Metastatic lung adenocarcinoma harboring an ERBB2 exon 20 insertion and low-level copy-number gain: hyperprogression after immunotherapy and sequential HER2-directed ADC therapy—a case report

Background HER2 (ERBB2) alterations in non-small cell lung cancer (NSCLC) comprise a molecularly heterogeneous group, including activating mutations, copy-number gain/amplification, and protein overexpression. HER2 mutation and high-level amplification are generally distinct biological events. HER2-directed antibody–drug conjugates (ADCs) have transformed treatment, yet questions remain regarding sequencing, coexisting HER2 alterations, and central nervous system (CNS) progression. Case description A never-smoking woman presented in August 2025 with stage IVB (T4N3M1c2, AJCC v9) right upper-lobe lung adenocarcinoma with nodal, brain, renal, bone, adrenal, and abdominal/retroperitoneal metastases (ECOG 1–2). A 919-gene NGS panel identified an ERBB2 exon 20 insertion, p.Y772_A775dup (VAF 58.4%), with low-level ERBB2 copy-number gain (copy number 3.1); TP53 p.I195T and p.R249S were also detected. PD-L1 tumor proportion score (TPS) was 40%. Because of symptomatic, high-volume disease, cycle 1 (August 31, 2025) consisted of pemetrexed plus carboplatin before biomarker results were available; ivonescimab was added in cycle 2 (September 23, 2025). Restaging on October 15, 2025 showed marked multi-compartment progression: the lung target lesion increased from 4.56 cm to 10.05 cm (>120%), with new brain, renal, and adrenal metastases, retroperitoneal lymphadenopathy, a large right pleural effusion, and deterioration to ECOG 3–4, consistent with hyperprogressive disease (HPD), which was temporally associated with immune checkpoint inhibitor (ICI) exposure—occurring approximately 3 weeks after the first, and only, dose of ivonescimab and without disease acceleration during the preceding chemotherapy-only cycle. Trastuzumab rezetecan was initiated on October 16, 2025 for six cycles. By December 5, 2025, the lung lesion had shrunk to 5.68 cm with reduced pleural effusion and partial intracranial improvement; best overall response was partial response (PR). Restaging on March 1, 2026 demonstrated spatially heterogeneous progression: thoracic disease and pleural effusion remained controlled, whereas renal, adrenal, retroperitoneal nodal, skeletal, and intracranial lesions progressed, with meningeal enhancement suspicious for leptomeningeal metastasis (lumbar puncture declined). No cranial radiotherapy or surgery was ever administered. Progression-free survival (PFS) was approximately 4.5 months and duration of response (DOR) approximately 2.9 months. Zongertinib 120 mg once daily was started on March 2, 2026, but was discontinued after 7 days because of financial constraints, precluding objective response assessment. The patient died on May 15, 2026, with an overall survival (OS) of approximately 9.5 months. Conclusion In this case of metastatic lung adenocarcinoma with a concurrent ERBB2 exon 20 insertion and low-level copy-number gain, urgent biomarker-agnostic chemo-immunotherapy was followed by HPD after a single ivonescimab cycle, whereas molecularly matched trastuzumab rezetecan produced a rapid partial response with systemic and transient intracranial control before spatially heterogeneous progression emerged. Salvage zongertinib was clinically rational but could not be objectively assessed because of limited exposure. This case highlights how biomarker turnaround time, drug accessibility, and compartment-specific resistance shape the real-world management of HER2-driven NSCLC, and emphasizes the diagnosis of HPD and its temporal association with ICI exposure. The case also has implications for patient selection, supporting early molecular characterization and the prioritization of molecularly matched HER2-directed therapy in patients with actionable oncogenic drivers.