HER2-targeted therapies

Mechanism & Class Overview

• Class mechanism: Target the extracellular HER2 (ErbB2) domain or the tyrosine kinase domain; ↓ growth signaling (MAPK, PI3K/AKT), and antibodies induce ADCC.
• Resistance: ↓ HER2 binding activity or expression, PTEN loss, PI3K/AKT pathway activation, HER2 L755S mutation, HER3/HER4 upregulation, T-DM1 resistance (↓ internalization, ↓ lysosomal action, p95HER2 (truncated HER2 lacking the extracellular domain; not a mutation), ↑ drug efflux).

Cardiotoxicity Monitoring (class theme)

• HER2-directed antibodies and TKIs cause a typically reversible, non-dose-cumulative decline in LVEF (distinct from anthracycline cardiotoxicity). Obtain a baseline TTE and repeat roughly q3 months. Risk rises with concurrent or prior anthracyclines and taxanes and with dual HER2 blockade (trastuzumab + pertuzumab). General hold thresholds: trastuzumab if LVEF drops ≥16 points, or falls below LLN with a ≥10-point drop; pertuzumab if LVEF <40%, or 40 to 45% with a ≥10-point drop.

Anti-HER2 Monoclonal Antibodies

Trastuzumab (Herceptin)

• Mechanism: mAb against HER2 extracellular domain IV → ↓ HER2 receptor expression, ↓ intracellular signaling, induces ADCC.
• Indications: HER2+ breast cancer (metastatic and adjuvant), HER2+ gastric cancer. Trastuzumab-pkrb (Herzuma) is a biosimilar.
• Toxicities: Cardiotoxicity (reversible; baseline/q3mo TTE; hold ≥4 wk if LVEF drops ≥16 points, or falls below institutional LLN with a ≥10-point drop; ↑ risk with anthracyclines, taxanes, and trastuzumab + pertuzumab; monitor for edema), infusion reactions (manage with diphenhydramine/acetaminophen ± steroids; rarely severe/ICU-level), myelosuppression, myalgias, headache, cough, rhinitis, sinusitis. Avoid in pregnancy (boxed warning, embryo-fetal toxicity: oligohydramnios, pulmonary hypoplasia, neonatal death); no letter category in current labeling.

Pertuzumab (Perjeta)

• Mechanism: IgG1 mAb against HER2 extracellular domain II (different epitope from trastuzumab); prevents HER2 heterodimerization with EGFR/HER3/HER4 → ↓ MAPK and PI3K signaling; induces ADCC.
• Indications: HER2+ breast cancer (used with trastuzumab ± chemotherapy for improved efficacy).
• Toxicities: Diarrhea (common; antidiarrheals), cardiotoxicity (reversible; baseline/q3mo TTE; hold if LVEF <40%, or 40 to 45% with a ≥10-point drop (early breast cancer: <50% with a ≥10-point drop)), infusion reactions, myelosuppression. Avoid in pregnancy (as with trastuzumab). Resistance can include HER2 L755S.

HER2-Targeted TKIs

Lapatinib (Tykerb)

• Mechanism: Reversible small-molecule TKI; inhibits HER2 and EGFR tyrosine kinases → ↓ ErbB signaling.
• Indications: HER2+ breast cancer: with capecitabine after prior anthracycline, taxane, and trastuzumab; with letrozole for HR+/HER2+ postmenopausal disease (no prior trastuzumab required)
• Pharmacokinetics/interactions: CYP3A4 substrate. Levels ↑ by inhibitors (azoles, erythromycin/clarithromycin) and ↓ by inducers (phenytoin, carbamazepine, rifampin, phenobarbital, St. John's Wort). Reduces warfarin metabolism; reduce starting dose only in severe (Child-Pugh C) hepatic impairment; discontinue without rechallenge for severe treatment-emergent hepatotoxicity; take 1h before or after food.
• Toxicities: Diarrhea (dose-limiting; severe in ~5%; antidiarrheals), rash, nausea, hepatotoxicity (↑ LFTs), cardiotoxicity (↓ LVEF; baseline TTE), QTc prolongation, myelosuppression, hand-foot syndrome.

Neratinib (Nerlynx)

• Mechanism: Irreversible pan-HER TKI; inhibits HER1, HER2, HER4.
• Indications: HER2+ early-stage breast cancer (extended adjuvant after trastuzumab), metastatic HER2+ breast cancer.
• Toxicities: Diarrhea (very common, often severe; prophylactic antidiarrheals recommended), rash, nausea, hepatotoxicity, ↓ LVEF (monitor TTE).

Tucatinib (Tukysa)

• Mechanism: Selective HER2 TKI; oral, brain-penetrant.
• Indications: HER2+ metastatic breast cancer (with trastuzumab + capecitabine).
• Toxicities: Diarrhea, nausea, fatigue, rash, hepatotoxicity. Brain penetration offers CNS benefit. Less cardiotoxicity than other HER2 TKIs. (Note: tucatinib is a strong CYP3A4 inhibitor, a source of drug interactions.)

ADCs Targeting HER2

Trastuzumab emtansine (T-DM1, Kadcyla)

• Mechanism: Trastuzumab linked to several molecules of DM1 (a maytansinoid microtubule inhibitor); trastuzumab blocks HER2 signaling and DM1 binds the plus ends of microtubules to halt cell division after HER2 binding and internalization. Resistance via ↓ HER2 expression, ↓ lysosomal action, p95HER2 (truncated HER2 lacking the extracellular domain; not a mutation).
• Indications: HER2+ metastatic breast cancer (trastuzumab-refractory), HER2+ early-stage breast cancer (adjuvant if residual disease after neoadjuvant therapy).
• Toxicities: Thrombocytopenia (monitor CBC), hepatotoxicity (↑ LFTs), peripheral neuropathy, left ventricular dysfunction (monitor TTE), nausea.

