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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

Conclusions and Clinical Implications

Matthew Gubens, MD, MS, FASCO:
HER2 is an important and actionable biomarker in NSCLC. Therefore, it is critical that tumor-specific HER2 status, particularly mutation and overexpression (IHC 3+), is determined at the time of advanced disease diagnosis so that molecular findings can be promptly and appropriately acted upon to achieve optimal treatment outcomes. ADCs are a novel class of agents that deliver targeted chemotherapy to cancer cells and possibly the neighboring cells, known as the bystander effect. Specifically, T-DXd has demonstrated good clinical activity in HER2-mutated and HER2-overexpressed (IHC 3+) NSCLC, and it is now approved in these settings in the United States and in the European Union. As we become more accustomed to using T-DXd for our patients with HER2-positive NSCLC, we need to be better aware and mindful of how to promptly recognize and appropriately manage the associated AEs, especially ILD/pneumonitis, congestive heart failure, and neutropenia, even when the patient is still asymptomatic. We also have to understand the importance of patient and caregiver education, as this aspect is very important for timely AE management.

T-DXd is not yet available in the first-line setting for patients with HER2-altered advanced NSCLC. However, it is currently being investigated both as monotherapy and in combination with other agents in the first-line setting for these patients. With the approvals and availability of non-ADC HER2-directed agents (zongertinib and sevabertinib) in NSCLC, we will encounter challenges in knowing when to use these agents and how well to optimally sequence them. With more available data from the ongoing clinical trials, we will understand these agents better and be more equipped in efficiently and effectively using and sequencing these agents for our patients with advanced NSCLC with HER2 alterations.

Estelamari Rodriguez, MD, MPH:
I agree. The development of ADCs has revolutionized the treatment landscape for patients with cancer, in general. It is important to point out that T-DXd has demonstrated intracranial activity. With a better understanding of the CNS efficacy of and durability of response to T-DXd in patients with NSCLC and brain metastasis, the use of targeted radiation therapy to the brain will be reduced, and so will the associated toxicities. This has the potential to lead to substantial improvements in the quality of life of our patients.

I am particularly excited about the different combination approaches under investigation and the potential of moving these HER2-directed ADCs and TKIs to the frontline setting. As we await the results from these ongoing trials, I remain hopeful that the future for our patients with HER2-positive NSCLC, whether those with disease harboring HER2 overexpression, HER2 amplification, and/or HER2 mutation(s), will become even brighter.

Matthew Gubens, MD, MS, FASCO:
With more time, we will get more real-world data about how the sequencing of the available HER2-directed agents works most effectively. We will have more evidence in various cohorts of patients with HER2-altered advanced NSCLC, including patients who were previously exposed to an ADC before receiving a TKI and vice versa. We will also have more information about the efficacy and safety of these agents when used in combination with other agents that have different mechanisms of action. Truly, this is an exciting and rapidly growing space. As we continue to learn more about different approaches to improve outcomes for our patients with HER2-positive advanced NSCLC, I have high hopes for the future.

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