Evolving Approaches in HER2-Mutant Non–Small Cell Lung Cancer: Emerging Evidence and Practical Considerations

Lung cancer is the leading cause of cancer-related mortality worldwide, and non–small cell lung cancer (NSCLC) represents approximately 87% of lung cancer cases.^1,2 HER2 (ERBB2) is a predictive biomarker in NSCLC, and several agents targeting HER2-mutated NSCLC received accelerated approval in the past year.^2-5 During a recent AJMC Peer Exchange, a panel of experts examined the latest developments in HER2-mutated NSCLC. The panel discussed the value of comprehensive molecular testing and the advancing clinical data supporting emerging HER2-targeted therapies. The session was moderated by Ryan Haumschild, PharmD, MS, MBA, CPEL, vice president of pharmacy at Emory University in Atlanta, Georgia.

Value of Comprehensive Molecular Testing in NSCLC

Histologically, NSCLC is divided into 3 subtypes: adenocarcinoma (40%), squamous cell carcinoma (25%-30%), and large cell carcinoma (5%-10%), along with combinations and variants of clinical subtypes.⁶ Although survival rates for patients with NSCLC have increased due to improved screening, biomarker testing, and available treatments, lung cancer remains the leading cause of cancer-related deaths worldwide.^1,2

Several NSCLC predictive biomarkers, which are gene alterations that influence therapy selection, have been identified in recent years, making molecular testing of lung cancer specimens important for identifying potentially efficacious targeted therapies.² National Comprehensive Cancer Network (NCCN) guidelines state that multigene biomarker testing should be performed for all patients with advanced or metastatic NSCLC with a nonsquamous histology and should be considered for those with squamous histology. Guidelines recommend biopsy and/or plasma-based testing, either concurrently or sequentially. Absence of a definitive driver mutation with one type of testing should prompt use of the other.²

HER2, encoded by ERBB2, is a predictive biomarker in NSCLC.² HER2 is found on the surface of normal epithelial cells and is often mutated or overexpressed in a variety of human malignancies. Approximately 2% to 4% of NSCLCs carry ERBB2 (HER2) mutations, which are most commonly found in the tyrosine kinase domain (TKD).^2,7 Patients with HER2 mutations are more likely to be women who never smoked and are also more likely to have a higher incidence of brain metastases.² With the advent of HER2-targeting treatments, assessing HER2 status has become increasingly relevant in recent years. NCCN guidelines recommend that HER2 mutations be included as part of broad molecular profiling with multigene panel tests, commonly performed using next-generation sequencing (NGS).

Stakeholder Insights

Panelists emphasized the importance of broad molecular profiling and the benefits of NGS. “In terms of real-world practice, I think academic centers certainly will send both the plasma-based and the tissue-based testing, because there is a chance that the tissue may come back insufficient and then the plasma can be helpful in that sense,” said Jingxiao Jin, MD, a thoracic medical oncologist at Temple Health’s Fox Chase Cancer Center in Philadelphia, Pennsylvania. “There’s even a recommendation, if a driver mutation is not found, to perhaps delay immunotherapy with the first cycle of chemotherapy while you pursue alternative modes of testing.”

Fred Hirsch, MD, PhD, Professor of Medicine at Icahn School of Medicine at Mount Sinai in New York, New York, highlighted that this isn’t always the case in community-based practices. “Even today, where we have all these options for molecular targeted therapies, there are still places where you do not perform multigene testing," he said. “In highly academic institutions, of course, we do it almost as a reflex testing…. We are also doing parallel tissue testing and blood-based testing.… We need to have a higher frequency of NGS testing.” Hirsch is the Ning Zhao Chair, professor of medicine (hematology and medical oncology) and pathology, and executive director of the Center for Thoracic Oncology at The Tisch Cancer Institute at Mount Sinai in New York, New York.

“It’s critical not to just do the testing, but to act upon the testing,” emphasized Joshua Sabari, MD, a thoracic medical oncologist at NYU Langone Health’s Perlmutter Cancer Center in New York, New York. “Matching patients to the correct targeted therapy is not only going to improve their outcome, but also improve their survival, their quality of life.” He ensures the initial testing is completed and the results are clearly documented in the patient’s chart. “There are integrated systems now that have the mutation placed into the pathology report. If not, I write it pretty big in my notes. Especially for therapies that are approved in the second-line setting, I want to make sure that at the time of progression on the first line, I’m aware and able to understand exactly what that mutation [means] for patients,” he said. He mentioned potential barriers in obtaining some of the therapies, such as prior authorization and access issues. “I talk to patients about that. I also talk to my pharmacist about integrating that plan from the get-go, to make sure that if I have a patient with a HER2 mutation, I know about it and I’m ready to go for a targeted therapy at the time of progression on first-line care,” he said.

