Additional Advances in HER2-Mutated NSCLC With Julia Kathleen Rotow, MD

i3 Health recently released the online educational activity titled, “What’s New with HER2: Charting New Paths in NSCLC Care,” consisting of two modules exploring the role of HER2 in this disease. In this additional advances interview, the chair of the activity, Dr. Julia Kathleen Rotow, the Clinical Director of Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and an Assistant Professor of Medicine at Harvard Medical School, provides a comprehensive update on the rapidly evolving landscape of HER2-mutated non–small cell lung cancer (NSCLC) treatment, the importance of continuing medical education in the context of HER2-mutated NSCLC, and the future direction of HER2-targeted therapies.

Click below to complete the full activities, available until December 5, 2025!

Module 1:

Module 2:

Emerging Advances in HER2-Directed Therapies

Dr. Rotow emphasizes that HER2 is a “relatively new actionable target for this particular patient population,” noting that the field is certainly fast-moving with ongoing advancements and emerging options for patients with HER2-driven NSCLC. HER2 mutations, while present in only a small percentage of lung adenocarcinomas, have become increasingly significant as new targeted therapies emerge. Dr. Rotow explains, “We have an ever-expanding list of actionable therapeutic targets which lend themselves to more personalized forms of therapy beyond, say, standard immunotherapy or standard chemo-immunotherapy in the frontline setting. HER2 mutations are one of these actionable drivers.”

The Significance of HER2 Mutations in NSCLC

Dr. Rotow stresses the need for comprehensive and up-to-date biomarker profiling, as “there are going to be patients who had their genomic profiling done in a more limited fashion several years ago, and that profiling is no longer comprehensive by modern standards.” She urges clinicians to “look back and double check. Was their original genomic profiling and biomarker profiling more broadly comprehensive by modern standards? If not, try to fill those gaps with supplementary testing.”

Recent Clinical Trial Data

Dr. Rotow details recent updates from major oncology meetings, including from the American Association for Cancer Research (AACR) in April and the American Society of Clinical Oncology (ASCO) in June, as well as new publications in the New England Journal of Medicine. Dr. Rotow discusses two key agents:

Zongertinib: A selective HER2 inhibitor designed to minimize epidermal growth factor receptor (EGFR) wild-type toxicities such as diarrhea and rash. Dr. Rotow reports, “This showed some updated efficacy data. It notably showed an overall response rate of just over 70% and a disease control rate of 96%. These are the kind of numbers we want when we’re talking about potent selective tyrosine kinase inhibitor (TKI)–based treatments in lung cancer.”
Sevabertinib: Another HER2 inhibitor, which is both an EGFR and HER2 inhibitor, for previously treated patients. Dr. Rotow notes, “Here, the response rates were all around 60%, a little better for the ES domain mutations, maybe a little better for a small first-line cohort.”

A key insight is the heterogeneity of HER2 mutations. “HER2 mutations are interesting in that they are more heterogeneous than some of the actionable mutation targets that we look at in lung cancer,” Dr. Rotow explains. Response rates are higher for tyrosine kinase domain (TKD) mutations, with “response rates down to 30% for other less common HER2 mutations” outside the TKD.

The Value of Educational Activities in Oncology

Dr. Rotow underscores the challenge that clinicians face in keeping up with the “immense amount of information that’s coming in all directions.” She notes, “I work as a subspecialist in lung cancer, and even in that area, the amount of new data to integrate into optimal clinical practice can be overwhelming.” For clinicians who must also cover other solid tumors and hematologic malignancies, the need for concise, high-yield educational programs is even greater. Dr. Rotow states, “Certainly, these sorts of programs that can condense and provide the Reader’s Digest version of the key updates are really helpful to all of us in clinical practice.”

Anticipated Changes in Standard of Care

Regarding the future of HER2-directed therapies in NSCLC. Dr. Rotow expresses optimism about the imminent approval of HER2 TKIs, stating, “I absolutely do expect that we’re going to see a HER2 TKI receive FDA approval and become a new standard of care, at least in patients who acquire platinum-based chemotherapy in lung cancer.” She highlights the compelling data for taletrectinib, noting, “With the response rate of 70% and progression-free survival of a little over a year, I think that’s going to become a very compelling option.” The convenience of oral TKIs, which patients can take at home, is also emphasized as an attractive feature for both patients and providers.

Front-Line Therapy and Ongoing Trials

A key question is whether HER2-directed therapies will move into the front-line setting. Dr. Rotow points out, “All of the trials I talked about were for previously treated patients, and that was defined as prior platinum doublet chemotherapy.” However, she notes that three key front-line trials are ongoing, each comparing HER2-directed treatments to chemoimmunotherapy:

The DESTINY-Lung04 trial, comparing trastuzumab deruxtecan—an antibody-drug conjugate (ADC)—to chemoimmunotherapy in the first-line setting.
The Beamion LUNG-2 trial, comparing first-line zongertinib to chemoimmunotherapy.
The SOHO-2 trial, comparing first-line sebavertinib to chemoimmunotherapy.

Dr. Rotow explains, “These may help us to better define the extent of what I hope will be advantage in the front-line setting to a directed therapy.” She also anticipates that, given the strength of the TKI data, “we’re going to see a lot of off-label frontline use simply weighing quality of life and relative efficacy data that we’ve seen with chemoimmunotherapy.” Ultimately, these decisions will depend on “risk-benefit discussions between patients and other individual physicians.”

The Critical Role of Biomarker Profiling and Clinical Trials

Dr. Rotow reiterates the “critical nature and increasingly critical nature of comprehensive biomarker profiling in lung cancer.” She emphasizes that the discussed therapies are available in clinical trials, not through standard of care, and encourages both patients and physicians to consider clinical trial participation. “Any center that runs trials is always really excited and happy to see patients to talk about all available potential options and help people access whatever might be the right treatment for them.”

Key Takeaways

HER2 is an emerging actionable target in NSCLC, with new therapies rapidly advancing the field.
Two main classes of HER2-targeted therapies—ADCs and TKIs—are showing significant clinical activity, though TKIs are not yet FDA-approved.
Recent clinical trial data demonstrate high response rates for selective HER2 TKIs, especially in patients with tyrosine kinase domain mutations (up to 71% overall reponse rate and 96% disease control rate).
HER2 mutations are heterogeneous, and response rates vary by mutation type, with lower efficacy seen in non-TKD mutations and in heavily pretreated patients.
Comprehensive, up-to-date biomarker profiling is essential to identify eligible patients and optimize treatment planning.
All current HER2 TKI options are available only through clinical trials; clinicians should actively consider trial enrollment for eligible patients.
Ongoing education and engagement with new data are critical for oncology professionals to deliver the best care in this evolving landscape.

All oncology physicians, nurses, and other members of the care team are encouraged to engage with this activity to stay at the forefront of HER2-driven NSCLC care and to help bring the latest advances to their patients.

About Dr. Rotow

Julia Kathleen Rotow, MD, is the Clinical Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and an Assistant Professor of Medicine at Harvard Medical School. She specializes in thoracic oncology, and her research interests include the development of targeted therapies and immunotherapies for the treatment of oncogene-driven lung cancer. Dr. Rotow has published numerous articles in peer-reviewed journals.