Monoclonal Antibodies & TKIs in Oncology

📋 Key Information Summary

📋

Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) are targeted cancer therapies that interfere with specific molecular pathways driving tumour growth and survival.
mAbs are large-molecule glycoproteins binding extracellular targets (e.g., HER2, EGFR, VEGF); TKIs are small-molecule inhibitors acting intracellularly on kinase domains.
Anti-EGFR agents (cetuximab, panitumumab) are indicated in RAS wild-type metastatic colorectal cancer; KRAS/NRAS mutation testing (MBS item 71553) is mandatory before initiation.
Anti-HER2 therapy (trastuzumab, pertuzumab, T-DM1) is standard in HER2-positive breast and gastric cancers; IHC and FISH testing is required to confirm HER2 status (score 3+ or amplified).
Anti-VEGF therapy (bevacizumab) inhibits angiogenesis and is used in colorectal, ovarian, renal, and non-small cell lung cancers.
Imatinib revolutionised CML treatment, achieving complete cytogenetic response in >80% of chronic-phase patients; BCR-ABL1 quantitative PCR monitoring is essential.
Erlotinib is an EGFR TKI indicated in EGFR-mutated advanced NSCLC; EGFR mutation testing (exon 19 deletion, L858R) guides therapy selection.
Resistance mechanisms include gatekeeper mutations (T315I in CML, T790M in NSCLC), bypass signalling, and efflux pump overexpression.
Common side effects across classes include skin toxicity (acneiform rash, paronychia), diarrhoea, hepatotoxicity, infusion reactions, and QT prolongation.
Cardiotoxicity screening is mandatory for anti-HER2 therapy; left ventricular ejection fraction (LVEF) assessment every 3 months during trastuzumab.
All targeted therapies require PBS Authority approval in Australia; companion diagnostic testing must be performed at NATA-accredited laboratories.
Aboriginal and Torres Strait Islander patients face lower rates of molecular testing access and higher barriers to specialist oncology services, particularly in remote and very remote areas.
Multidisciplinary team (MDT) discussion is required before initiation of any targeted therapy in accordance with Cancer Australia guidelines.

Introduction & Australian Epidemiology

Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) represent a paradigm shift in oncology, moving from non-specific cytotoxic chemotherapy to precision-targeted therapies directed against specific molecular alterations within tumour cells. These agents interfere with critical signalling pathways governing cell proliferation, survival, angiogenesis, and immune evasion.

In Australia, targeted therapies are now integral to the management of multiple solid and haematological malignancies. The Pharmaceutical Benefits Scheme (PBS) currently subsidises numerous mAbs and TKIs across approved indications, and their use is guided by companion diagnostic testing mandated under MBS item numbers.

Australian Cancer Burden & Relevance

According to the Australian Institute of Health and Welfare (AIHW), an estimated 162,000 new cancer cases were diagnosed in Australia in 2023. The malignancies most amenable to targeted therapy with mAbs and TKIs include:

Cancer Type	Approx. New Cases/Year (AU)	Key Targetable Alteration	Primary Targeted Agent
Colorectal	15,500	RAS wild-type (exon 2/3/4)	Cetuximab, panitumumab, bevacizumab
Breast (HER2+)	3,200 (≈20% of breast)	HER2 amplification	Trastuzumab, pertuzumab, T-DM1
Non-small cell lung	12,700	EGFR mutation (10–15%)	Erlotinib, osimertinib
Chronic myeloid leukaemia	330	BCR-ABL1 fusion	Imatinib
Renal cell	4,200	VEGF/VEGFR pathway	Bevacizumab, sunitinib
Melanoma	17,800	BRAF V600E (≈50%)	Vemurafenib, dabrafenib

ℹ️

MDT requirement: Cancer Australia mandates multidisciplinary team (MDT) discussion before initiation of any targeted therapy in the curative or metastatic setting. MDT participation should be documented in the patient record.

Classes of Targeted Therapy

Targeted therapies in oncology are broadly classified by molecular size, site of action, and mechanism. Understanding these classes is essential for rational drug selection, resistance anticipation, and toxicity management.

Monoclonal Antibodies (mAbs)

Monoclonal antibodies are large glycoprotein molecules (≈150 kDa) produced via recombinant DNA technology. They bind extracellular targets with high specificity and are administered intravenously or subcutaneously. Their mechanisms include:

Receptor blockade: Competitive inhibition of ligand binding (e.g., cetuximab blocks EGF binding to EGFR).
Signal transduction inhibition: Prevention of receptor dimerisation and downstream signalling (e.g., trastuzumab inhibits HER2 homo- and heterodimerisation).
Antibody-dependent cellular cytotoxicity (ADCC): Fc region recruits natural killer cells to destroy tumour cells.
Complement-dependent cytotoxicity (CDC): Activation of the classical complement cascade.
Angiogenesis inhibition: Neutralisation of VEGF ligand preventing new blood vessel formation (e.g., bevacizumab).
Immune checkpoint modulation: Blockade of PD-1/PD-L1 or CTLA-4 (e.g., pembrolizumab, nivolumab — outside scope of this article but relevant to immuno-oncology).

