Dr Sabari on Considerations for Conducting and Interpreting HER2 Testing in NSCLC

 alterations, and the fact that these are sometimes hard to diagnose or identify—particularly with older testing [modalities] such as PCR-based assays—we need to be performing broad-panel NGS to identify them.”

Joshua K. Sabari, MD, associate professor, Department of Medicine, New York University (NYU) Grossman School of Medicine; and medical director, Thoracic Medical Oncology, NYU Langone Health’s Perlmutter Cancer Center, discusses key considerations when testing for 

 alterations in patients with non–small cell lung cancer (NSCLC).

 alterations are increasingly being recognized as actionable driver mutations in NSCLC, with exon 20 insertion mutations—most commonly the YVMA variant—being the most frequent subtype, Sabari begins. These alterations are sometimes listed on next-generation sequencing (NGS) reports as either 

, though they refer to the same mutation, he notes. Although 

 mutations are relatively uncommon in NSCLC, their detection is critical for appropriate targeted treatment selection, Sabarisays. However, if not actively sought, they can be overlooked in clinical practice, he emphasizes.

Similar to EGFR, HER2 encompasses a range of alterations rather than a single uniform mutation, Sabari continues. Although exon 20 insertions within the HER2 kinase domain are the most well characterized and therapeutically relevant, other 

mutations exist outside the kinase domain, which serves as the receptor’s signaling region, Sabari says. Non–tyrosine kinase domain mutations, such as those occurring in the extracellular or transmembrane domains, are generally less responsive to HER2-directed therapies, underscoring the need for precise molecular characterization, he states.

Historically, older testing methods, such as polymerase chain reaction (PCR)–based assays, have had limitations in detecting the full spectrum of 

 alterations, Sabarishares. PCR-based testing may fail to identify uncommon variants or miss the presence of concurrent alterations that could affect therapeutic decision-making, he says. In contrast, broad-panel NGS has become the preferred approach for comprehensive molecular profiling, enabling more accurate identification of 

mutations alongside other clinically relevant alterations, Sabari concludes.

Videos

Joshua K. Sabari, MD, discusses key considerations when testing for HER2 alterations in non–small cell lung cancer

Dr Popat on the Efficacy and Safety Profiles of Zongertinib in HER2-Mutated NSCLC

“[Zongertinib] is very active against the [HER2] YVMA mutation…The drug also has some activity in the brain, with a response rate of 33%. It’s a very tolerable drug.” 

Sanjay Popat, BSc, MBBS, FRCP, PhD, consultant medical oncologist, The Royal Marsden NHS Foundation Trust; professor, thoracic oncology, the Institute of Cancer Research, discusses data that have been reported with zongertinib (BI 1810631) in patients with HER2-mutated non–small cell lung cancer (NSCLC) and how these findings may affect clinical practice in the future. 

Recent data with 2 leading HER2-targeted therapies for patients with HER2-mutated NSCLC highlight promising advancements in this treatment paradigm, Popat begins. One of the drugs, zongertinib, was evaluated in the phase 1 Beamion LUNG-1 trial (NCT04886804), whereas the second drug is earlier in development, he notes. 

Zongertinib has been studied extensively across several Beamion LUNG-1 analyses in patients with previously treated metastatic NSCLC, Popat says. In cohort 1 of the trial, patients with pretreated NSCLC harboring a HER2 TKD mutation were randomly assigned to receive zongertinib at 120 mg (n = 75) or 240 mg (n = 57) daily. The drug exhibited robust efficacy, with an overall response rate (ORR) of 71% (95% CI, 60%-80%; P less than .0001) among patients who received the agent at 120 mg, he explains. Notably, zongertinib is active against the YVMA insertion mutation within HER2 exon 20, which is the most common HER2 mutation in this setting, he emphasizes. HER2 mutations are relatively rare in NSCLC, and the YVMA insertion mutation presents a diagnostic challenge due to its variable nomenclature on mutation reports, he cautions. Furthermore, the agent demonstrated central nervous system activity among evaluable patients at the 120-mg dose (n = 27), generating an intracranial ORR of 33% (95% CI, 19%-52%). 

