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HER2 Altered NSCLC

CE / CME

HER2-Directed ADCs in HER2-Mutant and HER2-Overexpressing NSCLC

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Nurse Practitioners/Nurses: 1.00 Nursing contact hour

Released: March 18, 2026

Expiration: September 17, 2026

Matthew Gubens
Matthew Gubens, MD, MS, FASCO
Estelamari Rodriguez
Estelamari Rodriguez, MD, MPH
CME/CE Information

Activity

Progress
1 2 3
Course Completed

ADCs: Key Principles

Matthew Gubens, MD, MS, FASCO:
The use of ADCs to deliver drugs to target cells is associated with improved safety and efficacy.24-28 ADCs comprise a monoclonal antibody that is selective for an antigen with high copy numbers on the target tumor cell, and it is linked to a small molecule cytotoxic drug via a stable linker. The strategy to specifically target abundantly expressed antigens on tumor cells minimizes the internalization of the cytotoxic drug by normal cells upon ADC binding. The cytotoxic drug payload is highly potent with subnanomolar activity. Examples of payloads include microtubule inhibitors such as maytansines, as used in the conjugation chemistry for T-DM1, and DNA-damaging agents such as topoisomerase I inhibitors, as used in the conjugation chemistry for T-DXd.

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ADC Mechanism of Action 

Matthew Gubens, MD, MS, FASCO:
To reiterate, the conjugation chemistry for ADCs includes a monoclonal antibody that selectively binds to a specific and highly expressed target on the surface of the malignant tumor cell. Once it gets internalized into the cell, it releases its cytotoxic payload that, in turn, triggers tumor cell death.29-31 For some ADCs, the cytotoxic payload also is able to penetrate the cell membrane, and so, it has the ability to act on adjacent cancer cells to elicit a bystander effect, thereby killing the adjacent cancer cell.32 T-DXd is an ADC with bystander effects, so even if a neighboring tumor cell does not robustly express HER2, T-DXd has the ability to trigger cell death via this bystander effect. By contrast, the payload for T-DM1 does not have this capability.

Patient-specific variables relevant to the efficacy of ADCs include the level of epitope expression in the tumor tissue vs other tissues and the stability of epitope expression in each patient. The prior treatment received by the patient or current therapy that the patient is receiving may affect treatment resistance or drug uptake. Also, the disease-specific biology, such as sensitivity of the cancer cell to the cytotoxic payload, may influence the effectiveness of an ADC on an individual basis.30,33,34

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