Antibody-Drug Conjugates (ADCs)

ADCs combine the targeting specificity of mAbs with the cytotoxic potency of small-molecule chemotherapy. The antibody component delivers the payload selectively to antigen-expressing tumour cells, reducing systemic toxicity. Key examples include:

Trastuzumab emtansine (T-DM1, Kadcyla®): Anti-HER2 antibody conjugated to the microtubule inhibitor DM1. Indicated in HER2-positive metastatic breast cancer after prior trastuzumab and taxane therapy. PBS Authority Required.
Trastuzumab deruxtecan (T-DXd, Enhertu®): Anti-HER2 antibody conjugated to topoisomerase I inhibitor. Approved in Australia for HER2-positive and HER2-low metastatic breast cancer.
Ado-trastuzumab: ADC technology is expanding rapidly into other targets (TROP-2, Nectin-4, HER3).

Tyrosine Kinase Inhibitors (TKIs)

TKIs are small-molecule compounds (typically 400–900 Da) that penetrate the cell membrane and competitively inhibit the ATP-binding site of intracellular tyrosine kinases. Unlike mAbs, they are administered orally. Classification by generation:

Generation	Examples	Primary Target	Key Advantage
1st generation	Imatinib, erlotinib, gefitinib	BCR-ABL1, EGFR	Foundational efficacy; long-term safety data
2nd generation	Dasatinib, nilotinib, afatinib	BCR-ABL1 (mutant), EGFR/HER2	Broader mutant coverage; improved potency
3rd generation	Osimertinib, ponatinib	T790M EGFR, T315I BCR-ABL1	Activity against gatekeeper mutations

Key Pharmacological Differences: mAbs vs TKIs

Property	Monoclonal Antibodies	Tyrosine Kinase Inhibitors
Molecular size	≈150 kDa (large)	400–900 Da (small)
Route	IV infusion or SC injection	Oral tablet
Target location	Extracellular / cell surface	Intracellular
Half-life	Long (days to weeks)	Short to moderate (hours)
Metabolism	Proteolytic degradation (reticuloendothelial)	Hepatic CYP3A4 (major), CYP1A2, CYP2D6
Immunogenicity	Yes — human anti-drug antibodies (HADA)	Minimal
Infusion reactions	Common (1–10%)	Rare

Anti-EGFR, Anti-HER2 & Anti-VEGF Agents

Anti-EGFR Monoclonal Antibodies

Epidermal growth factor receptor (EGFR/HER1/ErbB1) is a transmembrane receptor tyrosine kinase overexpressed in many epithelial malignancies. Anti-EGFR mAbs bind the extracellular domain, preventing ligand activation and downstream RAS-MAPK and PI3K-AKT signalling.

💊

Cetuximab

Erbitux® · Chimeric IgG1 anti-EGFR mAb

Indication RAS wild-type metastatic colorectal cancer (mCRC) in combination with FOLFIRI or FOLFOX; locally advanced head & neck squamous cell carcinoma (with RT or chemo-RT)

Adult dose 400 mg/m² IV loading dose, then 250 mg/m² IV weekly (or 500 mg/m² IV q2w)

Mandatory testing RAS mutation testing (KRAS/NRAS exons 2, 3, 4) — MBS item 71553

Key side effects Acneiform rash (Grade 3: 10–18%), hypomagnesaemia, diarrhoea, infusion reactions, paronychia

PBS status ⚠ PBS Authority Required (Specialist)

💊

Panitumumab

Vectibix® · Fully human IgG2 anti-EGFR mAb

Indication RAS wild-type mCRC in combination with FOLFOX or as monotherapy after prior chemotherapy

Adult dose 6 mg/kg IV q2w (infusion over 60 min)

Renal adjustment No dose adjustment required — not renally cleared

Key side effects Skin toxicity (>90%), hypomagnesaemia (requiring fortnightly monitoring), interstitial lung disease (rare but fatal)

PBS status ⚠ PBS Authority Required (Specialist)

🚫

Anti-EGFR + left-sided CRC benefit: Post hoc analyses of CRYSTAL, FIRE-3, and CALGB 80405 trials demonstrate that anti-EGFR therapy confers superior overall survival compared to anti-VEGF therapy in RAS wild-type left-sided primary tumours. For right-sided primaries, anti-VEGF (bevacizumab) is preferred regardless of RAS status. Tumour laterality should be documented in all treatment plans.