Jin highlighted the risks associated with delays in starting targeted treatment. She said that immunotherapy in patients with actionable genomic alterations is often ineffective, and giving targeted therapy after immunotherapy risks increased adverse events (AEs) and immune-related AEs, such as pneumonitis and hepatitis. “You always want to give the most effective treatment first to your patient. Because failure to do that, things happen,” Jin said. “The cancer can progress. People end up in the hospital. Their [ECOG] performance status goes down. And then you’re not able to give the treatment that would have been most effective. I think starting the therapy promptly is really important,” she said.

Current HER2-Directed Therapies for NSCLC

Current FDA-approved HER2-directed therapies for HER2-mutant NSCLC include antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs).^3-5,8 Trastuzumab deruxtecan, an intravenous monoclonal antibody–based ADC, received accelerated FDA approval in 2022 as a second-line treatment for adults with unresectable or metastatic NSCLC with activating HER2 mutations.⁸ In the phase 2 DESTINY-Lung01 study (NCT03505710), patients receiving trastuzumab deruxtecan showed an objective response rate (ORR) of 55% and a median overall survival of 17.8 months.⁹ AEs of grade 3 or higher occurred in 46%, including neutropenia (19%) and anemia (10%), whereas treatment-related interstitial lung disease (ILD) occurred in 26% of patients.⁹

Since then, 2 oral TKIs have received accelerated approval by the FDA for the treatment of patients with activating HER2-mutated NSCLC: zongertinib and sevabertinib.^3-5 Zongertinib is an irreversible HER-selective TKI indicated for adults with unresectable or metastatic nonsquamous NSCLC and HER2 TKD–activating mutations.⁷ Zongertinib was initially approved by the FDA for pretreated patients in August 2025, with approval expanded for first-line treatment in February 2026.^3,5 Approval was based on results of the phase 1b Beamion LUNG-1 trial (NCT04886804).^3,5,7,10 In previously treated patients, zongertinib demonstrated an ORR of 71%, a median progression-free survival (PFS) of 12.4 months, and a median duration of response of 14.1 months.⁷ In patients with non–kinase-domain HER2 mutations, ORR was 30%.⁷ Recent data from treatment-naive patients showed a 77% overall response rate and a 6-month PFS of 79%.¹⁰ The most common AE associated with zongertinib in trials was diarrhea, occurring in 54% to 56% of patients.⁷ Elevations in aspartate aminotransferase (AST) and alanine aminotransferase levels occurred in 16% to 24% and 18% of patients respectively.^7,10

Sevabertinib is a reversible HER2 and EGFR TKI indicated for second-line treatment of adults with locally advanced or metastatic nonsquamous NSCLC and HER2 TKD–activating mutations.⁴ In the phase 1/2 SOHO-01 trial (NCT05099172), the ORR was 64%, and the median PFS (mPFS) was 8.3 months in patients previously treated with non–HER2-targeted therapy.¹¹ In patients who previously received HER2-targeted ADC therapy, ORR was 38%, and mPFS was 5.5 months. The most common AE associated with sevabertinib treatment was diarrhea, experienced by 84% to 91% of patients across cohorts.

In the latest NCCN guidelines, the NSCLC panel recommends zongertinib or systemic therapy regimens (chemotherapy with or without immunotherapy) as first-line treatment for advanced or metastatic NSCLC with a HER2 mutation.² At disease progression, NCCN guidelines recommend trastuzumab deruxtecan, zongertinib (if not previously given), or sevabertinib as second-line treatment options. Switching between agents with similar mechanisms of action (eg, sevabertinib and zongertinib) is not recommended unless specific toxicity of either agent is of concern.

Stakeholder Insights

Sabari highlighted the importance of discussing treatment options with patients: “When we talk about the HER2 space, there are 2 classes of medicines. Antibody-drug conjugates, which are not really conventional chemotherapies, are not really targeted therapies…. [They] have the conventional adverse effects from chemotherapy, things like nausea, fatigue, neutropenia…. So I explain that to patients. With our other agents—with zongertinib, a HER2-selective tyrosine kinase inhibitor, as well as sevabertinib, a HER2 and EGFR exon 20 inhibitor—we have different [adverse] effect profiles, but generally, patients are tolerating them far better than conventional chemotherapy. I talk to patients about their preference, frequency of visits, their performance status, and their goals.”

