Targeted Small Molecule Inhibitors

Mechanisms, companion diagnostics, and class toxicities

BTK = Bruton's tyrosine kinase  ·  CDK4/6 = cyclin-dependent kinase 4 and 6  ·  CLL = chronic lymphocytic leukemia  ·  AML = acute myeloid leukemia  ·  MM = multiple myeloma  ·  IMiD = immunomodulatory drug  ·  REMS = risk evaluation and mitigation strategy  ·  TLS = tumor lysis syndrome  ·  VTE = venous thromboembolism

BRAF/MEK & CDK4/6 Inhibitors

BRAF + MEK Combination (Melanoma)
  • Require BRAF V600E testing before use
  • Monotherapy prohibited in RAS-mutant tumors (paradoxical ERK activation)
  • MEK inhibitor added: eliminates cutaneous SCC risk, adds ocular/cardiac toxicity
  • Trametinib: baseline echo; repeat every 8–12 weeks (cardiomyopathy)
  • Colorectal BRAF V600E: encorafenib + cetuximab (not BRAF/MEK)
CDK4/6 Inhibitors (ER+ HER2− Breast Cancer)
  • Palbociclib, ribociclib, abemaciclib — all oral, all CYP3A4 substrates
  • Dominant toxicity: neutropenia (non-febrile; CBC before each cycle)
  • Ribociclib: QTc prolongation — baseline ECG mandatory; hold if QTc > 480 ms
  • Abemaciclib: continuous dosing; most diarrhea; only agent approved as monotherapy
  • All: VTE risk elevated

PI3K/mTOR & BTK Inhibitors

Alpelisib (PI3K-alpha)
  • PIK3CA mutation testing required
  • Hyperglycemia in 64% — insulin resistance mechanism
  • Monitor fasting glucose each cycle
  • Stevens-Johnson syndrome reported
Everolimus (mTOR)
  • Stomatitis (40–60%) — corticosteroid mouthwash, not antifungals
  • Non-infectious pneumonitis (10–14%) — stop drug; corticosteroids
  • Hyperglycemia, hypertriglyceridemia
Ibrutinib (BTK — 1st gen)
  • Atrial fibrillation 6–16%
  • Platelet dysfunction (BTK/TEC kinase in platelets)
  • Inhibits CYP2C9 (warfarin ↑) and P-gp (DOAC ↑)
  • Hold 3–7 days pre-major surgery

BCL-2, PARP, FLT3 & IDH Inhibitors

Class Agent(s) Companion Dx Key Toxicity Emergency
BCL-2 inhibitor Venetoclax None required TLS — ramp-up mandatory TLS within hours of dose 1
PARP inhibitor Olaparib, Niraparib, Rucaparib BRCA1/2 testing; HRD testing (ovarian) Anemia, nausea; niraparib: thrombocytopenia MDS/AML risk (1–2%) long-term
FLT3 inhibitor Midostaurin, Gilteritinib FLT3 mutation (ITD and TKD) QTc prolongation; CYP3A4 interactions QTc monitoring required
IDH inhibitor Ivosidenib (IDH1), Enasidenib (IDH2) IDH1 or IDH2 mutation Differentiation syndrome; QTc prolongation Differentiation syndrome wks 1–12 → dexamethasone

Proteasome Inhibitors & IMiDs

Proteasome Inhibitors (MM)
  • Bortezomib: reversible; SC preferred (less neuropathy); herpes zoster prophylaxis required
  • Carfilzomib: irreversible; IV only; cardiomyopathy/hypertension; hydrate before each infusion
  • Ixazomib: oral; least neuropathy; no cardiac concern
IMiDs — REMS + VTE
  • Mechanism: cereblon → degrades Ikaros/Aiolos → myeloma cell death
  • Teratogenicity: single dose can cause phocomelia
  • All require REMS enrollment; 28-day dispensing limit
  • Lenalidomide: renally cleared; dose-reduce if CrCl < 60 mL/min
  • VTE prophylaxis: aspirin (low risk) or anticoagulation (high risk)

Cross-Class Rules

BRAF inhibitor monotherapy is contraindicated in RAS-mutant tumors. Venetoclax always requires dose ramp-up with TLS prophylaxis. Differentiation syndrome with IDH inhibitors requires immediate dexamethasone — do not wait for confirmation. All proteasome inhibitors require herpes zoster prophylaxis. All IMiDs require REMS enrollment before dispensing.