Anti-HER2 Therapy

Human epidermal growth factor receptor 2 (HER2/ERBB2) is amplified in approximately 15–20% of breast cancers and 15–20% of gastric/gastro-oesophageal junction (GOJ) cancers. HER2 status must be confirmed by immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) at a NATA-accredited laboratory prior to therapy.

IHC Score	FISH Result	HER2 Status	Eligibility for Anti-HER2
0 or 1+	Negative	HER2-negative	Not eligible (standard chemo/IO)
2+	Equivocal → confirm by FISH	Pending FISH	Await FISH result
3+	Positive (or not required)	HER2-positive	Eligible for anti-HER2 therapy
1+ or 2+	Negative	HER2-low	T-DXd eligible (2nd-line mBC)

💊

Trastuzumab

Herceptin® · Ogivri® (biosimilar) · Humanised IgG1 anti-HER2 mAb

Indications HER2+ early breast cancer (adjuvant/neoadjuvant); HER2+ metastatic breast cancer; HER2+ metastatic gastric/GOJ cancer

Adult dose — loading 8 mg/kg IV over 90 min (1st dose)

Adult dose — maintenance 6 mg/kg IV over 30 min q3w (or 2 mg/kg IV weekly)

Duration (adjuvant) 12 months (18 cycles q3w)

Key monitoring LVEF by ECHO/MUGA at baseline, q3 months during therapy, and 6 months post-completion

PBS status ⚠ PBS Authority Required (Specialist)

💊

Pertuzumab

Perjeta® · Humanised IgG1 anti-HER2 (subdomain II) mAb

Indication HER2+ metastatic or locally advanced breast cancer (with trastuzumab + docetaxel); neoadjuvant HER2+ breast cancer (with trastuzumab + chemotherapy)

Adult dose 840 mg IV loading, then 420 mg IV q3w (flat dose)

Key side effects Diarrhoea (up to 67%), febrile neutropenia (with docetaxel), rash, LVEF decline

PBS status ⚠ PBS Authority Required (Specialist)

💊

Trastuzumab emtansine (T-DM1)

Kadcyla® · ADC — anti-HER2 + DM1 cytotoxin

Indication HER2+ metastatic breast cancer after prior trastuzumab + taxane; adjuvant HER2+ early breast cancer with residual disease after neoadjuvant therapy (KATHERINE trial)

Adult dose 3.6 mg/kg IV q3w

Key side effects Thrombocytopenia (Grade 3–4: 13%), hepatotoxicity (elevated transaminases), peripheral neuropathy

PBS status ⚠ PBS Authority Required (Specialist)

⚠️

Cardiotoxicity — mandatory monitoring: Trastuzumab and pertuzumab cause Type II (reversible) cardiotoxicity. Baseline LVEF must be ≥50% before initiation. If LVEF drops to <45%, or to 45–49% with ≥10% absolute decline from baseline, treatment must be withheld. Cardiology referral is recommended for LVEF <50% during therapy. Concurrent anthracyclines should be avoided due to synergistic cardiotoxicity risk.

Anti-VEGF Therapy

Vascular endothelial growth factor (VEGF) is the principal mediator of tumour angiogenesis. By promoting new blood vessel formation, VEGF supports tumour growth beyond 1–2 mm³. Anti-VEGF agents starve tumours of oxygen and nutrients.

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Bevacizumab

Avastin® · Mvasi® (biosimilar) · Humanised IgG1 anti-VEGF-A mAb

Indications mCRC (with FOLFOX/FOLFIRI); advanced non-squamous NSCLC (with platinum-doublet); recurrent ovarian cancer (with carboplatin/paclitaxel); metastatic renal cell carcinoma

Adult dose — mCRC 5 mg/kg IV q2w (with FOLFOX) or 7.5 mg/kg IV q3w (with FOLFIRI or XELOX)

Adult dose — NSCLC 15 mg/kg IV q3w (with carboplatin/paclitaxel)

Key side effects Hypertension (requiring antihypertensive therapy), proteinuria, haemorrhage, GI perforation (1–2%), thromboembolism, impaired wound healing (discontinue ≥4 weeks pre-surgery)

Renal adjustment No adjustment — not renally eliminated

PBS status ⚠ PBS Authority Required (Specialist)

⚠️

Bevacizumab surgical safety: Bevacizumab inhibits wound healing due to its anti-angiogenic mechanism. Discontinue bevacizumab at least 4–6 weeks before elective surgery. Do not restart until wound healing is confirmed, typically ≥4 weeks postoperatively. GI perforation risk is elevated in patients with recent colonoscopy, diverticular disease, or intra-abdominal abscess.

