Martin Dietrich, MD, PhD

In their concluding remarks, the experts highlight critical future directions and unmet needs in non-small cell lung cancer (NSCLC). A major focus is on improving lung cancer screening. They note that current screening rates are unacceptably low (~20%) and emphasize the need to better integrate it into primary care. Furthermore, they call for expanded screening criteria to include populations not currently eligible, such as never-smokers and light smokers, especially women, who are increasingly being diagnosed.

Experts discuss the critical factors for recommending adjuvant chemotherapy after surgery for early-stage non-small cell lung cancer (NSCLC). They confirm that lymph node involvement (N1 disease) is a clear indicator for offering platinum-based chemotherapy due to the higher risk of recurrence.

Experts emphasize the indispensable role of a multidisciplinary team (MDT) in managing non-small cell lung cancer (NSCLC). They highlight that complex cases, like the one discussed, demonstrate how knowledge evolves and how critical collaborative decision-making is for optimal patient outcomes.

Experts address the critical differences between pre-operative biopsies and post-operative surgical specimens for biomarker testing. They confirm that a surgical specimen is far more reliable, as it provides a larger, higher-quality sample, allowing a pathologist to select a more tumor-rich area for analysis. This was key in finally identifying the patient's RET fusion.

Experts discuss how the final pathology report, which included an RNA-based NGS test, definitively resolved the case by identifying a RET fusion. They highlight this finding as a critical justification for comprehensive biomarker testing, especially in never-smoker patients where initial results are negative.

Experts discuss how to manage a complex non-small cell lung cancer (NSCLC) case with ambiguous neuroendocrine markers and initially negative biomarker testing. They note that mixed biphenotypic tumors are not uncommon but present a diagnostic challenge.

Experts address a complex case of a never-smoker with early-stage non-small cell lung cancer (NSCLC). The diagnosis is complicated by ambiguous neuroendocrine markers on the biopsy, a PD-L1 score of 0%, and a negative NGS panel for common drivers, which is unusual for a never-smoker.

Experts discuss the critical importance of including RNA sequencing in comprehensive biomarker testing for non-small cell lung cancer (NSCLC). They highlight that while DNA-based NGS is foundational, it is insufficient for reliably detecting key gene fusions like RET and ROS1

Experts address managing recurrent non-small cell lung cancer (NSCLC) after definitive treatment with surgery and immunotherapy (IO). The experts outline a strategy based on the timing of recurrence.

Experts discuss treatment options for stage III non-small cell lung cancer (NSCLC) without actionable driver mutations and with a PD-L1 expression of 30%. The experts emphasize a multidisciplinary evaluation to decide between a surgical or non-surgical approach.

The oncologists delve into the specifics of which non-small cell lung cancer (NSCLC) patients to test. They recommend testing all non-squamous cases and, increasingly, squamous cases as well, especially those with a light smoking history, to ensure no actionable biomarker is missed.

The oncologists delve into the specifics of which non-small cell lung cancer (NSCLC) patients to test. They recommend testing all non-squamous cases and, increasingly, squamous cases as well, especially those with a light smoking history, to ensure no actionable biomarker is missed.

The oncologists delve into the specifics of which non-small cell lung cancer (NSCLC) patients to test. They recommend testing all non-squamous cases and, increasingly, squamous cases as well, especially those with a light smoking history, to ensure no actionable biomarker is missed.

Two expert oncologists discuss the critical role of comprehensive biomarker testing in non-small cell lung cancer (NSCLC). They emphasize that molecular testing is an essential part of the initial diagnosis, not an optional add-on, as it identifies specific mutations and fusions that dictate the most effective first-line treatment.

Panelists discuss clinical pearls for community oncologists, emphasizing that comprehensive testing is essential since zongertinib offers dramatic improvements with 75% response rates and progression-free survival exceeding 12 months in HER2 exon 20 mutations, while noting that HER2 immunohistochemistry testing shouldn’t be neglected for identifying patients who may benefit from trastuzumab deruxtecan, requiring a multilayered molecular profiling approach encompassing DNA, RNA, and protein analysis to provide new hope for patients with HER2-mutant disease.

Panelists discuss how combination therapies represent the future of HER2 mutation treatment, drawing parallels to successful EGFR combination strategies, with particular interest in anti-VEGF agents and potentially anti-PD-1/PD-L1 therapies, while noting that zongertinib’s favorable tolerability profile makes it an ideal candidate for combination approaches compared with more toxic agents like trastuzumab deruxtecan or sevabertinib, though current trial designs should incorporate 3-armed studies to evaluate up-front combination strategies rather than sequential monotherapy comparisons.

