Hernexeos (zongertinib)

P1, N=16, Not yet recruiting, Boehringer Ingelheim

P2, N=60, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

Concerning treatment, in advanced HER2-positive, Non-Squamous NSCLC tumors, the first-line treatment is Platinum-based + Pemetrexed chemotherapy, with or without immunotherapy, because no HER2-targeted antibody therapy has yet been approved for initial treatment. After progression, HER2-targeted antibody-drug conjugates like Trastuzumab-Deruxtecan and Ado Trastuzumab-Emtansine may offer patients clinical benefits. New HER2-selective tyrosine kinase inhibitors, such as zongertinib and sevabertinib, have shown promising results, including patients previously treated with antibody-drug conjugates (ADCs). Recent advances, including next-generation ADCs such as SHR-A1811 and A166, and bispecific antibodies, such as zenocutuzumab for NRG1 fusion-positive disease, which are also expanding treatment options. Overall, advances in diagnostics and new targeted therapies are changing how HER2-altered NSCLC is treated and are helping to make care more personalized.

A 55-year-old female with HER2-mutant non-small cell lung cancer (NSCLC) was treated with zongertinib as second-line therapy following chemo-immunotherapy with pembrolizumab. Serial chest radiographs confirmed significant tumor shrinkage in the left lung, achieving a partial response without recurrence of severe scAEs. A cautious dose-escalation strategy can allow for the continuation of zongertinib even after severe EM-like eruptions, preserving a potent treatment option.

P2, N=25, Not yet recruiting, MedSIR

For EGFR-mutant NSCLC, sequential development of tyrosine kinase inhibitors (TKIs) from first- to third-generation agents-culminating in osimertinib-has markedly improved survival. Similarly, successive generations of ALK inhibitors, including alectinib, brigatinib, and lorlatinib, have extended disease control, particularly within the central nervous system. The introduction of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan for HER2-mutant NSCLC, and emerging TKIs like zongertinib, represent new therapeutic milestones...Beyond lung cancer, our group, in collaboration with Juntendo University ARO (academic research organization) and fifteen institutions in Japan, conducted the MARBLE phase II trial of atezolizumab plus chemotherapy for thymic carcinoma, achieving a 56% objective response rate and 9.6-month median progression-free survival, supporting potential ICI approval in Japan...The DLL3-targeted BiTE tarlatamab significantly improved overall survival to 13.6 months in the phase III DeLLphi-304 trial for relapsed SCLC, with manageable cytokine release syndrome. Collectively, these advances signify a shift toward biologically driven, molecular-targeted or immune-integrated therapy, aiming to transform lung cancer into a chronic, manageable disease in the future, hopefully.

P1/2, N=181, Recruiting, Boehringer Ingelheim International GmbH

Trastuzumab deruxtecan, zongertinib and sevabertinib have been approved in the United States for the treatment of patients with advanced metastatic HER2 mutated non-small-cell lung cancer (NSCLC). Unfortunately, tumor progression is inevitable in many cases. In this case report, we share our experience with a patient with HER2 mutated NSCLC who responded to the combination of trastuzumab deruxtecan and zongertinib after progressing on each agent when given alone, highlighting the potential for such combinations.

P3, N=400, Recruiting, Boehringer Ingelheim

Three such agents have gained accelerated US Food and Drug Administration (FDA) approval for use in previously treated HER2-mutant NSCLC: the antibody-drug conjugate, trastuzumab deruxtecan; the HER2-specific tyrosine kinase inhibitor (TKI), zongertinib; and the HER2/EGFR TKI, sevabertinib. Zongertinib has also been granted accelerated FDA approval in a first-line setting. The emergence of multiple treatment options highlights the importance of early HER2 mutation testing to guide treatment sequencing and maximize patient benefit.

Trastuzumab deruxtecan (T-DXd) was the first targeted therapy approved for patients with HER2-mutant NSCLC, demonstrating robust and durable responses in about 50% of these patients...On the other hand, novel orally available TKIs with higher specificity and inhibitory potency against HER2 over wild type EGFR such as sevabertinib (a dual HER2/EGFR mutant-selective reversible TKI) or zongertinib (an irreversible HER2-selective TKI that spares EGFR, including mutant EGFR) have further demonstrated deep and durable responses in this disease...In this review, we first describe the molecular landscape and clinical features of HER2-mutant NSCLC. Then, we summarize the clinical and preclinical evidence of HER2-targeted therapies and provide a forward-looking perspective of the treatment landscape of HER2-mutant NSCLC.

Among 74 patients newly diagnosed with HER2-mutant NSCLC who received a daily dose of zongertinib, the objective response rate was 76% and the median progression-free survival was 14.4 months. That bests chemotherapy, to which about 30% of patients typically respond for less than 7 months.