Tyrosine Kinase Inhibitors — Imatinib & Erlotinib

Imatinib — The Paradigm of Precision Oncology

Imatinib mesylate (Gleevec®, Glivec®) is a first-generation TKI that competitively inhibits the ATP-binding site of the BCR-ABL1 fusion oncoprotein, as well as c-KIT (CD117) and PDGFRα. Its introduction in 2001 transformed chronic myeloid leukaemia (CML) from a fatal disease to one with >90% 5-year survival in chronic phase.

💊

Imatinib

Gleevec® · Generic available · BCR-ABL1 / c-KIT / PDGFRα TKI

Indications Philadelphia chromosome-positive (Ph+) CML (all phases); Ph+ ALL (with chemotherapy); unresectable/metastatic GIST (c-KIT or PDGFRα mutation positive); dermatofibrosarcoma protuberans; hypereosinophilic syndrome

Adult dose — CML chronic phase 400 mg PO once daily with food and a full glass of water

Adult dose — CML accelerated/blast phase, GIST 400–600 mg PO daily (800 mg may be considered in advanced CML, split BID)

Paediatric dose Ph+ CML: 340 mg/m² PO daily (max 600 mg); Ph+ ALL: 340 mg/m² daily

Renal adjustment eGFR 20–40: reduce dose by 50%; eGFR <20: avoid or use 100 mg daily with caution

Hepatic adjustment Mild impairment (Child-Pugh A): reduce to 300 mg; moderate-severe: avoid

Key side effects Oedema (periorbital, peripheral), nausea, myalgia/cramps, rash, cytopenias (neutropenia, thrombocytopenia), hepatotoxicity, fluid retention

Drug interactions CYP3A4 substrate — avoid strong CYP3A4 inhibitors (ketoconazole, ritonavir) and inducers (rifampicin, phenytoin, St John's wort)

PBS status ⚠ PBS Authority Required (Specialist)

BCR-ABL1 Monitoring in CML

Response monitoring with quantitative reverse transcription PCR (qRT-PCR) for BCR-ABL1 transcript levels is the cornerstone of CML management. The International Scale (IS) is used to standardise results across laboratories.

Timepoint	Optimal Response (IS)	Warning	Failure — Consider TKI Switch
3 months	BCR-ABL1 ≤10%	>10%	>10% (assess compliance, mutation testing)
6 months	BCR-ABL1 ≤1%	1–10%	>10%
12 months	Major molecular response (MMR): ≤0.1%	0.1–1%	>1%; loss of CHR or CCyR
Any time	Stable MMR or deeper	Rising BCR-ABL1 >0.1% after MMR	Loss of MMR; new mutations on ABL kinase domain sequencing

ℹ️

Treatment-free remission (TFR): Patients with sustained deep molecular response (DMR, MR4 or MR4.5 — BCR-ABL1 ≤0.01%) for ≥3 years on TKI therapy may be candidates for treatment-free remission under close molecular monitoring (qRT-PCR monthly × 12 months, then q2–3 months). TFR programmes require specialist haematology oversight and informed patient consent. Approximately 40–60% of patients maintain DFR after TKI cessation.

Erlotinib — EGFR TKI in NSCLC

Erlotinib (Tarceva®) is a first-generation reversible EGFR TKI that binds the intracellular ATP-binding domain of EGFR, blocking autophosphorylation and downstream RAS-MAPK and PI3K-AKT signalling. It is indicated in EGFR-mutation-positive advanced NSCLC.

💊

Erlotinib

Tarceva® · EGFR TKI (1st generation)

Indications First-line treatment of EGFR exon 19 deletion or exon 21 L858R mutation-positive locally advanced or metastatic NSCLC; maintenance or 2nd-line in unselected NSCLC (limited use)

Adult dose 150 mg PO once daily, at least 1 hour before or 2 hours after food

Mandatory testing EGFR mutation testing (exon 18–21) on tumour tissue or ctDNA — prior to treatment

Renal adjustment No adjustment — minimally renally cleared

Hepatic adjustment Use with caution in hepatic impairment; discontinue if ALT/AST >5× ULN or bilirubin >3× ULN

Key side effects Acneiform rash (Grade 3: 9%, correlated with efficacy), diarrhoea, stomatitis, hepatotoxicity, interstitial lung disease (ILD, 1–2%, potentially fatal), paronychia

Drug interactions CYP3A4 and CYP1A2 substrate — smoking reduces plasma levels by ~60%; proton pump inhibitors reduce bioavailability; avoid concurrent warfarin (↑ INR)

PBS status ⚠ PBS Authority Required (Specialist)

⚠️

Interstitial lung disease (ILD): EGFR TKIs, including erlotinib, can cause severe and potentially fatal ILD. Incidence is 1–2%, higher in Japanese and East Asian populations. Immediately investigate new or worsening dyspnoea, cough, and fever. If ILD is confirmed, permanently discontinue erlotinib and initiate corticosteroids. Pre-existing pulmonary fibrosis is a relative contraindication.

