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.

Videos

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

Articles

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

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

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

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

Zongertinib Demonstrates Clinically Meaningful Efficacy in HER2-Mutated NSCLC