Trastuzumab deruxtecan (T-DXd, Enhertu)

• Mechanism: Trastuzumab linked to deruxtecan (a topoisomerase I inhibitor, exatecan derivative, ~10× more potent than SN-38); high drug-to-antibody ratio and bystander killing via membrane-permeable payload.
• Indications: HER2+ metastatic breast cancer (T-DM1-refractory or prior trastuzumab), HER2-low breast cancer, gastric cancer.
• Toxicities: Myelosuppression (monitor CBC), interstitial lung disease/pneumonitis (~12%, ~0.8 to 0.9% fatal; baseline and serial monitoring), cardiotoxicity (↓ LVEF; baseline TTE; hold if LVEF <40% or drops >20%), infusion reactions, nausea, diarrhea, neuropathy, hepatotoxicity.

Other Anti-HER2 Agents

Margetuximab (Margenza)

• Mechanism: Next-generation anti-HER2 mAb with an engineered Fc region for enhanced ADCC.
• Indications: HER2+ metastatic breast cancer (with chemotherapy).
• Toxicities: Cardiotoxicity (monitor LVEF), infusion reactions, myelosuppression, myalgias.

2026 update: expanded HER2-targeted landscape

Trastuzumab deruxtecan (T-DXd): new indications

• DESTINY-Breast04 (Modi NEJM 2022; mature 2024): established HER2-low (IHC 1+ or 2+/ISH-negative) as an actionable subset; mOS 23.4 vs 16.8 mo in HR+/HR-negative combined.
• DESTINY-Breast06 (Bardia NEJM 2024): T-DXd vs chemo in HR+ MBC HER2-low or HER2-ultralow (IHC 0 with membrane staining) post-endocrine, chemo-naive; mPFS 13.2 vs 8.1 mo. FDA Jan 2025 sBLA extended to HER2-ultralow, the first ADC into the IHC 0 subgroup.
• DESTINY-PanTumor02 (Meric-Bernstam JCO 2024): tumor-agnostic HER2 IHC 3+ solid tumors (cervical, endometrial, ovarian, biliary, urothelial, other). Endometrial ORR 84%. FDA Apr 5, 2024 tumor-agnostic accelerated approval.
• DESTINY-Lung02: HER2-mutant (kinase-domain, mostly ex20) NSCLC after prior systemic therapy; FDA accelerated approval Aug 2022 (still accelerated).
• DESTINY-Gastric04 (Shitara NEJM 2025): T-DXd vs paclitaxel + ramucirumab 2L HER2+ gastric/GEJ; PFS/OS positive.
• HER2+ breast expansion (FDA Dec 2025 to May 2026): T-DXd + pertuzumab 1L HER2+ MBC (DESTINY-Breast09); neoadjuvant T-DXd then THP for stage II to III (DESTINY-Breast11); adjuvant T-DXd for residual invasive disease after neoadjuvant therapy (DESTINY-Breast05).

Zanidatamab (Ziihera): biparatopic anti-HER2 mAb

• Mechanism: bispecific-biparatopic, two arms target different HER2 epitopes (ECD IV like trastuzumab + ECD II like pertuzumab) → enhanced HER2 clustering, internalization, ADCC.
• HERIZON-BTC-01 (Harding Lancet Oncol 2023): HER2 IHC 3+ or 2+/FISH+ unresectable/metastatic BTC post-gem/cis; cohort ORR 41%. FDA Nov 20, 2024 accelerated approval for IHC 3+ only (label ORR 52%), first HER2-directed therapy for BTC.
• HERIZON-GEA-01 (Shitara NEJM 2026): zanidatamab + chemo (+/- tislelizumab) vs trastuzumab + chemo 1L HER2+ gastric/GEJ; PFS positive. FDA Aug 2026 1L approval (with tislelizumab for IHC 3+ or 2+/ISH+; without it for IHC 3+).

Tucatinib: HER2CLIMB program mature

• HER2CLIMB (Murthy NEJM 2020; final OS Curigliano Ann Oncol 2022): tucatinib + trastuzumab + capecitabine vs T + capecitabine in HER2+ MBC (including brain mets) after prior trastuzumab, pertuzumab, and T-DM1. mOS 24.7 vs 19.2 mo at final analysis (HR 0.73; 21.9 vs 17.4 mo at primary analysis); brain-mets subset CNS-PFS 9.9 vs 4.2 mo (conventional PFS 7.6 vs 5.4 mo). Confirmed intracranial activity.
• HER2CLIMB-02 (Hurvitz SABCS 2023, Ann Oncol 2026): tucatinib + T-DM1 vs T-DM1 in HER2+ MBC previously treated with trastuzumab and a taxane (any setting); mPFS 9.5 vs 7.4 mo (HR 0.76). CNS mPFS benefit; regulatory filing pending.

Trastuzumab duocarmazine (SYD985 / Byondis)

• TULIP (Turner JCO 2025): SYD985 vs physician's choice (trastuzumab-based combo or lapatinib + capecitabine) in HER2+ MBC after ≥2 HER2 regimens or prior T-DM1; mPFS 7.0 vs 4.9 mo. EMA marketing authorisation application withdrawn Sept 2023 (no CHMP positive opinion). Ocular toxicity distinctive (keratopathy).

ADC-related class safety

• ILD/pneumonitis: deruxtecan class-effect (T-DXd, Dato-DXd). Baseline chest CT; hold for G≥1; permanent discontinuation for G≥2.