Comparison: Imatinib vs Erlotinib

Feature	Imatinib	Erlotinib
Primary target	BCR-ABL1, c-KIT, PDGFRα	EGFR (HER1/ErbB1)
Indication	Ph+ CML, GIST	EGFR-mutated NSCLC
Dose	400 mg PO daily	150 mg PO daily (fasting)
Monitoring	BCR-ABL1 qRT-PCR; FBC; LFTs	CT chest q6–12 weeks; LFTs; clinical ILD assessment
Signature toxicity	Oedema, myalgia	Acneiform rash, ILD
Renal adjustment	Required (eGFR <40)	Not required
Smoking interaction	Minimal	Major — ↓ plasma levels ~60%

Indications, Resistance & Side Effects

Approved Indications Summary

Agent	Cancer Type	Biomarker Requirement	Line of Therapy
Cetuximab	mCRC, HNSCC	RAS wild-type (mCRC)	1st or 2nd line (mCRC); 1st line (HNSCC)
Panitumumab	mCRC	RAS wild-type	1st or 2nd line
Trastuzumab	Breast, gastric/GOJ	HER2-positive (IHC 3+ or FISH+)	Adjuvant, neoadjuvant, metastatic
Pertuzumab	Breast	HER2-positive	Neoadjuvant, 1st-line metastatic
T-DM1	Breast	HER2-positive	2nd-line metastatic; adjuvant (residual disease)
Bevacizumab	CRC, NSCLC, ovarian, renal	None (non-biomarker selected)	1st/2nd line (varies by tumour)
Imatinib	CML, GIST	Ph+/BCR-ABL1+ (CML); c-KIT/PDGFRα+ (GIST)	1st line
Erlotinib	NSCLC	EGFR mutation (exon 19 del or L858R)	1st line (mutation+); 2nd/3rd line (limited)

Mechanisms of Resistance

Acquired resistance is the principal limitation of targeted therapies. Resistance mechanisms can be broadly classified as on-target (target-dependent) or off-target (bypass/alternative pathway) and inform subsequent therapy selection.

Anti-EGFR Resistance (Cetuximab/Panitumumab)

Primary (de novo) resistance: Occult RAS mutations below standard testing sensitivity; BRAF V600E mutation; HER2 amplification; PIK3CA mutation; PTEN loss.
Acquired resistance: Emergence of RAS-mutant clones detectable on liquid biopsy (ctDNA); EGFR extracellular domain mutations (S492R preventing cetuximab binding); MET amplification; HER2 amplification.
Clinical approach: Re-biopsy or liquid biopsy at progression; if acquired RAS mutation, consider rechallenge after clonal decay (anti-EGFR holiday ≥4 months).

Anti-HER2 Resistance

On-target: Truncated HER2 (p95-HER2) lacking extracellular trastuzumab binding domain; HER2 mutations (not amplification — e.g., L755S).
Bypass: PIK3CA mutation (≈30% of HER2+ BC at diagnosis); PTEN loss; upregulation of IGF-1R, HER3, or MET signalling.
Clinical approach: Continue anti-HER2 backbone; switch from trastuzumab to T-DM1 (which does not require extracellular binding for internalisation) or T-DXd; add CDK4/6 inhibitor or PI3K inhibitor in clinical trial settings.

BCR-ABL1 Resistance (Imatinib)

Point mutations in ABL kinase domain: >100 mutations described; most common: T315I (gatekeeper — resistant to imatinib, dasatinib, nilotinib; sensitive to ponatinib); E255K/V; Y253H; G250E.
Amplification: BCR-ABL1 gene amplification causing overproduction of the target.
Clinical approach: On imatinib failure, perform ABL kinase domain mutation analysis; switch to 2nd generation (dasatinib, nilotinib) or 3rd generation (ponatinib for T315I) TKI. Allogeneic transplant remains an option in advanced phases.

EGFR TKI Resistance (Erlotinib/Gefitinib)

T790M gatekeeper mutation: Present in 50–60% of acquired resistance; increases EGFR affinity for ATP relative to 1st-generation TKIs. Treat with osimertinib (3rd-generation TKI active against T790M).
MET amplification: 5–20% of cases; bypass signalling via ERBB3. Treat with MET inhibitors (capmatinib, tepotinib) or clinical trials.
Small cell lung cancer (SCLC) transformation: 5–15%; histological transformation to SCLC with retained EGFR mutation. Treat with SCLC-standard platinum-etoposide chemotherapy.
Clinical approach: Repeat biopsy (tissue or ctDNA) at progression to identify mechanism and guide next-line therapy.

