From ADC Resistance to Renewed Immunotherapy Benefit: MDT-Guided Multi-Line Treatment Decisions in Advanced HER2-Mutant Lung Adenocarcinoma

This article is a de-identified educational case review. It describes the clinical course of one patient managed at Beijing Arion Cancer Hospital and reflects the team's approach to multidisciplinary decision-making across multiple lines of therapy. It is not medical advice, nor does it guarantee outcomes for other patients. Treatment decisions must be individualized by qualified physicians.

Case Introduction

This issue discusses the MDT-managed full course of treatment for a 47-year-old man with stage IV lung adenocarcinoma. He was initially diagnosed with stage IVB lung adenocarcinoma carrying an ERBB2 p.Y772_A775dup mutation with a PD-L1 TPS of 15%. During treatment the patient successively received platinum-based chemotherapy combined with immunotherapy, trastuzumab deruxtecan (T-DXd), a HER2-TKI, and immunotherapy combined with chemotherapy across multiple lines. As treatment progressed, the tumour moved through a dynamic process from initial HER2-driven disease with ADC benefit, to clonal evolution after resistance and a shift in immune phenotype. At several points the team faced difficult decisions: how to choose the treatment sequence for advanced HER2-mutant lung cancer, how to identify the resistance mechanism after ADC resistance, and how to find new treatment opportunities after HER2-targeted therapy failed. This case reflects the rapid progress of advanced HER2-mutant lung cancer from "few options" to "multiple available lines", and offers a practical reference for the comprehensive management of such patients.

I. Case Preview

The patient was a 47-year-old man who presented with chest tightness. In July 2024 PET-CT showed a patchy and streaky shadow in the right upper lobe with abnormally increased metabolism, involving the pleura, chest wall and ribs; multiple hypermetabolic lymph nodes in the right hilum and mediastinum; and a hypermetabolic focus in the L2 vertebral body, considered suspicious for malignancy. Percutaneous lung biopsy showed poorly differentiated adenocarcinoma of the right upper lobe.

Immunohistochemistry showed: TTF-1 (+), Napsin A (+), CK7 (+), P40 (−), P63 (−), Ki-67 (+20%). Genetic testing showed an ERBB2 mutation (p.Y772_A775dup, mutant allele frequency 16.3%), a TP53 mutation, PD-L1 TPS = 15% and CPS = 20. The clinical stage was cT3N2bM1, stage IVB. Past history was unremarkable.

II. MDT Full-Course Management

First MDT: Determining the First-Line Regimen

Core topic: choosing the initial treatment strategy for stage IV HER2-mutant lung adenocarcinoma.

Key question 1: Is surgical resection feasible? The patient was stage IV, with intrapulmonary metastatic lesions beyond the scope of surgery; from a clinical staging standpoint there was no surgical indication, and the MDT unanimously did not recommend surgery.

Key question 2: Should first-line treatment be targeted therapy or chemo-immunotherapy? Controversy: genetic testing showed an ERBB2 mutation with available ADCs and targeted drugs (trastuzumab deruxtecan, pyrotinib and others) — should these be used directly in the first line? Evidence: at that time both domestic and international guidelines and clinical practice listed targeted drugs such as trastuzumab deruxtecan as later-line therapy. First-line treatment of HER2-mutant NSCLC mainly followed that for the driver-gene-negative population. HER2-mutant patients usually have low PD-L1 expression, single-agent immunotherapy has limited efficacy, and chemo-immunotherapy remained the standard choice. Decision: chemo-immunotherapy was adopted as the first-line regimen — toripalimab + pemetrexed disodium + carboplatin, with denosumab added for bone metastases. Targeted drugs were reserved for later lines, consistent with the treatment sequence recommended by guidelines at the time.

Treatment response: the patient started chemo-immunotherapy on August 9, 2024. After 2 cycles, imaging and tumour markers showed stable disease (SD), and bevacizumab was added. After 6 cycles the overall assessment remained SD, but imaging showed a trend toward enlargement of small intrapulmonary metastatic lesions and tumour markers gradually rose, suggesting that although the first-line regimen controlled the bulk disease, a potential trend toward progression had emerged. After 1 cycle of toripalimab maintenance monotherapy, repeat PET-CT showed a hypermetabolic right upper lobe mass, considered residual tumour activity after treatment, confirming that first-line efficacy had reached a plateau and that a second-line decision was required.

