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HER2 Altered Advanced NSCLC
FAQs: Management of HER2-Altered Advanced NSCLC

Released: April 06, 2026

Matthew Gubens
Matthew Gubens, MD, MS, FASCO
Estelamari Rodriguez
Estelamari Rodriguez, MD, MPH
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Key Takeaways
  • T-DXd is the only HER2-directed agent with approval for use in patients with HER2-overexpressing (IHC 3+) advanced NSCLC.
  • On February 26, 2026, the FDA granted accelerated approval to zongertinib for an expanded indication in the first-line setting for patients with advanced NSCLC harboring HER2 TKD-activating mutations.
  • T-DXd, zongertinib, and sevabertinib are preferred second-line options for the treatment of patients with HER2 mutation–positive NSCLC after first-line platinum-based chemotherapy with or without an immune checkpoint inhibitor.

In this commentary, Matthew Gubens, MD, MS, FASCO, and Estelamari Rodriguez, MD, MPH, address key questions posed by the audience during a recent webinar titled, “Unlocking the Full Potential of HER2-Directed ADCs in HER2-Mutant and Overexpressing Lung Cancer: Testing Applications, Data Insights, and Effective Decision-making for Patient-Centric Care”. During this webinar, Dr Gubens and Dr Rodriguez reviewed the rationale for targeting HER2 in non-small-cell lung cancer (NSCLC), optimal testing strategies for HER2, data on HER2-directed antibody–drug conjugates (ADCs) in NSCLC, and the practical applications of HER2-targeted therapy and emerging HER2-directed approaches in NSCLC.

What are the best practices for sequencing trastuzumab deruxtecan (T-DXd), zongertinib, and sevabertinib, now that all 3 HER2-directed agents are available for patients with advanced NSCLC? 

Matthew Gubens, MD, MS, FASCO:
T-DXd, zongertinib, and sevabertinib are currently FDA approved for patients with HER2-altered advanced NSCLC. Both zongertinib and sevabertinib are TKIs with approval for patients with HER2 mutation–positive NSCLC only. T-DXd, an ADC, is the only HER2-directed agent with approval for use in patients with HER2-overexpressing (IHC 3+) advanced NSCLC and/or those with activating HER2 mutations. Therefore, for patients with HER2 overexpressing unresectable or metastatic NSCLC who have received prior systemic treatment, the clear-cut second-line treatment option is T-DXd, especially if the patient has no known or suspected cardiac dysfunction or interstitial lung disease (ILD)/pneumonitis, conditions which may make the choice to recommend T-DXd challenging.

On February 26, 2026, the FDA granted accelerated approval to zongertinib for an expanded indication for adults with unresectable or metastatic NSCLC whose tumors have HER2 tyrosine kinase domain (TKD)–activating mutations, as detected by an FDA-authorized test. However, the approval for sevabertinib is for the treatment of patients with locally advanced or metastatic NSCLC whose tumors have HER2 TKD-activating mutations, as detected by an FDA-approved test, and who have previously received a systemic therapy. Following the recent expanded indication for zongertinib for use in the first-line advanced disease setting, the recommended first-line therapy for patients with HER2 mutation–positive metastatic NSCLC by the NCCN is zongertinib. After disease progression on zongertinib, T-DXd, T-DM1, and platinum-based chemotherapy with or without an immune checkpoint inhibitor (ICI) are all reasonable second-line options.

For patients with HER2 mutation–positive NSCLC who received first-line systemic therapy with platinum-based chemotherapy with or without an ICI, the NCCN-preferred second-line options are T-DXd, zongertinib, and sevabertinib. T-DM1 may also be considered in this scenario under certain circumstances.

Regarding how I sequence these agents after progression on platinum-based chemotherapy with or without an ICI, I always have a discussion with my patient and caregiver(s) about the benefits vs the associated risks. T-DXd is available as an intravenous injection, whereas zongertinib and sevabertinib are for oral use. Based on the different routes of administration, some patients may prefer the ease and convenience of the orally available agents, with the knowledge that they can receive the intravenously administered T-DXd in subsequent settings. It really is a shared decision-making process.

Estelamari Rodriguez, MD, MPH:
I agree. Because the 2 orally available drugs were recently added to the treatment landscape for HER2 mutation–positive advanced NSCLC, we have less experience with how to optimally sequence these agents for our patients who received first-line systemic therapy with platinum-based chemotherapy with or without an ICI. Over time and as we gain more experience with these agents, we will be better able to sequence them in a way that will maximize treatment outcomes and quality of life for our patients.

In oncology in general, we have more experience with T-DXd, especially because in addition to being approved for patients with advanced NSCLC, it is also approved in different settings for patients with advanced solid tumors. Although it is well recognized that T-DXd is associated with ILD/pneumonitis, it is important to note that these oral agents are also not free of toxicities. The boxed warning for sevabertinib includes diarrhea, hepatoxicity and ILD/pneumonitis, and that for zongertinib includes left ventricular dysfunction, hepatoxicity, and ILD/pneumonitis.

That we have many more options in the treatment armamentarium for our patients is exciting. The selection of treatment needs to be personalized with careful considerations for each patient’s preexisting comorbidities and concomitant drug use and interactions. The patient’s preference and treatment goals also need to be considered before treatment recommendations are made. Of importance, all 3 agents have demonstrated central nervous system activity.

Truly, these times are exciting, and as we continue to use these agents, we will increasingly have a better understanding of the optimal sequencing strategies.

How should patients with advanced NSCLC who develop grade 1 ILD/pneumonitis while receiving T-DXd be managed?