Hirsch agreed: “ADCs are promising in general, but ADCs also have a significant toxicity. We don’t have a direct comparison between ADCs and the new TKIs, but for me, clearly, toxicity might be a difference [in favor] of TKIs. The TKIs have also shown a very high response rate.” He added that another difference between ADCs and TKIs is that ADCs are approved not only for patients with specific mutations but also for those with high HER2 protein expression, expanding the potential patient population.

Sabari called the results with zongertinib in the Beamion LUNG-1 trial “best in class....We haven’t seen data with response rates this high.… So, to me, [these data were] practice-changing.” He added, “Interestingly, in the patients who’ve had prior trastuzumab deruxtecan, or other HER2 antibody-drug conjugates, the response rate was still about 50%. So we do see activity even after progression on trastuzumab deruxtecan.” Jin agreed: “I think these numbers are on par with other first-line targeted therapies and other mutations, and higher than we normally see with chemo-IO [immunotherapy] in the first line, which is response rates about 50%.”

Discussing the response after sevabertinib treatment in the SOHO-01 trial, Hirsch said, “It is very clearly an effective drug, and a tolerable drug as well.” He added, “We need to see the current study, SOHO-02 [phase 3; NCT06452277], which is a study in the first line, and of course, we need to see more data from that study to make a conclusive assessment of the role. But on this stage, it looks very promising. I’m a strong believer that we will have that option in the first line very soon.”

Sabari discussed the benefits of using patient-reported outcomes in evaluating the physical functioning and symptoms in patients, which were measured in the Beamion LUNG-1 trial: “When you ask patients for their improvement in symptoms, within 5 to 7 days of receiving zongertinib, we saw dramatic improvement. When we measure functional quality of life or functional quality scales, we saw dramatic improvement. We saw improvement in respiratory scales, cough, shortness of breath. These are really important to patients…. I think the PROs [patient-reported outcomes] really drive home the dramatic benefit that patients are experiencing with these targeted therapies, in contrast to antibody-drug conjugates, where day 3 to day 8, patients do have chemotherapy-like adverse effects from the topoisomerase I inhibitor, the deruxtecan payload. I think we do need to take into account PROs, and we do need to report these to our patients and allow them to make the best decisions for themselves.”

Hirsch explained the importance of central nervous system (CNS) penetration of treatments. “Patients with HER2 mutation have a tendency to brain metastasis, and it is reported that up to 40% of the patients already from the beginning have a CNS metastasis.… There are currently other combined HER2-EGFR targeted therapies in development. ORIC-114 [enozertinib] is a drug that is dual-targeting but has already shown very promising CNS penetration.… The TKIs have penetration to CNS as well, and I don’t know whether one is better than the other at this stage.”

Regarding AEs, Jin said, “In terms of comparing sevabertinib and zongertinib, I think sevabertinib had a higher reported rate of rash and diarrhea, as well as some more GI [gastrointestinal] toxicity. And so, not having a direct comparison but just based on reviewing the safety data from these 2 TKIs, it would seem that zongertinib might be a little better tolerated. In terms of comparing it [with] the ADCs, I think it’s a very different profile there, because with the ADCs you do get those chemo adverse effects with the cytopenias; you get a lot more nausea, fatigue, and that’s really not seen with the TKIs. [There is also] ILD, which you do see quite a bit with trastuzumab deruxtecan; that was not reported in the trials of zongertinib and sevabertinib. So, especially if you have a patient with underlying ILD or perhaps developed pneumonitis from their immunotherapy, that’s an important consideration to bring forward when choosing between the TKIs and the ADCs.”

Sabari discussed ongoing phase 3 trials for first-line treatment in HER2-mutant NSCLC. “Trastuzumab deruxtecan, the HER2-directed ADC, is being studied against chemotherapy and immunotherapy in the frontline setting. That study has completed accrual, and we look forward to seeing [those] data. There’s also a study of zongertinib vs chemotherapy and immunotherapy. That’s the Beamion LUNG-2 study,” he said.

He added that the SOHO-02 trial will also be looking at sevabertinib vs chemotherapy and immunotherapy. “Personally, I think any one of these targeted approaches would be better than chemotherapy or chemoimmunotherapy. We need to see that prospectively on trial. It then comes to a discussion of which is the best-tolerated regimen. And I think it’s important that we flesh those out with our patients in the clinical practice setting,” Sabari said. “The trials are assuming that chemo and immunotherapy are the standard of care. And the question is, in our current sort of landscape of HER2-targeted therapies, zongertinib, sevabertinib, the targeted chemo, trastuzumab deruxtecan, are those going to be better than chemo and immunotherapy? And I think they will be.”