The safety profile of zongertinib is favorable, he adds. In Beamion LUNG-1, 5% of patients required dose reductions. Since zongertinib was designed to target HER2, it has minimal off-target effects on EGFR, resulting in low rates of EGFR-associated toxicities like diarrhea and skin toxicity, Popat concludes.


Sanjay Popat, BSc, MBBS, FRCP, PhD, discusses data that have been reported with zongertinib in patients with HER2-mutated NSCLC.

Dr Piotrowska on Treatment Sequencing Decisions in HER2-Mutated NSCLC

“In addition to the ongoing trials helping to inform the ultimate optimal placement of T-DXd, we’ve also seen exciting clinical trials with HER2-directed oral TKIs.”

Zosia Piotrowska, MD, MHS, instructor, Harvard Medical School; medical oncologist, Massachusetts General Hospital, discusses patient characteristics and disease factors that guide treatment decision-making and sequencing for patients with 

-mutated non–small cell lung cancer (NSCLC), as well as ongoing research that may expand this treatment paradigm.

Treatment selection for patients with advanced 

-mutated NSCLC begins with first-line therapy considerations, Piotrowska says. Currently, the only FDA-approved therapy for patients with 

fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu)

, a HER2-directed antibody-drug conjugate that is indicated for patients in the post-chemotherapy setting, she explains. Therefore, platinum-based doublet chemotherapy remains the preferred first-line treatment for newly diagnosed patients, she notes. Immunotherapy is typically avoided for patients with frontline 

-mutated NSCLC, particularly those with minimal or no smoking history, a common characteristic of this disease, she reports. However, shared decision-making should be employed when selecting between chemotherapy alone or chemoimmunotherapy, she adds.

Upon disease progression following first-line treatment, second-line therapy with T-DXd or enrollment in a clinical trial is typically considered, according to Piotrowska. Findings from the ongoing phase 3 DESTINY-Lung04 trial (NCT05048797), which is investigating T-DXd in the first-line 

-mutated NSCLC setting, may alter the standard of care in the future, she continues. Additionally, despite the limitations of earlier agents in this class, HER2-directed oral TKIs are showing activity in clinical research. Prior HER2-directed TKIs included pyrotinib and poziotinib, which are associated with high rates of off-target toxicities like severe diarrhea, she says.

Emerging mutant-selective HER2 inhibitors are also demonstrating improved efficacy and safety profiles, Piotrowska continues. Zongertinib (BI 1810631), the most advanced of these agents in development, elicited an overall response rate (ORR) of 66.7%(97.5% CI, 53.8%-77.5%; 

-mutated NSCLC treated with 120 mg of the agent (n = 75) in the phase 1b portion of the phase 1 Beamion LUNG-1 trial (NCT04886804). Moreover, early signals of intracranial activity were observed with zongertinib at the 120 mg (n = 27) and 240 mg (n = 25) dose levels. This agent was also associated with manageable grade 3 toxicities, including diarrhea and rash, she explains.

Another HER2-directed TKI, BAY2927088, generated a 72.1% (95% CI, 56.3%-84.7%) ORR among 43 patients with 

in cohort D of the phase 1 SOHO-01 trial (NCT05099172)

. However, this agent was associated with a relatively high rate of grade 3 or greater diarrhea, which was observed in 25.0% of patients, Piotrowska concludes.

Zosia Piotrowska, MD, MHS, discusses disease factors that guide treatment decision-making and sequencing for patients with HER2-mutated NSCLC.

Tailoring treatment approaches for patients with 

-mutant non–small cell lung cancer (NSCLC) requires identifying the specific type of 

 alteration at diagnosis, understanding distinctions between HER2-directed TKIs and antibody-drug conjugates (ADCs), and using data from ongoing research to elucidate appropriate sequencing of these therapeutic classes, according to Nicolas Girard, MD.