Estelamari Rodriguez, MD, MPH:
As previously mentioned, T-DXd has been available for some time, and it is broadly approved for patients with pretreated HER2 overexpressing (IHC 3+) advanced solid tumors. So, in oncology practice today, we have a lot of experience with T-DXd and its associated adverse events. ILD/pneumonitis is uncommon with T-DXd, but it is an adverse event of special interest.

Specifically, because most patients with pretreated advanced NSCLC are already experiencing shortness of breath, and because in NSCLC, T-DXd targets the cancer cells in the lungs, it is particularly important to monitor these patients for ILD/pneumonitis. It is critical that we are able to recognize the early signs and symptoms of T-DXd–related ILD/pneumonitis, which can be fatal if not appropriately managed as soon as suspected.

Any-grade ILD/pneumonitis was reported in approximately 15% of patients with NSCLC in the DESTINY-Lung02 trial with the use of T-DXd at the FDA-approved dose of 5.4 mg/kg (mostly grade 1/2). Grade ≥3 ILD/pneumonitis was reported in only 2% (2/101) of the patients. As soon as ILD/pneumonitis is suspected, it is important to hold T-DXd until diagnosis is confirmed. Appropriate mitigation strategies include carefully ruling out all other causes of ILD/pneumonitis, such as adverse events associated with radiation therapy or the use of other concomitant medications, and other pathologies, such as infection or pulmonary embolism. Laboratory tests for complete blood counts, tumor markers, and autoimmune antibodies should also be performed as clinically indicated.

Screening for ILD/pneumonitis is important at baseline and regularly when receiving T-DXd. It is necessary to ensure that the patient does not have any signs or symptoms of ILD at baseline. The patient’s medical history should also be reviewed to ensure that there is no known history of ILD/pneumonitis based on the most recent treatments received and on the patient’s most recent scans.

For asymptomatic ILD/pneumonitis (grade 1), T-DXd should be interrupted until resolution to grade 0. If symptoms resolve ≤28 days from onset, T-DXd can be resumed at the same dose. However, if symptoms resolve >28 days from the time of onset, T-DXd dose should be reduced by 1 dose level as stated in the prescribing information. The use of corticosteroids should be considered as soon as ILD/pneumonitis is suspected. In NSCLC, the recommended starting dose of T-DXd is 5.4 mg/kg, and the first dose reduction is to 4.4 mg/kg as indicated.

In my practice, I see patients every 3 weeks during treatment and make patient-specific treatment adjustments as needed. I typically administer corticosteroids as soon as I suspect ILD/pneumonitis, even when the patient is asymptomatic. Prompt corticosteroid administration will help with the rapid resolution of ILD/pneumonitis symptoms, especially because my intention is to resume treatment with T-DXd as soon as possible.

Matthew Gubens, MD, MS, FASCO:
I agree. This question is particularly important because for patients with grade 1 ILD/pneumonitis, there are no obvious signs or symptoms. So, it is very easy to miss the onset of ILD/pneumonitis without regularly monitoring patients using appropriate imaging techniques. We have learned from our colleagues who treat patients with breast cancer about how to mitigate and manage ILD/pneumonitis, because they have had more experience with T-DXd. However, for patients with NSCLC, there is the need for additional considerations and extra vigilance because more patients with lung cancer also have chronic obstructive pulmonary disease compared to patients with breast cancer. For these reasons, I appreciate Dr Rodriguez’s points about being very proactive and, of importance, doing due diligence while erring on the side of caution by holding T-DXd as soon as ILD/pneumonitis is suspected and carefully monitoring the patient until resolution to grade 0. Promptly getting the ILD/pneumonitis under control even when the patient is asymptomatic is important.

Estelamari Rodriguez, MD, MPH:
I also need to point out that some patients previously received immunotherapy-based therapy and experienced pneumonitis from immunotherapy. So, anyone who could be at increased risk of developing ILD/pneumonitis should be very closely monitored as soon as T-DXd is initiated because these adverse events are chemotherapy-related autoimmune effects.

What are the benefits of using the ADC technology in the management of patients with NSCLC? 

Estelamari Rodriguez, MD, MPH:
Besides the fact that the conjugation chemistry for ADCs involves multiple mechanisms of action, the development of ADCs has advanced over time. T-DXd is associated with high efficacy, high response rates, and prolonged durability of response. However, unlike earlier-generation ADCs such as T-DM1, T-DXd has a bystander effect. In other words, even if a neighboring tumor cell does not highly express HER2, T-DXd can still trigger cell death via this bystander effect. Together, these characteristics make the potential benefits from the use of newer-generation ADCs exceptional.

We are increasingly learning that the efficacy and toxicities associated with any ADC are strongly dependent on the type of cytotoxic payload, linker, level of expression of the cellular target, and location of the malignant tumors. With more research and as the field continues to advance and evolve, we will be able to better fine-tune this technology in a more targeted way to improve upon already high efficacy and reduce the associated toxicities. As yet, we have no data from randomized head-to-head trials comparing T-DXd to any of the available HER2-directed TKIs (zongertinib and sevabertinib), but I am hopeful that over time, we will have more real-world data and will become better able to compare these agents.

Matthew Gubens, MD, MS, FASCO:
I agree. The engineering scaffolding integrated into the conjugation chemistry of ADCs is exciting, and we are continuously getting savvier with this technology.

Your Thoughts
What other questions do you have about the use of the available HER2-directed agents T-DXd, zongertinib, and sevabertinib to achieve optimal outcomes in the management of your patients with advanced NSCLC harboring HER2 alterations?

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Which HER2-targeted therapies are you currently using in your practice for patients with advanced NSCLC and HER2 alterations including mutations or overexpression?

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