Oncology · Module 2 of 4

Targeted Small Molecule Inhibitors

Mechanisms, companion diagnostics, and class toxicities

BRAF V600E inhibitors (vemurafenib, dabrafenib) must never be used as monotherapy in RAS-mutant tumors — paradoxical ERK activation accelerates tumor growth. Combination with a MEK inhibitor (trametinib, cobimetinib) is mandatory; this eliminates the cutaneous squamous cell carcinoma risk of BRAF monotherapy but adds cardiomyopathy and ocular toxicity. Colorectal BRAF V600E is treated with encorafenib plus cetuximab, not a BRAF/MEK doublet.
CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) block the G1-to-S cell cycle transition in ER-positive, HER2-negative breast cancer. All three are oral CYP3A4 substrates with neutropenia as the primary toxicity. Ribociclib uniquely prolongs QTc — baseline ECG is mandatory and the drug must be held if QTc exceeds 480 ms. Abemaciclib is the only agent approved as monotherapy and the only one given continuously rather than on a 3-weeks-on/1-week-off schedule; diarrhea is its most prominent toxicity.
Venetoclax is a selective BCL-2 inhibitor that requires a mandatory dose ramp-up protocol over 5 weeks before reaching the full dose. Tumor lysis syndrome can occur within hours of the first dose — laboratory monitoring 6–8 hours after each dose escalation is required. Ibrutinib (first-generation BTK inhibitor) causes atrial fibrillation in 6–16% of patients and impairs platelet function through BTK/TEC kinase inhibition in platelets, creating a complex bleeding and anticoagulation challenge; acalabrutinib and zanubrutinib are more selective second-generation BTK inhibitors with lower cardiovascular toxicity.
IDH inhibitors (ivosidenib for IDH1, enasidenib for IDH2) work by restoring normal myeloid differentiation in AML blasts that have accumulated an oncometabolite (2-hydroxyglutarate) due to mutant IDH activity. Differentiation syndrome — fever, dyspnea, pulmonary infiltrates, and edema — occurs in the first 12 weeks as leukemic cells differentiate en masse. It requires immediate dexamethasone without waiting for diagnostic confirmation; withholding treatment risks fatal respiratory failure.
Among proteasome inhibitors, bortezomib (reversible, subcutaneous preferred to reduce neuropathy) and carfilzomib (irreversible, IV only; requires pre-infusion hydration; causes cardiomyopathy and hypertension) differ substantially in their toxicity profiles. All proteasome inhibitors require herpes zoster prophylaxis throughout therapy and for at least three months after completion. All IMiDs require REMS enrollment, monthly pregnancy testing, and dual contraception; VTE prophylaxis — at minimum aspirin — is required for all IMiD-containing regimens.

AML = acute myeloid leukemia · BRCA = breast cancer susceptibility gene · BTK = Bruton's tyrosine kinase · CDK4/6 = cyclin-dependent kinase 4 and 6 · CLL = chronic lymphocytic leukemia · CYP = cytochrome P450 · DOAC = direct oral anticoagulant · ERK = extracellular signal-regulated kinase · FLT3 = FMS-like tyrosine kinase 3 · HRD = homologous recombination deficiency · IDH = isocitrate dehydrogenase · IMiD = immunomodulatory drug · ITD = internal tandem duplication · MEK = mitogen-activated protein kinase kinase · MM = multiple myeloma · mTOR = mechanistic target of rapamycin · PARP = poly(ADP-ribose) polymerase · PI3K = phosphoinositide 3-kinase · REMS = Risk Evaluation and Mitigation Strategy · TKD = tyrosine kinase domain · TLS = tumor lysis syndrome · VTE = venous thromboembolism

BRAF/MEK & CDK4/6 Inhibitors

BRAF + MEK Combination

Melanoma & Other BRAF V600E Tumors

BRAF V600E testing required before any BRAF inhibitor — do not treat without confirmed mutation
BRAF inhibitor monotherapy absolutely contraindicated in RAS-mutant tumors: paradoxical MAPK pathway activation via CRAF dimerization → tumor acceleration
Combination with MEK inhibitor (trametinib, cobimetinib): eliminates cutaneous squamous cell carcinoma risk; adds cardiomyopathy (baseline and serial echocardiograms) and ocular toxicity (serous retinopathy)
Colorectal BRAF V600E: use encorafenib + cetuximab (not BRAF/MEK doublet) — different biology, requires wild-type RAS confirmation
Fever is common with dabrafenib; dose interruption plus antipyretics usually sufficient

CDK4/6 Inhibitors

ER-Positive, HER2-Negative Breast Cancer

All three agents (palbociclib, ribociclib, abemaciclib) are oral, all CYP3A4 substrates; combine with aromatase inhibitor or fulvestrant
Dominant toxicity: neutropenia (non-febrile; CBC before each cycle; dose-reduce for grade 3–4)
Ribociclib: QTc prolongation — baseline ECG mandatory; hold if QTc >480 ms; discontinue if QTc >500 ms recurrently; avoid with other QTc-prolonging drugs
Abemaciclib: continuous dosing (no 1-week break); most prominent diarrhea; only agent approved as monotherapy in heavily pretreated HR+ breast cancer
All: elevated VTE risk — assess and consider prophylaxis