“The ultimate objective is to expose patients to all the mechanisms of action that we have in our hands [between various classes of drugs]. In the end, the overall survival of patients is related not only to the efficacy of first-line [treatment], but also of subsequent lines, and how you best individualize the treatment strategy,” said Girard, a professor of respiratory medicine at Versailles Saint Quentin University, head of Curie-Montsouris Thorax Institute, and chair of the Medical Oncology Department at Institut Curie in France.

, Girard emphasized the importance of distinguishing between 

alterations; explained how prognostic and predictive values, drug sensitivity, and mechanisms of action differ between HER2-targeted TKIs vs ADCs; and discussed the need for data regarding the optimal sequencing of 

-directed therapies to maximize efficacy and minimize toxicities for patients with 

: Why is it important to distinguish between the types of 

 alterations when talking about drug development in lung cancer?

It's important because, ultimately, there are several alterations. There may be some 

 exon 20 insertions as well as point mutations, and the sensitivity to the available drugs may be different from 1 mutation to another, and between mutations and 

 exon 20 insertion mutations. There is also some high variability in the frequency of each of these alterations. In the end, [this variance] is probably more important for the TKIs as opposed to the ADCs, which might be more potent.

How do the prognostic and predictive values differ between the various 

It's clear that the prognostic and predictive values of each mutation and alteration are different. [These values] may also be different from 1 compound to another, especially in terms of mechanism of action. It [also important] to distinguish between TKIs and ADCs. With TKIs, it's a matter of confirmation of the tyrosine kinase domain, and the impact of 1 mutation or another may be very important regarding the efficacy in inhibiting the kinase activity. With ADCs, we are moreso targeting the extracellular part of HER2; the type of intracellular alterations may actually be lower.

It is fairly easy to ascertain if the patients have symptoms. I'm hopeful that, at some point, we may be able to decrease the role of the eye specialist. However, at this point, the visual acuity fields are important, and seeing an ophthalmologist or optometrist is advised.

 de novo and resistance alterations within tumor types?

We know that HER2 may be activated after exposure to a TKI, especially in patients with common

 mutations. For example, a patient may develop acquired resistance related to the proliferation of cancer cells with 

 amplification or pathway activation. This is a very different situation compared with that of patients with de novo 

 alterations for whom the objective is to start with HER2-directed treatment. In NSCLC, de novo 

 mutations are present in approximately 2% to 3% of patients. Next-generation sequencing [NGS] is required to identify those mutations. If we use PCR-based assays, there is a high risk to miss some of these alterations.

The other point is that there are multiple ways to investigate 

 [alterations]. Mutations [can be detected] with NGS; amplifications may require RNA-based NGS or fluorescent in situ hybridization. We also have HER2 expression, which may be associated with mutations or amplifications, but [expression] may also be independent from mutations and amplifications. When looking at HER2 expression in patients with NSCLC, it's important to look at the methods that were used to assess 

How do the mechanisms of action differ for HER2-targeted TKIs vs ADCs?

With TKIs, we are inhibiting the intracellular domain of HER2—the kinase domain—which is associated with the activation of those pathways involved in cell proliferation and resistance to apoptosis. TKIs are binding to this ATP binding pocket in the intracellular part of HER2. If [a patient] has a 

 mutation in the ATP domain, some TKIs may not work, and we would need TKIs with a different conformation that will work and bind to the ATP pocket. The advantage of TKIs is that they’re usually oral drugs with a known safety profile; however, the sensitivity of each mutation may differ from one TKI to another.

With ADCs, it's a completely different strategy, where you have drugs that [comprise] an antibody targeting the extracellular part of HER2 [and] a cytotoxic payload. The idea is to inhibit signaling pathways through the inhibition of the extracellular domain and also let this cytotoxic payload enter specifically into cancer cells, leading to a higher specificity for the cancer cells compared with systemic, cytotoxic chemotherapy. [There is] also an opportunity to have efficacy [irrespective of] the type of alteration, including

mutations, amplifications, or even overexpression.