Comprehensive Side Effect Management

Mild

Grade 1–2 Toxicity

Acneiform rash (Grade 1–2), mild diarrhoea (≤4 episodes/day), Grade 1 hepatotoxicity, mild oedema

Setting: Continue treatment with supportive care; topical corticosteroids for rash; loperamide for diarrhoea

Moderate

Grade 3 Toxicity

Grade 3 acneiform rash (extensive, painful), severe diarrhoea (≥7 episodes/day), hepatotoxicity (ALT 5–20× ULN), symptomatic LVEF decline

Setting: Interrupt treatment; dose reduction on resolution; oral antibiotics for rash; IV fluids for diarrhoea; cardiology referral if LVEF decline

Severe

Grade 4 / Life-threatening

ILD (erlotinib), GI perforation (bevacizumab), severe infusion reaction/anaphylaxis, T315I progression (CML), fulminant hepatic failure

Setting: Emergency department / ICU; permanent discontinuation of offending agent; IV corticosteroids for ILD; adrenaline for anaphylaxis

Key Side Effects by Agent

Side Effect	Cetuximab	Trastuzumab	Bevacizumab	Imatinib	Erlotinib
Acneiform rash	✓✓✓	—	—	✓	✓✓✓
Diarrhoea	✓✓	—	✓	✓✓	✓✓
Hypomagnesaemia	✓✓✓	—	—	—	—
Cardiotoxicity	—	✓✓✓	—	—	—
Hypertension	—	—	✓✓✓	—	—
GI perforation	—	—	✓✓	—	—
Oedema	—	—	—	✓✓✓	—
Myalgia/cramps	—	—	—	✓✓✓	—
ILD	—	—	—	—	✓✓
Infusion reaction	✓✓✓	✓✓	✓	N/A (oral)	N/A (oral)
Cytopenias	—	—	—	✓✓	—

✅

Rash as efficacy biomarker: Multiple studies (NCIC CTG BR.21, FLEX, OPUS) have demonstrated that the severity of cetuximab and erlotinib-induced acneiform rash correlates with improved tumour response and overall survival. Grade 2–3 rash is associated with superior outcomes compared to no rash. Prophylactic minocycline 100 mg PO daily reduces rash incidence without compromising efficacy.

Molecular Testing & Companion Diagnostics

Appropriate molecular testing is the prerequisite for targeted therapy. All companion diagnostic testing must be performed at NATA-accredited laboratories. The following MBS item numbers are relevant:

Essential

RAS mutation testing (KRAS/NRAS exons 2, 3, 4)

MBS item 71553 · Required before anti-EGFR therapy (cetuximab, panitumumab) in mCRC · Tumour tissue preferred; ctDNA acceptable if tissue unavailable

Essential

HER2 testing (IHC + FISH)

IHC scored 0–3+; FISH for equivocal (2+) cases · Required for trastuzumab, pertuzumab, T-DM1 · NATA-accredited laboratory

Essential

EGFR mutation testing

Exon 18–21 sequencing · Required before erlotinib/gefitinib in NSCLC · Tumour tissue or ctDNA

Essential

BCR-ABL1 quantitative PCR

International Scale (IS) · Baseline, q3 months in first year, q3–6 months thereafter · CML response monitoring

Available

ABL kinase domain mutation analysis

Sanger sequencing or NGS panel · On imatinib failure or suboptimal response · Guides TKI switch selection

Available

ctDNA (circulating tumour DNA) liquid biopsy

Guardant360, FoundationOne Liquid CDx · Detects emerging resistance mutations (e.g., RAS, T790M) · Useful when tissue re-biopsy not feasible

Available

LVEF assessment (ECHO or MUGA)

MBS item 55114 (ECHO) · Baseline, q3 months during anti-HER2 therapy, 6 months post-completion · Cardiology referral if <50%

Monitoring During Targeted Therapy

Structured monitoring is essential for efficacy assessment, early detection of resistance, and toxicity management.

Anti-EGFR Monitoring (Cetuximab/Panitumumab)

Serum magnesium fortnightly (mandatory — hypomagnesaemia develops in 20–50%); supplement as needed.
Serum calcium and potassium fortnightly.
Skin assessment each visit — grade acneiform rash (CTCAE v5.0).
CT chest/abdomen/pelvis q8–12 weeks for response assessment.
ctDNA RAS mutation monitoring at progression (if previously RAS wild-type).

Anti-HER2 Monitoring (Trastuzumab/Pertuzumab)

LVEF by ECHO or MUGA scan at baseline, q3 months during therapy, and 6 months post-completion.
Hold trastuzumab if LVEF <45%, or 45–49% with ≥10% absolute decline from baseline.
FBC and LFTs prior to each cycle.
CT imaging q9–12 weeks for metastatic disease.