PI3K/mTOR & BTK Inhibitors

PI3K-alpha Inhibitor

Alpelisib

PIK3CA mutation testing required (tissue or liquid biopsy) — used in HR+/HER2− breast cancer after CDK4/6 inhibitor
Hyperglycemia in 64% — PI3K-alpha inhibition in adipose/liver/muscle → insulin resistance; escalate: diet → metformin → insulin
Monitor fasting glucose before each cycle; pre-treat diabetes intensively before starting
Severe hypersensitivity and Stevens-Johnson syndrome reported — monitor skin closely

mTOR Inhibitor

Everolimus

Stomatitis (40–60%): corticosteroid mouthwash (dexamethasone alcohol-free) prevents and treats — not antifungals (no Candida cause)
Non-infectious pneumonitis (10–14%): new dyspnea → CT chest → stop drug; corticosteroids for grade 2+
Hyperglycemia and hypertriglyceridemia: mTORC1 inhibition impairs insulin secretion and sensitivity; monitor fasting glucose and lipids
Indications: HR+ breast cancer (+ exemestane), renal cell carcinoma, neuroendocrine tumors, renal angiomyolipoma (TSC)

BTK Inhibitor

Ibrutinib (1st Gen) vs Acalabrutinib

Ibrutinib: atrial fibrillation in 6–16% (off-target TEC kinase); platelet dysfunction (BTK in platelets) → hold 3–7 days before major surgery
Ibrutinib inhibits CYP2C9 (warfarin ↑) and P-glycoprotein (DOAC levels ↑) — complex anticoagulation decisions when AF develops
Acalabrutinib/zanubrutinib: more selective; lower AF incidence; less drug interaction burden
All BTK inhibitors: increased risk of invasive fungal infections in heavily pretreated patients

BCL-2, PARP, FLT3 & IDH Inhibitors

Class	Agent(s)	Companion Dx Required	Key Toxicity	Clinical Emergency
BCL-2 inhibitor	Venetoclax	None required; del(17p)/TP53 guides prognosis, not eligibility	Neutropenia; TLS during ramp-up	TLS within hours of dose 1 and each escalation — labs at 6–8 h after each increase; hydrate and allopurinol before start
PARP inhibitor	Olaparib, Niraparib, Rucaparib	BRCA1/2 testing; HRD testing for expanded ovarian cancer indication	Anemia, nausea, fatigue; niraparib: thrombocytopenia (dose by weight/platelet count)	MDS/AML in 1–2% of long-term users; monitor CBC; stop drug if MDS confirmed
FLT3 inhibitor	Midostaurin, Gilteritinib	FLT3 mutation (ITD and TKD subtypes) at AML diagnosis	QTc prolongation; nausea; CYP3A4 interactions (midostaurin)	QTc monitoring required; avoid with strong QTc-prolonging agents
IDH inhibitor	Ivosidenib (IDH1), Enasidenib (IDH2)	IDH1 or IDH2 mutation confirmed at AML diagnosis	Differentiation syndrome (weeks 1–12); QTc prolongation	Differentiation syndrome: fever + dyspnea + infiltrates → start dexamethasone immediately — do not wait for confirmation; fatal if delayed

Proteasome Inhibitors & IMiDs in Multiple Myeloma

Proteasome Inhibitors

Bortezomib, Carfilzomib, Ixazomib

Bortezomib (reversible, 26S proteasome): subcutaneous preferred over IV — equivalent efficacy, substantially less peripheral neuropathy; herpes zoster prophylaxis required
Carfilzomib (irreversible): IV only; pre-infusion hydration required; cardiomyopathy and hypertension are class-defining toxicities; baseline and serial cardiac monitoring
Ixazomib (oral): least neuropathy; no cardiac concern; CYP3A4 substrate; convenient for maintenance
All proteasome inhibitors: herpes zoster prophylaxis with acyclovir or valacyclovir throughout therapy and ≥3 months after completion

IMiDs — Cereblon Mechanism

Thalidomide, Lenalidomide, Pomalidomide

Mechanism: bind cereblon → CRL4-CRBN E3 ligase degrades Ikaros and Aiolos → myeloma cell apoptosis
Teratogenicity: single dose can cause phocomelia — absolute contraindication in pregnancy
All require REMS enrollment before first dispensing; 28-day dispensing limit; monthly pregnancy testing for women of childbearing potential
Lenalidomide: renally cleared — dose-reduce if CrCl <60 mL/min
VTE prophylaxis required: aspirin for low-risk patients; anticoagulation for high-risk (prior VTE, immobility, high-risk disease features)

Cross-Class Rules

Five Non-Negotiable Principles for This Module

BRAF inhibitor monotherapy is contraindicated in RAS-mutant tumors — always combine with a MEK inhibitor. Venetoclax requires mandatory dose ramp-up with tumor lysis syndrome prophylaxis and laboratory monitoring at 6–8 hours after each dose increase. Differentiation syndrome with IDH inhibitors requires immediate dexamethasone — do not wait for diagnostic confirmation, as delay risks fatal respiratory failure. All proteasome inhibitors require herpes zoster antiviral prophylaxis throughout treatment and for at least three months after stopping. All IMiDs require REMS enrollment and active pregnancy prevention before the first dose can be dispensed.

References

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