Insights: NCCN Adds Zongertinib as Preferred Therapy for HER2-Mutant NSCLC

In an interview with Pharmacy Times®, Joshua K. Sabari, MD, assistant professor in the department of medicine at NYU Grossman School of Medicine, explained how the recent National Comprehensive Care Network (NCCN) guideline update naming zongertinib (Hernexeos; Boehringer Ingelheim) as a preferred therapy marks a pivotal shift in treating HER2-mutant non-small cell lung cancer (NSCLC). Sabari highlighted zongertinib’s superior efficacy, tolerability, and patient quality of life compared to antibody-drug conjugates, as well as its role in sequencing treatment decisions. Sabari also noted that he prefers to start with zongertinib in the second-line setting and reserve trastuzumab deruxtecan (Enhertu; AstraZeneca) for later lines.

This transcript was edited for grammar and clarity using artificial intelligence.

Pharmacy Times: Given the recent NCCN guideline inclusion of zongertinib tablets as a preferred therapy for HER2-mutant NSCLC, what impact do you foresee this having on the treatment landscape, especially compared to existing options like antibody-drug conjugates?

Joshua K. Sabari, MD: So first off, Luke, thanks for having me. HER2-mutant NSCLC occurs in about 2% to 4% of NSCLC cases. It’s a common entity, but I think an underappreciated one. Historically, we haven’t had any FDA-approved targeted therapies for HER2 mutations. We’ve had antibody-drug conjugates, or targeted chemotherapy, in the second-line setting, but not tyrosine kinase inhibitors (TKIs). We just saw the approval of zongertinib, a HER2-specific TKI, on August 8, 2025. More recently, the NCCN updated its guidelines to include zongertinib as a preferred subsequent therapy option for patients with advanced or metastatic non-small cell lung cancer harboring HER2 mutations who have received prior systemic therapy.

I think this is a game changer for patients—not only in terms of efficacy, with a 71% response rate, a progression-free survival of 12.4 months, and a duration of response of 14.1 months—but also in quality of life. Rates of toxicity with zongertinib are quite low. Rates of grade 3 diarrhea are about 1%, and we don’t see significant dermatologic side effects such as rash. The rates of pneumonitis, or lung inflammation, are essentially zero. When compared to an antibody-drug conjugate such as trastuzumab deruxtecan, which was previously the standard of care, the differences are clear. With trastuzumab deruxtecan, we see chemotherapy-like toxicities, including neutropenia, anemia, fatigue, nausea, and a 15% rate of interstitial lung disease. The approval of a true targeted therapy like zongertinib is a game changer for both efficacy and safety.

Pharmacy Times: The NCCN Guidelines list Hernexeos as a "preferred subsequent therapy." From a clinical perspective, what does this specific designation mean, and how does it influence the sequence of treatments you would consider for a patient?

Sabari: Standard of care in the frontline setting for patients newly diagnosed with a HER2 mutation unfortunately remains chemotherapy or chemotherapy plus immunotherapy. There’s a lot of controversy here, but in a patient who is a never-smoker with an HER2 mutation, I generally give carboplatin and pemetrexed, plus or minus a drug like bevacizumab (Avastin; Genentech). I do not treat with immunotherapy in these cases, although it is included in the label. Median progression-free survival in the frontline setting is about 7 to 8 months.

Now, in the second-line setting, we have accelerated approvals for both zongertinib, the HER2-specific TKI, and trastuzumab deruxtecan, the HER2-directed antibody-drug conjugate. With zongertinib now listed as a preferred therapy in the NCCN guidelines, either drug can be used in this setting. My preference is to use zongertinib first because of its superior efficacy, cross-trial comparisons, and tolerability. I would reserve trastuzumab deruxtecan for later-line therapy.