What are some relevant clinical features commonly observed among patients with 

A majority of [these] patients are never smokers, but you also have some smokers who develop lung cancer associated with 

 mutations. Therefore, it's important to look for those alterations in all patients, usually using NGS. It's important to obtain HER2 status at [a patient’s initial] diagnosis because many clinical trials and potentially the standard of care in the future will likely [be to deliver HER2-directed therapies] in the first-line setting. Usually, the clinical radiological presentation is variable; [however,] in many patients [with NSCLC harboring HER2 alterations], there are multiple nodules and lymphangitis. [These patients have] quite extensive and aggressive disease with frequent metastases, especially in the brain.

Going forward, how might efficacy and safety considerations influence the selection and sequencing of ADCs and TKIs in NSCLC?

All those new drugs are of interest, including the ADCs and TKIs. The key question for me as a clinician is: ‘What is the best treatment sequence?’ I want to expose my patients with 

-mutant NSCLC to ADCs, cytotoxic chemotherapy, and dedicated TKIs. Perhaps the best sequence may be to start with ADCs, and if progression occurs, the HER2-directed TKIs may work. Maybe it will be the reverse, starting with an oral drug and then [addressing] resistance with an ADC. [Sequencing choices will be] a matter of efficacy. We need to see the data, especially in the first-line setting, for ADCs and HER2-directed TKIs.

The adverse effects [AEs] also [need to be considered]. With ADCs, there may be some AEs that are quite similar to that of cytotoxic chemotherapy, [including] hematological toxicity, low blood pressure, nausea, vomiting, and possibly interstitial lung disease. With TKIs, [these AEs may include] more digestive tract–related toxicities with diarrhea. There may be some rash and cutaneous toxicities. Balancing the efficacy with the safety profile [is critical].

Articles

Nicolas Girard, MD, compares the predictive value, mechanisms of action, and safety or efficacy profile of HER2-targeted TKIs vs ADCs in NSCLC.

Distinctions Between Alteration Types, Therapeutic Classes Could Drive Optimal Treatment Selection in HER2-Mutant NSCLC 

Dr Girard on De Novo and Acquired Resistance Alterations in HER2-Altered NSCLC

“We know that HER2 may be activated after exposure to a TKI, especially in patients with common 

 mutations. A patient [can] develop a kind of acquired resistance related to the proliferation of cancer cells with 

 amplification or HER2 pathway activation.”

Nicolas Girard, MD, professor, respiratory medicine, Versailles Saint Quentin University; head, Curie-Montsouris Thorax Institute, chair, Medical Oncology Department, Institut Curie, discusses de novo vs acquired resistance alterations in HER2-positive non–small cell lung cancer (NSCLC).

In HER2-positive NSCLC, alterations can be broadly categorized as either de novo mutations or acquired resistance mutations, Girard begins. De novo mutations refer to initial alterations present from the onset of disease, whereas resistance mutations often arise following treatment exposure, particularly in patients with 

 mutations who undergo TKI therapy, he explains. In these cases, resistance develops through mechanisms such as 

 amplification or activation within the HER2 pathway, which ultimately facilitates the proliferation of resistant cancer cells, according to Girard. This phenomenon contrasts with the treatment of patients who present with de novo 

 alterations, he reports, adding that for those patients, initiating HER2-targeted therapy at diagnosis is the primary objective.

 mutations occur in approximately 2% to 3% of patients. However, accurate mutation detection requires next-generation sequencing (NGS), as PCR-based assays carry a significant risk of overlooking some of these alterations, he continues. NGS technology offers a more comprehensive analysis of 

 mutations by enabling the identification of multiple alteration types, such as 

 amplification, which may require RNA-based NGS or fluorescence in situ hybridization (FISH), Girard explains. Additionally, it is essential to examine HER2 expression levels in these tumors, he says. HER2 expression may co-occur with mutations or amplifications; however, it can also exist independently from these alterations, he notes. Therefore, when evaluating HER2 status in patients with NSCLC, it is crucial to understand the methods used to assess 

 alterations, as each diagnostic approach—whether PCR, RNA-based NGS, or FISH—provides distinct insights, Girard concludes.