Panelists discuss how shared decision-making between zongertinib and trastuzumab deruxtecan (T-DXd) in second-line treatment involves presenting key differences to patients, including that T-DXd requires intravenous (IV) infusion with chemotherapy-like toxicities and closer monitoring (including cardiac function), while zongertinib is an oral, once-daily targeted therapy with better patient-reported outcomes and functional status improvements, fewer clinic visits after initial monitoring, and superior tolerability, leading to a preference for zongertinib first followed by T-DXd sequencing.

Panelists discuss how treatment sequencing for HER2-mutation non–small cell lung cancer (NSCLC) prioritizes zongertinib over trastuzumab deruxtecan in the second-line setting due to superior efficacy and tolerability, while noting that special populations like patients with baseline lung dysfunction (favoring zongertinib to avoid interstitial lung disease risk) or CNS (central nervous system) metastases (where zongertinib shows promising brain activity but may require concurrent radiation for larger lesions) require individualized, case-by-case management with close monitoring and early imaging follow-up.

Panelists discuss a clinical scenario involving a 73-year-old Asian woman with stage 4 lung adenocarcinoma harboring a HER2 exon 20 insertion mutation (A775-G776 YVMA) who initially responded to carboplatin, pemetrexed, and pembrolizumab for 4 cycles followed by maintenance therapy, but now presents with progressive cough and shortness of breath suggesting clinical progression, requiring decisions about next-step management in this fit patient with good performance status.

Panelists discuss how emerging second-line treatment options for HER2-mutant non–small cell lung cancer (NSCLC) include sevabertinib (a dual HER2/EGFR exon 20 inhibitor with higher gastrointestinal toxicity but similar efficacy to zongertinib) and other brain-penetrant tyrosine-kinase inhibitors (TKIs) in development, while noting that multiple ongoing phase 3 trials are studying frontline comparisons of these targeted therapies vs chemotherapy plus immunotherapy, creating a complex treatment landscape where the principle of using the best therapy first must consider efficacy, tolerability, and quality-of-life factors.

Martin Dietrich, MD, PhD presents insights from an exploratory analysis of the Phase I/II SOHO-01 trial of sevabertinib in HER2-mutant NSCLC, highlighting how clinical and molecular factors, such as prior therapy, HER2 subtype, and TP53 co-alterations, impact treatment outcomes.

Panelists discuss how the Beamion LUNG-1 trial demonstrated zongertinib’s impressive efficacy in second-line treatment of HER2–mutant non–small cell lung cancer (NSCLC)with a 75% response rate and 14.1-month duration of response in previously treated patients, while showing a favorable safety profile as a true targeted therapy with mainly low-grade diarrhea and minimal toxicities compared with chemotherapy-like side effects, and maintaining activity even after prior trastuzumab deruxtecan treatment with a 50% response rate.

Panelists discuss how second-line treatment options for HER2-mutant non–small cell lung cancer (NSCLC), particularly trastuzumab deruxtecan (T-DXd), require careful management of significant adverse effects, including interstitial lung disease/pneumonitis (especially concerning after prior immunotherapy due to the antibody’s immune-active properties), topoisomerase inhibitor–related gastrointestinal toxicity requiring strong antiemetic protocols, and cytopenias leading to fatigue and infection risk, making it more complex to manage than traditional precision medicine targeted therapies.

Panelists discuss how frontline treatment for HER2 mutant non–small cell lung cancer (mNSCLC) lacks FDA-approved targeted therapies, with current approaches varying between platinum-based chemotherapy with or without immunotherapy (such as the KEYNOTE-189 regimen), though some clinicians avoid immunotherapy in this population due to limited proven benefit in never-smokers who make up 60% of HER2-mutation patients, while considering whether to extrapolate from recently approved second-line targeted therapies like zongertinib.

Panelists discuss how community oncologists can best serve patients by understanding that lung cancer is no longer 1 disease requiring uniform treatment, emphasizing that comprehensive molecular testing including both next-generation sequencing and immunohistochemistry (IHC) is critical for identifying targetable alterations like HER2 mutations that now have FDA-approved targeted therapies, making broad panel testing essential for optimal patient outcomes in 2025.

Panelists discuss how circulating tumor DNA (ctDNA) testing is valuable for up-front molecular profiling in all locally advanced or metastatic lung cancer patients to accelerate treatment decisions, but longitudinal ctDNA monitoring is not yet standard practice for assessing treatment response in HER2 mutations, though it can be useful at disease progression to identify resistance mechanisms and guide subsequent therapy decisions.

Panelists discuss how HER2 alterations in lung cancer differ from other cancers like breast cancer, where overexpression is more common and targetable with antibody-drug conjugates (ADCs), while in lung cancer the focus is primarily on HER2 exon 20 insertion mutations and other tyrosine kinase domain mutations, requiring both next-generation sequencing (NGS) and immunohistochemistry (IHC) testing since liquid biopsies can detect mutations but not overexpression.

Martin Dietrich, MD, PhD, discusses the FDA accelerated approval of zongertinib for HER2-mutated or metastatic nonsquamous NSCLC.