Jin said, “The potential benefit [of accelerated approval] is earlier access to potential lifesaving or life-prolonging drugs. And that’s huge for patients, especially those without access to clinical trials in the community setting. In terms of how to communicate [that] to patients, I think you can explain that it’s not a traditional approval and that the data are still pending, but that it’s been very promising…and patients usually will understand that.”

Emerging HER2-Targeted Therapies in NSCLC

Additional HER2-targeting therapies are currently being investigated in active clinical trials, with several focusing on CNS penetration or combination treatments. Enozertinib is an oral brain-penetrant agent with HER2-EGFR exon 20 mutant dual-targeting activity.¹² Its clinical activity is being investigated in a phase 1/2 trial (NCT05315700) as a single agent or in combination with chemotherapy in patients with advanced solid tumors with EGFR or HER2 mutations.¹³ Preliminary data from a patient with EGFR exon 20–mutated NSCLC who progressed with new brain metastases after previously receiving combination chemotherapy followed by amivantamab showed a complete systemic and CNS response after 2 cycles of enozertinib.¹² NVL-330 is an oral, brain-penetrant, HER2-selective investigational TKI under investigation in the phase 1a/1b HEROEX-1 dose-escalation and-expansion trial (NCT06521554) in patients who previously received systemic therapy.^14,15 CGT4255 is an oral HER2-targeting agent with high CNS activity in preclinical studies that is being investigated in a phase 1/1b trial (NCT07361562) in patients with advanced HER2-mutated solid tumors.¹⁶ Preclinical studies suggest increased efficacy when combining CGT4255 with trastuzumab deruxtecan.¹⁷ IAM1363 is an oral, irreversible, and brain-penetrant small molecule inhibitor targeting both wild-type HER2 and oncogenic HER2 mutations.¹⁸ It is currently being studied in participants with advanced HER2-mutated cancers in a phase 1/1b open-label, multicenter dose-escalation and-optimization trial (NCT06253871) designed to evaluate the safety and preliminary efficacy of IAM1363 alone or in combination with trastuzumab deruxtecan.^18,19

Stakeholder Insights

The panelists were excited about the potential of additional HER2-targeted therapies becoming available. “The field probably will be even more crowded in the future because there are several new TKIs in development in the same space, so it will be interesting,” Hirsch said. “The good thing is…that the patients have opportunities. That is what we are here for.”

Jin agreed: “We can learn a lot from EGFR and ALK in terms of the TKIs. You know, over time, [they are] getting better, more selective, with fewer adverse events, and greater brain penetration to control any brain metastases. And I see that happening with HER2 as well, with second- and third-line TKIs. Also [with] combination therapies, so potentially combining the ADC and the TKI, or maybe even with immunotherapy, to see how these could also improve efficacy.”

Sabari added, “What this shows me is that we can build upon our successes with [TKIs], and I think we’re only going to get better, and the outcomes will improve for patients over time. Can we combine ADCs with tyrosine kinase inhibitors? I think it’s feasible, but we need to mitigate and manage adverse events, toxicity, particularly interstitial lung disease, which occurs in about 15% to 20% of patients treated with trastuzumab deruxtecan. Would we increase that if we combine it with a tyrosine kinase inhibitor? I would not recommend doing that off-label. I would do it in the context, obviously, of a clinical trial.”

Hirsch highlighted the potential for further combination treatment: “There have been scientific reports…that there is overlap of protein expression [among] EGFR, HER2, HER3, TROP2—more overlap than I had expected and we knew about. That gives a potential for combination therapies in the future.… And hopefully, biomarkers come into the scenario; many of the new drugs today, including ADCs, come without a specific biomarker for selection of patients.”

Sabari said, “We’ve really been talking about HER2 or ERBB2 mutations, which are identified by next-generation sequencing. We don’t have a lot of data on overexpression, which is measured by immunohistochemistry, or amplification, which is the copy number of a gene measured by next-generation sequencing or by [fluorescence in situ hybridization]. I think we need better data for understanding resistance and how to build the next generation of combinations.… I think the future is very bright in the HER2 mutation–positive space.”