Imatinib Monitoring (CML)

Baseline

FBC (weekly × 1 month, then fortnightly × 1 month, then monthly); LFTs; UEC; BCR-ABL1 IS; bone marrow biopsy (CML phase confirmation)

3 months

BCR-ABL1 qRT-PCR — optimal ≤10% (IS); assess cytopenias

6 months

BCR-ABL1 qRT-PCR — optimal ≤1% (IS)

12 months

BCR-ABL1 qRT-PCR — target MMR (≤0.1%); if failure, ABL kinase domain mutation testing and TKI switch

Ongoing (annually)

BCR-ABL1 qRT-PCR q3–6 months; FBC; LFTs; compliance assessment; consider TFR candidacy if sustained MR4.5 ≥3 years

Erlotinib Monitoring (NSCLC)

CT chest/abdomen/pelvis q6–12 weeks for response.
LFTs at baseline and q4–6 weeks (hepatotoxicity monitoring).
Clinical assessment for ILD symptoms (new dyspnoea, cough, fever) each visit — low threshold for CT chest.
Skin toxicity management — prophylactic minocycline 100 mg PO daily from initiation.
ctDNA EGFR mutation testing at progression (T790M, C797S).

Special Populations

🤰 Pregnancy

All mAbs and TKIs

Category D — teratogenic. Contraception mandatory during therapy and for at least 7 months post-last dose (trastuzumab), 3 months (bevacizumab), or per drug SPC. Pregnancy testing prior to each cycle of IV agents is recommended.

Imatinib

Teratogenic in animal studies (exomphalos, renal agenesis). Discontinue before conception. Dasatinib or interferon-alpha may be considered as bridging if TKI cessation is not feasible.

Erlotinib

Category D — effective contraception required during and for ≥2 weeks after last dose. Advise on non-hormonal contraception due to CYP3A4 interaction with hormonal contraceptives.

👶 Paediatrics

Imatinib

TGA-approved for paediatric Ph+ CML (≥2 years) at 340 mg/m² PO daily (max 600 mg). Growth retardation reported — monitor height/weight. Paediatric haematology MDT involvement essential.

Trastuzumab

Limited paediatric data. Not routinely used in paediatric oncology outside clinical trials.

👴 Elderly (≥70 years)

Imatinib

Well tolerated in elderly CML patients; age alone should not preclude treatment. Monitor for increased fluid retention and oedema. GFR-based dose adjustment may be needed.

Bevacizumab

Higher risk of arterial thromboembolic events in patients ≥65 years. Assess cardiovascular risk before initiation. Caution in those with history of stroke, TIA, or MI.

All agents

Comprehensive geriatric assessment recommended. Polypharmacy review essential due to CYP3A4 interactions with common geriatric medications (statins, calcium channel blockers, anticoagulants).

🫘 Renal Impairment

Imatinib

Dose reduction required: eGFR 20–40 → reduce by 50% (200 mg daily); eGFR <20 → avoid or 100 mg daily with extreme caution. Not dialysable.

Cetuximab, panitumumab

No dose adjustment — large molecules cleared by reticuloendothelial system. However, monitor electrolytes (magnesium, calcium) more frequently in CKD patients.

Erlotinib

No renal dose adjustment — minimally renally cleared.

🫁 Hepatic Impairment

Imatinib

CYP3A4 metabolised — dose reduction to 300 mg in Child-Pugh A; avoid in Child-Pugh B/C. Monitor LFTs closely.

Erlotinib

Use with caution — discontinue if ALT/AST >5× ULN or bilirubin >3× ULN. Consider starting at 75 mg in moderate hepatic impairment.

🛡️ Immunocompromised

All mAbs

mAbs may increase infection risk through ADCC-mediated neutropenia (rare) or immunomodulation. Screen for hepatitis B (HBsAg, anti-HBc) before rituximab-containing regimens (though rituximab is outside this article's scope). No specific infection prophylaxis required for anti-EGFR/anti-HER2/anti-VEGF agents.

Imatinib

Cytopenias (neutropenia Grade 3–4 in 15–45% of accelerated/blast phase) may require growth factor support. Monitor FBC closely.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Aboriginal and Torres Strait Islander peoples experience significant disparities in cancer outcomes, with a 1.4× higher cancer mortality rate compared to non-Indigenous Australians (AIHW 2023). These disparities are driven by later stage at diagnosis, reduced access to optimal treatment including targeted therapies, and systemic barriers to specialist care.