Nicolas Girard, MD, discusses both de novo and acquired resistance alterations in HER2-altered non–small cell lung cancer.

Dr Baik on the Clinical Utility of Zongertinib in Previously Treated HER2-Mutant NSCLC

Christina S. Baik, MD, MPH, physician, associate professor, Clinical Research Division, Fred Hutchinson Cancer Center; clinical research director, Thoracic, Head and Neck Oncology, associate professor, Division of Hematology and Oncology, University of Washington School of Medicine, discusses the clinical utility of zongertinib (BI 1810631) in patients with previously treated non–small cell lung cancer (NSCLC) harboring 

 tyrosine kinase domain (TKD) mutations. She went on to highlight the investigation of the agent 

in cohort 1 of the phase 1b Beamion LUNG-1 trial (NCT04886804)

, as well as the ongoing Beamion phase 3 LUNG-2 trial (NCT06151574).

There is still much to learn about zongertinib, particularly in patients with previously treated NSCLC, Baik begins. Current insights come primarily from data in the Beamion LUNG-1 trial and reveal that the adverse effects (AEs) associated with zongertinib appear to be dose dependent, she explains. As seen with other TKIs, dose reduction can often alleviate AEs, such as severe diarrhea, Baik says. She notes that although the severity of AEs varies among patients, dose adjustments have generally shown effectiveness in improving the tolerability of zongertinib.

The Beamion LUNG-2 trial includes a cohort evaluating zongertinib in treatment-naive patients with 

-mutant NSCLC to explore whether it may outperform the current standard of care (SOC), which consists of chemotherapy combined with immunotherapy, she continues. There is still uncertainty regarding the efficacy of immunotherapy for patients with 

-mutated NSCLC compared with patients without 

 mutations or other oncogenic drivers, Baik reports. However, chemoimmunotherapy remains a SOC in the NSCLC treatment paradigm, which is why the control arm of this trial involves chemoimmunotherapy, according to Baik. 

The trial’s results are expected to provide clarity on zongertinib’s potential as a first-line treatment for 

-mutated NSCLC, Baik expands. These data will help define zongertinib’s role compared with current SOCs and clarify whether it can serve as a viable initial treatment option. The findings from this study are highly anticipated as they could establish zongertinib as a significant therapeutic option in the first-line setting for this patient population, she concludes.

Christina S. Baik, MD, MPH, discusses the clinical utility of zongertinib in previously treated non–small cell lung cancer harboring HER2 TKD mutations.

Effective frontline treatment of patients with 

-mutated non–small cell lung cancer (NSCLC) will require comprehensive HER2 testing and further research to pinpoint the efficacy and safety of HER2-targeted therapies in development in this setting, according to Christina S. Baik, MD, MS.

-mutated NSCLC, we would use a next-generation sequencing [NGS] assay, which would test for 

 and all other actionable alterations to identify the subtype of lung cancer,” Baik said in an interview with 

. “That would be the best way to test for the 

 mutation. However, also remember to test [for HER2 expression] using immunohistochemistry [IHC], which is a separate test from NGS assays.”

In the interview, Baik expanded on the types of HER2 testing that should be performed in all patients with NSCLC, notable aspects of the AE profile of the HER2-targeted TKI zongertinib (BI 1810631), and the design of the ongoing phase 3 Beamion LUNG-2 trial (NCT06151574).

Beamion LUNG-2 is evaluating zongertinib vs pembrolizumab (Keytruda) plus platinum-pemetrexed chemotherapy in patients with 

 Progression-free survival serves as the primary end point. Key secondary end points include overall response rate (ORR), overall survival, duration of response, symptoms, and quality of life outcomes.

Previously, findings from the phase 1a/2b Beamion LUNG-1 trial (NCT04886804) demonstrated that zongertinib generated an ORR of 74% and a disease control rate of 91% among 23 efficacy-evaluable patients with 

 Two dose-limiting toxicities were observed during the maximum tolerated dose evaluation period: grade 3 decreased platelet counts and grade 3 diarrhea.

