FDA Grants Priority Review Zongertinib for HER2-Mutant NSCLC | Breakthrough in Lung Cancer Treatment

A Novel Tyrosine Kinase Inhibitor Poised to Transform Advanced Lung Cancer Care

Boehringer Ingelheim | Ridgefield, Conn., and Ingelheim, Germany | February 19, 2025

On February 19, 2025, Boehringer Ingelheim announced that the U.S. FDA has granted Priority Review to zongertinib (BI 1810631), an investigational oral tyrosine kinase inhibitor (TKI) targeting HER2 (ERBB2) mutations in non-small cell lung cancer (NSCLC). This milestone underscores the urgent need for targeted therapies in this molecularly defined subset of lung cancer patients.

• Indication: Adult patients with unresectable or metastatic NSCLC harboring HER2 (ERBB2) mutations, who have progressed on prior systemic therapy.
• Mechanism: Zongertinib selectively inhibits HER2 tyrosine kinase activity, offering a precision approach distinct from broader-spectrum TKIs.
• Regulatory Timeline: The Prescription Drug User Fee Act (PDUFA) action date is set for Q3 2025, leveraging a 6-month Priority Review timeline versus the standard 10 months.

Scientific Context: HER2 Mutations in NSCLC

HER2 (ERBB2) mutations represent a rare but clinically significant driver in NSCLC, distinct from HER2 amplification seen in breast cancer. These alterations, primarily exon 20 insertions and point mutations, activate oncogenic signaling pathways, conferring aggressive tumor behavior.

• Prevalence: Found in approximately 2-4% of NSCLC cases, with a higher incidence in adenocarcinoma histology and never-smokers.
• Prognosis: Patients face poor survival outcomes with conventional treatments like chemotherapy and PD-1/PD-L1 inhibitors, which show limited efficacy against HER2-driven disease.
• Current Landscape: No oral HER2-specific therapies are approved for NSCLC, with options limited to off-label use of trastuzumab or ado-trastuzumab emtansine (T-DM1), yielding modest responses.
• Significance: Zongertinib could fill this therapeutic void, offering a convenient, targeted oral option.

Beamion LUNG-1 Trial: Robust Phase Ib Data

The Priority Review submission is anchored by compelling results from the Phase Ib Beamion LUNG-1 trial, evaluating zongertinib in previously treated patients with HER2-mutant NSCLC.

• Study Design: Open-label, multicenter Phase Ib, Cohort 1 enrolled 75 patients who had progressed after at least one line of systemic therapy.
• Primary Endpoint: Objective Response Rate (ORR) per RECIST 1.1 reached 71%, indicating significant tumor shrinkage.
• Secondary Endpoints:
  • Progression-Free Survival (PFS): 69% of patients were progression-free at 6 months.
  • Duration of Response (DoR): 73% of responders maintained response at 6 months.
• Patient Population: Focused on tumors with mutations in the HER2 tyrosine kinase domain, validated via next-generation sequencing (NGS).
• Context: These outcomes compare favorably to historical ORRs of 20-50% with anti-HER2 antibodies in similar cohorts.

Safety and Tolerability Profile

Zongertinib’s safety data further bolster its clinical promise, demonstrating a tolerable profile that could support long-term use and combination strategies.

• Treatment-Related Adverse Events (TRAEs):
  • Most common: Diarrhea (51%) and rash (27%), primarily Grade 1-2, manageable with supportive care.
  • Grade 3 or higher TRAEs: Observed in only 1 patient, highlighting low severe toxicity.
• Dose Adjustments:
  • Dose reductions: 5% of patients.
  • Treatment discontinuations: 3% of patients.
• Key Finding: No cases of treatment-related interstitial lung disease (ILD), a notable advantage over other TKIs like osimertinib or afatinib.
• Implication: Favorable tolerability enhances feasibility for combination with immunotherapy or other agents.

Clinical Implications: A Precision Oncology Advance

Zongertinib’s efficacy and safety profile position it as a potential game-changer for HER2-mutant NSCLC, addressing a critical unmet need in precision oncology.

• Efficacy: The 71% ORR and durable responses in pretreated patients suggest superior activity compared to existing options.
• Safety: A low rate of dose adjustments and discontinuations supports its use in frail or heavily pretreated populations.
• Benchmarking: Outperforms historical data for chemotherapy (ORR ~20%) and anti-HER2 monoclonal antibodies (ORR ~40-50%) in this setting.
• Broader Impact: Could redefine treatment algorithms, shifting reliance from IV biologics to oral TKIs.

Biomarker-Driven Approach: The Role of NGS

Identifying HER2 mutations is pivotal to zongertinib’s success, emphasizing the importance of molecular profiling in NSCLC management.

• Mutation Types: Predominantly exon 20 insertions (e.g., YVMA) and activating point mutations in the kinase domain.
• Diagnostic Tool: Next-generation sequencing (NGS) is essential, as immunohistochemistry (IHC) for HER2 overexpression is unreliable for mutation detection.
• Expert Insight: “Biomarker testing guides targeted therapies in personalized medicine, offering hope to patients with rare driver mutations.” – Courtney Granville, Chief Scientific Officer, GO2 for Lung Cancer
• Clinical Action: Oncologists should prioritize NGS in NSCLC workups to identify eligible patients, especially in never-smokers and adenocarcinoma cases.

Regulatory Designations: Fast-Tracking Innovation

Zongertinib’s accelerated regulatory path reflects its potential to address a serious condition with limited alternatives.

• U.S. FDA Designations:
  • Priority Review: Recognizes potential for substantial improvement over available therapies.
  • Breakthrough Therapy: Based on preliminary evidence of superior efficacy from Beamion LUNG-1.
  • Fast Track: Addresses unmet need in a life-threatening disease.
• Japan PMDA: Orphan Drug Designation, reflecting rarity of HER2-mutant NSCLC.
• Global Impact: These designations expedite development and review, potentially bringing zongertinib to patients by late 2025.

Research Opportunities: Beyond NSCLC

The Beamion LUNG-1 trial is just the beginning, with zongertinib poised to influence broader oncology research.

• Ongoing Studies: Expansion cohorts in Beamion LUNG-1 are evaluating higher doses and additional patient subsets.
• Future Directions:
  • First-Line Therapy: Assessing zongertinib in treatment-naïve patients.
  • Combination Strategies: Pairing with PD-1/PD-L1 inhibitors or ADCs to enhance efficacy.
  • Other Indications: Exploring activity in HER2-mutant gastric, colorectal, or breast cancers.
• Research Question: Could zongertinib establish a new standard for HER2-targeted therapy across tumor types?
• Call to Researchers: Engage in trials to define its role in the evolving precision oncology landscape.

Takeaways for Oncologists & Researchers

Zongertinib represents a significant step forward in NSCLC management, with implications for both clinical practice and research.

• Clinical Utility: If approved, zongertinib could become the first oral TKI specifically for HER2-mutant NSCLC, offering a convenient and effective option.
• Research Horizon: Phase Ib data are promising; Phase II/III trials will clarify long-term outcomes and optimal positioning.
• Practice Recommendation: Advocate for routine HER2 mutation screening via NGS to identify candidates early.
• Next Milestone: Await the FDA’s Q3 2025 decision, which could reshape treatment paradigms.

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https://www.boehringer-ingelheim.com/us/zongertinib-granted-priority-review-us-fda