Molecular testing access

Indigenous Australians are less likely to receive timely molecular testing (RAS, EGFR, HER2) due to diagnostic pathway delays, inadequate tissue sampling at peripheral sites, and limited NATA-accredited laboratory access in remote regions. All efforts should be made to expedite companion diagnostic testing and ensure specimen transport logistics are arranged.

Specialist oncology access

Patients in remote and very remote areas face long travel distances to tertiary cancer centres for IV infusions (cetuximab, trastuzumab, bevacizumab). Telehealth oncology consultations and shared-care models with local health services can improve access. Oral TKIs (imatinib, erlotinib) may be more feasible for patients unable to travel for infusion therapy.

PBS and out-of-pocket costs

While most targeted agents are PBS-listed, out-of-pocket costs for associated care (travel, accommodation for treatment, allied health) can be prohibitive. Aboriginal Medical Services (AMS) can assist with Closing the Gap PBS co-payment relief and patient-assisted travel schemes (PATS).

Cultural safety

Treatment decisions should be made in partnership with Indigenous patients and their families, with respect for cultural preferences. Aboriginal Health Workers and Liaison Officers should be involved in care planning. Yarning-based communication and visual aids can support informed consent for complex molecular therapies.

Comorbidity burden

Higher rates of renal impairment (CKD) and hepatic disease in Indigenous populations necessitate careful dose adjustment for imatinib and erlotinib. Baseline renal and hepatic function must be assessed before initiating any TKI.

Support services

Aboriginal and Torres Strait Islander Cancer Care Coordinators (where available) provide navigation support. Cancer Australia's Optimal Care Pathway for Aboriginal and Torres Strait Islander people with cancer should guide service delivery. Referral to local AMS for psychosocial support, smoking cessation, and nutritional support is recommended.

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Key resource: Cancer Australia's National Aboriginal and Torres Strait Islander Cancer Framework (2015) and Optimal Care Pathway for Aboriginal and Torres Strait Islander People with Cancer (2nd edition, 2024) provide comprehensive guidance on equitable cancer care delivery. All treating teams should be familiar with these resources.

Quick Reference — Treatment Selection

RAS WT left-sided mCRC (1st line)

FOLFOX or FOLFIRI + Cetuximab or Panitumumab

Until progression or toxicity

Anti-EGFR superior to anti-VEGF in left-sided primaries

RAS WT right-sided mCRC (1st line)

FOLFOX or FOLFIRI + Bevacizumab

Until progression or toxicity

Anti-VEGF preferred regardless of RAS status in right-sided primaries

HER2+ early breast cancer (adjuvant)

Trastuzumab ± Pertuzumab (with chemo backbone)

12 months (18 cycles q3w)

LVEF monitoring q3 months; consider T-DM1 if residual disease post-neoadjuvant

HER2+ metastatic breast cancer (1st line)

Trastuzumab + Pertuzumab + Docetaxel

Until progression

CLEOPATRA regimen; 2nd-line → T-DM1

Ph+ CML chronic phase (1st line)

Imatinib 400 mg PO daily

Indefinite (or TFR if eligible)

BCR-ABL1 IS q3 months; switch to 2nd-gen TKI if failure

EGFR-mutated advanced NSCLC (1st line)

Erlotinib 150 mg PO daily (or osimertinib preferred)

Until progression

Osimertinib now preferred 1st-line (FLAURA trial); erlotinib 2nd/3rd generation options

Imatinib-resistant CML (T315I mutation)

Ponatinib 45 mg PO daily (reduce to 15 mg if achieved response)

Until progression or toxicity

Arterial occlusive events require cardiovascular risk assessment

📚 References

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2. Australian Institute of Health and Welfare (AIHW). Cancer in Australia 2023. Cat. no. CAN 144. Canberra: AIHW; 2023.
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4. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065–1075.
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6. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer (CLEOPATRA): overall survival results from a double-blind randomised placebo-controlled phase 3 study. Lancet Oncol. 2013;14(6):461–471.
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11. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC (FLAURA). N Engl J Med. 2020;382(1):41–50.
12. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer (AVF2107g). N Engl J Med. 2004;350(23):2335–2342.
13. Cancer Australia. National Aboriginal and Torres Strait Islander Cancer Framework. Surry Hills, NSW: Cancer Australia; 2015.
14. Cancer Australia. Optimal Care Pathway for Aboriginal and Torres Strait Islander People with Cancer. 2nd edition. Surry Hills, NSW: Cancer Australia; 2024.
15. Pharmaceutical Benefits Scheme (PBS). Australian Government Department of Health and Aged Care. Available from: pbs.gov.au. Accessed 2024.
16. Australian Commission on Safety and Quality in Health Care (ACSQHC). National Safety and Quality Health Service Standards. 2nd edition. Sydney: ACSQHC; 2021.