-BCR-ABL; active vs T315I. Arterial occlusion risk (boxed warning).

STAMP

Asciminib

Myristoyl pocket (not ATP site). Overcomes T315I at high dose.

2nd-Generation Toxicity Distinguishers

Dasatinib
  • Pleural effusion
  • Pulmonary arterial hypertension
  • Avoid proton pump inhibitors
Nilotinib
  • QTc prolongation (ECG required)
  • Take on empty stomach
  • Hyperglycemia; peripheral arterial disease
Bosutinib
  • Diarrhea (majority of patients)
  • Leading cause of dose modification
  • Minimal KIT/PDGFR inhibition

EGFR Inhibitor Generations — Non-Small Cell Lung Cancer

Gen Agent(s) Mechanism Key Point
1st Erlotinib, Gefitinib Reversible, ATP-competitive Classic sensitizing mutations (ex19del, L858R). T790M → resistance.
2nd Afatinib, Dacomitinib Irreversible, pan-HER (EGFR/HER2/HER4) More severe diarrhea/mucositis. Does not cover T790M.
3rd Osimertinib Irreversible, mutant-selective; covers T790M First-line preferred (FLAURA). CNS penetration. Spares wild-type EGFR.

ALK Inhibitor Generations

1st Gen — Crizotinib
  • ALK + MET + ROS1
  • Visual disturbances (light flashes)
  • Poor CNS penetration → brain relapse
2nd Gen — Alectinib
  • Superior to crizotinib (ALEX trial)
  • Good CNS penetration
  • Myalgia, elevated creatine kinase
3rd Gen — Lorlatinib
  • Broadest mutation coverage; best CNS activity
  • Hyperlipidemia (most patients)
  • CNS adverse effects (mood, cognition)

T315I Rule

The T315I gatekeeper mutation in BCR-ABL confers resistance to all 1st- and 2nd-generation agents. Molecular testing at resistance is required. Only ponatinib (3rd gen) or high-dose asciminib (STAMP) retain activity. For EGFR, T790M drives resistance to 1st/2nd-gen agents — switch to osimertinib.