Baik is an associate professor in the Clinical Research Division at Fred Hutchinson Cancer Center, as well as the clinical research director of Thoracic, Head and Neck Oncology at University of Washington Medicine and an associate professor in the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle.

: What are some of the current treatment challenges for patients with 

: There are currently several areas of unmet need. Number one is that we do not yet have a [frontline] targeted therapy for this patient population. For example, for patients with lung cancer [harboring] 

 mutations, we know there’s a targeted therapy [available] and we start with that [in the frontline]. We don’t have such an oral targeted therapy [for patients harboring] 

 mutations. I’m hoping that will change in the near future, but a huge unmet need is that there are no available [HER2]-targeted therapies that we can start with [in the first line]. There is a targeted therapy—fam-trastuzumab deruxtecan-nxki [Enhertu]—a HER2-directed antibody-drug conjugate [ADC] that is effective in 

-mutated lung cancer, but we give it in the second-line setting.

The second unmet need is that we do not fully understand the role of immunotherapy in patients with 

-mutated NSCLC. Do we need to add immunotherapy to chemotherapy or use immunotherapy by itself? There are some data, but not robust data, [that address these questions so far].

What is the standard practice for HER2 testing in NSCLC?

There are 2 types of HER2 tests, and it’s important to clarify between those. There is the 

 mutation, which we would see [based on] a change in genetic testing. Often, we can identify [

 mutations] through an NGS assay. These are usually insertion mutations in [

] exon 20, for example, as well as other point mutations. The second type of test is IHC. This is used to test for protein overexpression of HER2 and is different from mutation testing.

What is your advice for streamlining HER2 testing expectations between medical oncologists and pathologists?

Communication and workflow are specific to each institution. What’s done in 1 institution is not necessarily the same for another institution, or even for private practices that will use a third-party lab. That’s the challenge behind this.

At the University of Washington, we have tried to create a workflow so that all patients with NSCLC undergo molecular testing up-front when they’re first diagnosed, which would include 

 mutational testing; we are working on getting HER2 IHC testing as well for all patients. [However, this testing requires] close communication with the pathologist to set the workflow.

Although a HER2-directed TKI is not yet approved for patients with 

-mutated NSCLC, what should be known about the adverse effect (AE) profile of this class of agents?

The AEs will be specific to the drug that gets approved. The oral targeted agent that is furthest along in [development is] zongertinib. [This agent is] not yet FDA approved, but there are good data to show that it’s effective in patients with 

-mutated NSCLC. Intracranial responses have been observed as well.

[Regarding] zongertinib, some of the common AEs have been diarrhea, gastrointestinal AEs, and transaminitis. [However, transaminitis] is not unique to this drug; transaminase is a common toxicity [associated with] all different TKIs. [Overall], I don’t think we can generalize [the AE profile of zongertinib] for all future HER2 inhibitors.

How might dose adjustment help mitigate some of the AEs seen with zongertinib?

There’s more to learn about the drug as we gather more clinical experience. What we have now is based on what’s been publicly presented in the [Beamion LUNG-1] trial, and the AEs appear to be dose related. However, the severity of AEs can vary by patient. [If a patient has severe diarrhea], for example, dose reduction helps. A lot of these AEs are dose dependent, similar to many other TKIs.

What are the design and rationale of the ongoing phase 3 Beamion LUNG-2 trial?

That study is evaluating zongertinib treatment-naive patients [with 

-mutated advanced NSCLC] to determine whether this drug will be better than the current standard of care [SOC], which is chemotherapy plus immunotherapy. We do not fully know whether patients with 

-mutated NSCLC benefit from immunotherapy as much as those who may not have a 

 mutation or any other oncogenes or oncogene drivers. That said, [immunotherapy] is still considered a SOC [for these patients].