Hirsch added, “Clinical trials are important. We want to see many more patients go into clinical trials. Clinical trials are the tool we have for bringing science forward, for bringing treatment forward…and we would like to see the accrual much better than we have today. What is the most meaningful outcome from a clinical trial? That is a question that is sometimes difficult to answer. The FDA is currently focusing on survival, and I can totally agree with that. Survival is for the patient, in my opinion, the most important thing.”

Sabari agreed: “Overall survival is king. In the [United Kingdom], for example, we don’t see approvals until we see the overall survival. But I think the accelerated approval process is important because we’re getting therapies to patients in time of need, right? As oncologists in practice, we sit with patients and tell them these are the therapies available. And we don’t know how long an individual patient has.… Efficacy is important. Toxicity, the [adverse] effect profile, is important. But the third thing that most systems look at, both payers as well as health systems, is cost.”

He continued, “First and foremost, do the testing, know the guidelines. If you identify a HER2 or ERBB2 mutation on a next-generation sequencing report, understand that you have accelerated approval for these 3 agents.… Even if you can’t get the therapy directly covered or fully covered, if there’s a large co-pay, there are many patient assistance programs available from the pharmaceutical companies making these therapies. Understanding how to access those and not giving up at the first rejection is critical.… Remember, we have to go to bat for our patients. We have to achieve the best possible treatment selection for them.”

Jin highlighted the benefits of oral TKIs: “When I think of community oncology, I think of their patient population as being perhaps more rural or remote, and I think oral therapies are always really key for this patient population.”

Future Outlook in HER2-Mutant NSCLC

Looking into the future, Hirsch discussed the importance of real-world studies: “Clinical trials, as mentioned before, are, of course, a selected group of patients. I think we need to have that in mind when we interpret data. It is usually patients with good [ECOG] performance status who come into clinical trials and are evaluated in them, and real-world data, in my opinion, should include a broader population-based assessment. Survival will still be, for me, the most important measurement. That is what counts.… How do we measure survival in clinical trials? We are talking about median survival very often, and I try to forget the median survival…. What the patient wants to be is in the tail of the curve. That is what is important for the patient, and we need to be very careful when we communicate with the patient whose median survival is, in my opinion, artificial measurement, and I like to say it is for the statisticians. It is not for the individual patient. He wants to be in the tail of the curve, and it is important how we communicate the survival measurement as well.”

Jin agreed: “How long can patients be taking this therapy, tolerate it well, and have a good quality of life, and live longer? I think duration of response, tail of the curve, are all important things. I think we’re unlikely to get a clinical trial that directly compares the ADC and the TKI. Real-world data will be really important in that aspect to see how patients are doing on these therapies in a standard-of-care setting, and what toxicities they are experiencing. Does that correlate with what we’re seeing from the trial data?”

Sabari highlighted the potential of sequencing therapies in the future. “Just at our own institution, we’ve started looking at how do people do on zongertinib if they’ve had prior trastuzumab deruxtecan,” he said. “Do they do better if they get zongertinib first and then trastuzumab deruxtecan? I think we can answer that question from real-world analyses. I don’t think we’ll see head-to-head studies.… Remember, our clinical trials [enroll] very fit, selected patients. At academic or community practices, where they’re meeting the inclusion and exclusion criteria, what if a patient has hepatitis B? Or what if their baseline AST is 55 or 60? Or their renal function, creatinine clearance, is 52, and they’re not eligible for the trial? How are those patients benefiting from these therapies? It’s very important to collect the adverse event data. One that I’m very specifically interested in is interstitial lung disease and pneumonitis, both for the TKI, but moreso for the ADCs with trastuzumab deruxtecan, especially in an IO-pretreated patient population. We’re starting to hear about cases of patients with ILD prior to immunotherapy being treated with these ADCs in practice. Are they at increased risk, and what are their outcomes? And then lastly, CNS is very important.… But I think the future is bright, and for any fellows, residents, trainees listening, these are data at your fingertips that you can collect at your institution.”

Hirsch concluded, “We are talking about a population where we, a few years ago, did not have any good treatment option. And we have today several good treatment options in second line, and we will hopefully soon have it in first line. It is very encouraging.… All patients with lung cancer need to have molecular, comprehensive molecular testing today, and that is one thing. The future, we need to learn more about the drugs we have been talking about. We need to learn more about the biology, sensitive mutations, resistant mutations, how to eventually combine these drugs with other drugs…so I’m very excited about the future.”

References

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19. A phase 1/​1b study of IAM1363 in HER2 cancers. ClinicalTrials.gov. Updated June 4, 2026. Accessed August 13, 2026. https://clinicaltrials.gov/study/NCT06253871