Antibody-Drug Conjugates: SCE Oncology Exam Research Update

Antibody-Drug Conjugates (ADCs): The Oncology Revolution for SCE Candidates

The landscape of oncology is perpetually evolving, moving rapidly towards highly targeted and precise treatments. For candidates preparing for the Specialty Certificate Examination (SCE) in Medical Oncology, staying abreast of these cutting-edge developments is not just recommended—it’s mandatory for success. One of the most significant recent breakthroughs involves Antibody-Drug Conjugates (ADCs), often referred to as 'guided missiles' or 'Trojan horses' in cancer therapy.

Why ADCs are High-Yield for Your SCE

ADCs bridge the gap between targeted therapy (antibodies) and traditional chemotherapy (cytotoxic drugs), offering enhanced efficacy with potentially fewer systemic side effects. The recent proliferation of approved ADCs and their expanded indications mean questions about their mechanism, specific drug names, indications, and, crucially, their unique adverse effect profiles, are highly likely to appear in the SCE.

1. Understanding the ADC Architecture

Every ADC consists of three critical components that candidates must internalize:

1. Monoclonal Antibody (mAb): This acts as the targeting system. It recognizes and binds specifically to an antigen highly expressed on the surface of cancer cells (e.g., HER2, Trop-2, Nectin-4).

2. Cytotoxic Payload (Toxin): The potent chemotherapy agent. These are often highly toxic compounds (e.g., microtubule inhibitors like monomethyl auristatin E [MMAE] or topoisomerase I inhibitors like deruxtecan) that would be too harmful for systemic use alone.

3. Linker: The crucial connector that tethers the payload to the antibody. The linker must be stable in the circulation but cleavable once internalized by the cancer cell, allowing the release of the payload.

Mechanism of Action Simplified: The ADC binds to the tumour antigen, the complex is internalized via endocytosis, the linker is cleaved (either enzymatically or non-enzymatically depending on the linker type) within the lysosome, and the potent cytotoxic payload is released to kill the cancer cell.

2. Key Recent ADC Advances to Master for SCE

SCE questions test knowledge of approved agents and common off-label uses based on robust trial data. Focus on these agents and their expanded roles:

A. Trastuzumab Deruxtecan (T-DXd)

• Target: HER2 (Human Epidermal Growth Factor Receptor 2).

• Payload: Deruxtecan (a topoisomerase I inhibitor).

• Indications:

  • Breast Cancer: Now a critical option for HER2-positive metastatic breast cancer (often post-T-DM1). Crucially, T-DXd has also shown breakthrough efficacy in HER2-low metastatic breast cancer—a new classification that significantly expands its use.

  • Gastric/Gastroesophageal Junction Cancer: Used in advanced settings.

  • Non-Small Cell Lung Cancer (NSCLC): Approved for HER2-mutant metastatic NSCLC.

• High-Yield Adverse Effect (AE): Interstitial Lung Disease (ILD)/Pneumonitis. This is a major concern with T-DXd and requires careful monitoring, prompt intervention (corticosteroids), and dose modification/discontinuation. SCE candidates must recognize the signs and symptoms (new or worsening cough, dyspnoea, hypoxia) and understand the management protocol.

B. Sacituzumab Govitecan (SG)

• Target: Trop-2 (Trophoblast cell-surface antigen 2).

• Payload: SN-38 (an active metabolite of Irinotecan, a topoisomerase I inhibitor).

• Indications:

  • Triple-Negative Breast Cancer (TNBC): A standard of care in refractory metastatic TNBC.

  • Hormone Receptor-Positive/HER2-Negative Breast Cancer: Expanding use in pre-treated metastatic disease.

  • Urothelial Carcinoma: Used in advanced, previously treated urothelial cancer.

• High-Yield AE: Neutropenia and Diarrhoea (due to the SN-38 payload). Candidates should be prepared to manage neutropenic fever and chemotherapy-induced diarrhoea effectively.

C. Enfortumab Vedotin (EV)

• Target: Nectin-4 (highly expressed in urothelial cancer).

• Payload: Monomethyl Auristatin E (MMAE, a microtubule inhibitor).

• Indication: Locally advanced or metastatic urothelial carcinoma, often in combination with immunotherapy (PD-1 inhibitors).

• High-Yield AE: Peripheral Neuropathy (due to the MMAE payload), skin reactions (rash), and hyperglycemia. These are distinct from the AEs of other ADCs.

3. ADC Toxicities: A Specialist’s Perspective

For SCE success, moving beyond efficacy and mastering the safety profile is crucial. The toxicity profile of an ADC is determined by both the target (antibody) and the payload. Always consider:

The Critical Concept: Bystander Effect

Some newer ADCs utilize linkers that allow the payload to diffuse out of the target cell and kill surrounding tumour cells, even if they express low levels of the antigen (the 'bystander effect'). This is a key reason for the efficacy of agents like T-DXd in HER2-low cancers. Understanding this concept helps explain the superior potency of these newer generation agents.

Conclusion for SCE Preparation

ADCs represent a pillar of modern oncology practice. To excel in the SCE, you must be able to confidently discuss the mechanism, name the three key components, list the main indications (especially the newer expanded ones like HER2-low breast cancer), and differentiate the critical, often life-threatening, adverse effects associated with each major agent. Incorporate the latest clinical trial data (e.g., DESTINY-Breast04, ASCENT) into your revision, focusing on how these trials led to the current guidelines for ADC usage.