The control arm [of Beamion LUNG-2] is chemoimmunotherapy, which is being compared with zongertinib in the first-line setting. Crossover [is allowed], meaning that if patients are randomly assigned to receive chemoimmunotherapy and their disease progresses, they can [switch to receive] zongertinib. This trial may give us a definitive answer regarding the role of zongertinib in the first-line setting.

What are the key things to know regarding the current state of treating 

-mutated NSCLC and where ongoing research could take the treatment paradigm?

Make sure [HER2 is] being tested for. Whatever assay you’re using, make sure HER2 is called out and that [it is being] tested for along with the other actionable alterations that can make a huge difference [in determining treatment] for patients. Remember that HER2 IHC testing, or even HER2 fluorescence in situ hybridization testing for [HER2] amplification, is not going to detect the 

 mutation. Make sure all these different types of 

Secondly, we have a HER2-directed ADC for patients [with HER2-mutated disease] in the later-line setting. However, we have exciting data with zongertinib, as well as other HER2[-targeted therapies]. This field will continue to move forward and evolve in the years to come.

Beamion LUNG-2: a study to test whether zongertinib (BI 1810631) helps people with advanced non-small cell lung cancer with HER2 mutations compared with standard treatment. ClinicalTrials.gov. Updated November 1, 2024. Accessed November 1, 2024. https://clinicaltrials.gov/study/NCT06151574

Heymach J, Opdam F, Barve MA, et al. Phase Ia/Ib trial of zongertinib (BI 1810631), a HER2-specific tyrosine kinase inhibitor (TKI), in patients (pts) with HER2 aberration-positive solid tumors: updated phase Ia data from Beamion LUNG-1, including progression-free survival (PFS) data. 

. 2024;42(suppl 16):abstr 8514. doi:10.1200/JCO.2024.42.16_suppl.8514

Christina S. Baik, MD, MS, discusses the types of HER2 testing that should be performed in NSCLC and the design of the phase 3 Beamion LUNG-2 trial.

Zongertinib Research Could Represent Next Wave in HER2-Mutated NSCLC Management

Treatment with zongertinib (BI 1810631) led to clinically meaningful and statistically significant efficacy, as well as tolerable safety, in patients with previously treated non–small cell lung cancer (NSCLC) harboring 

 tyrosine kinase domain (TKD) mutations, according to data from cohort 1 of the phase 1b Beamion LUNG-1 trial (NCT04886804) shared at the 

2024 IASLC World Conference on Lung Cancer

Among patients in the 120 mg cohort (n = 75), zongertinib elicited an objective response rate (ORR) of 66.7% (97.5% CI, 53.8%-77.5%; 

 <.0001) per blinded independent central review (BICR). Data showed that the primary end point of confirmed response by BICR was reached for patients who received the agent at 120 mg in cohort 1 during the phase 1b portion of the trial.

Additionally, 94% (n = 124/132) of patients experienced tumor shrinkage of any magnitude based on investigator assessment. Although duration of response (DOR) and progression-free survival (PFS) data were not yet mature at the time of the analysis, approximately two-thirds of the study population were still receiving treatment as of the data cutoff of May 23, 2024.

The confirmed ORR per central review was 72.4% (n = 42/58) in the 120 mg group compared with 78.2% (n = 43/55) in the 240 mg group. Data showed that 1.7% (n = 1/58) and 3.6% (n = 2/55) of each respective group achieved a complete response (CR), and 70.7% (n = 41/58) and 74.5% (n = 41/55) had a partial response (PR). Study treatment also yielded a disease control rate (DCR) of 94.8% (n = 55/58) and 100.0% (n = 55/55) in each respective group.

Regarding intracranial responses per BICR using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, the ORR was 33% (n = 9/27; 95% CI, 19%-52%) with zongertinib at 120 mg and 40% (n = 10/25; 95% CI, 23%-59%) at 240 mg. In each respective group, the CR rate was 15% (n = 4/27) and 20% (n = 5/25), and the PR rate was 19% (n = 5/27) and 20% (n = 5/20). Additionally, the DCR was 74% (n = 20/27; 95% CI, 55%-87%) and 92% (n = 23/25; 95% CI, 75%-98%).

“Zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated [NSCLC] with a 

 [TKD] mutation, including in those with brain metastases,” Gerrina Ruiter, MD, PhD, of the Department of Clinical Pharmacology and Department of Thoracic Oncology at Netherlands Cancer Institute in Amsterdam, the Netherlands, said in the presentation. “Zongertinib was very well tolerated, with no deaths attributed to treatment and a low incidence of dose reductions and treatment discontinuations.”

Ruiter further illustrated the potential efficacy of zongertinib in this population by highlighting a specific patient case involving a 67-year-old woman with stage IV 

mutated NSCLC. After disease progression at 7 months following frontline treatment consisting of carboplatin, pemetrexed, and pembrolizumab (Keytruda), second-line therapy with zongertinib at 120 mg elicited a PR lasting for 13 months to date; the patient currently remains on study treatment.

Developers designed zongertinib as an investigational, orally available HER2 tyrosine kinase inhibitor (TKI) that can selectively and covalently bind to the TKD of mutated and wild-type HER2 receptors. By sparing wild-type EGFR, treatment with zongertinib may avoid toxicities associated with this receptor.

Investigators of the Beamion LUNG-1 trial assessed treatment with zongertinib at the recommended expansion doses of 120 mg and 240 mg once daily. Cohort 1 included patients with previously treated NSCLC harboring a 

 TKD mutation, where investigators selected the 120 mg dose at interim analysis.

The primary end point of the phase 1b portion of the trial was confirmed objective response per RECIST 1.1 criteria according to central independent review.

With a median follow-up of approximately 13 weeks for efficacy, 132 patients received treatment with zongertinib as of the data cutoff, including 75 in the 120 mg group and 57 in the 240 mg group. The median patient age was 62 years (range, 30-80) and 62 years (range, 36-82) in the 120 mg and 240 mg group, respectively, with most patients in each group being female (68% and 44%). Additionally, most patients in each group were Asian (53% and 58%), received 1 prior line of systemic therapy (56% and 49%), and had an ECOG performance status of 1 (63% and 70%). Of note, 37% and 46% of patients in each group had brain metastases.

Across the 120 mg group and 240 mg groups, respectively, 92% and 100% of patients had any-grade treatment-related adverse effects (TRAEs), with the most common including diarrhea (48% and 65%), rash (24% and 30%), and aspartate aminotransferase increases (21% and 25%). Additionally, grade 3 or higher TRAEs affected 17% and 19% of these groups, with the most common types including alanine aminotransferase increases (8% and 11%) and aspartate aminotransferase increases (5% and 7%).

Investigators reported no fatal TRAEs, and 11% (n = 14) of patients required dose reductions following toxicity. Additionally, 3% (n = 4) had AEs resulting in treatment discontinuation.

The FDA previously granted breakthrough therapy designation to zongertinib for adults with advanced, unresectable, or metastatic NSCLC harboring activating 

 mutations following prior systemic therapy.

Ruiter concluded by stating that the phase 3 Beamion LUNG-2 trial (NCT06151574) was open for enrollment. Investigators of Beamion LUNG-2 will compare zongertinib with standard-of-care therapy in the frontline treatment of patients with advanced 

Ruiter G, Tu H-Y, Ahn M-J, et al. Phase 1b analysis of Beamion LUNG-1: zongertinib (BI 1810631) in patients with HER2-mutant NSCLC. Presented at the 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL04.04.

Boehringer Ingelheim to unveil groundbreaking oncology research at WCLC, demonstrating strength of portfolio. News release. Boehringer Ingelheim. August 27, 2024. Accessed September 9, 2024. https://tinyurl.com/4nr9ntwy

Zongertinib demonstrated clinically meaningful efficacy in previously treated HER2-mutated non–small cell lung cancer.

Harnessing the Activity of Targeted Therapy in HER2-Mutant NSCLC | Supplements and Featured Publications