Second MDT: Adjusting Second-Line Treatment

Core topic: after stable disease but with a trend toward progression on first-line chemo-immunotherapy, how should the subsequent regimen be adjusted?

Key question 1: How to choose subsequent systemic therapy? Controversy: with signs of resistance emerging on first-line therapy, should second-line treatment be immunotherapy combined with later-line chemotherapy or an antibody-drug conjugate (ADC)? Evidence: trastuzumab deruxtecan is the first targeted drug approved for HER2-mutant NSCLC. The DESTINY-Lung05 study showed an ORR of 56.9% and a median DOR of 11.6 months in Chinese patients with pretreated HER2-mutant metastatic NSCLC. Based on this evidence, the MDT team unanimously considered trastuzumab deruxtecan the most appropriate second-line systemic regimen at this stage.

Key question 2: Should the TILs opportunity be used for prospective reserve? Background: at that time the hospital was conducting a clinical study of tumour-infiltrating lymphocyte (TILs) therapy, and the patient met the enrolment criteria. TIL therapy is one of the most promising directions in solid tumour immunotherapy. The MDT team suggested that, before changing systemic therapy, the lung primary lesion could first be resected by thoracoscopy to obtain tissue for TILs preparation and cryopreservation, preserving an "individualized cell therapy product" for the patient for later elective use. Decision: after full informed discussion, the patient declined the TILs preparation because of concern about the invasive thoracoscopic procedure. The MDT team respected the patient's wishes and decided not to proceed with the TILs process, starting trastuzumab deruxtecan systemic therapy directly. This decision reflects the MDT's core "patient-centred" philosophy — while offering cutting-edge treatment options, it fully respects the patient's autonomy and helps them make an informed choice, rather than forgoing options because of information asymmetry.

Treatment response: the patient started trastuzumab deruxtecan on January 23, 2025 and completed 11 cycles by August 29, 2025. Multiple assessments during treatment showed SD, and on June 20, 2025 the assessment was shrinkage SD, showing good antitumour activity of the ADC. However, a repeat contrast-enhanced chest CT on August 29, 2025 showed that the nodule in the anterior segment of the right upper lobe and surrounding nodular lesions were markedly larger than before, considered local progression; CEA rebounded, confirming trastuzumab deruxtecan resistance, with a PFS of about 7 months — broadly consistent with the median PFS data in the DESTINY-Lung series.

Third MDT: Comprehensive Decisions After ADC Resistance

Core topic: after local progression following 11 cycles of trastuzumab deruxtecan, how should subsequent treatment be chosen?

Key question 1: With an unclear resistance mechanism, is a repeat biopsy needed? Controversy: must a repeat biopsy be performed to guide subsequent treatment decisions? MDT recommendation: after resistance to targeted therapy, tumours often undergo clonal evolution and new genetic variants, and a repeat biopsy helps clarify the resistance mechanism and discover new therapeutic targets. The MDT team unanimously agreed to first perform a puncture biopsy of the right upper lobe lesion to clarify the nature of the progressing lesion and to repeat genetic testing. On September 5, 2025 the patient underwent CT-guided percutaneous lung biopsy, which went smoothly.

Biopsy result: pathology showed poorly differentiated carcinoma, consistent with INI1 (SMARCB1)-deficient lung cancer. Immunohistochemistry: CK7 (+), TTF-1 (−), Napsin A (−), P40 (partially +), INI-1 (−), Ki-67 70%. Genetic testing: ERBB2 p.Y772_A775dup (mutant allele frequency 43.50%, markedly higher than the 16.3% at initial diagnosis), TP53 p.I195T (59.80%), MYC gene amplification (copy number 4.06). PD-L1: TPS = 75%, CPS = 80 (a sharp rise from the TPS of 15% at initial diagnosis).

Clinical insight: under the pressure of trastuzumab deruxtecan, the tumour underwent significant clonal evolution — acquisition of MYC amplification, loss of INI1 expression, and a sharp upregulation of PD-L1 expression.

Key question 2: How to manage the locally progressing lesion? MDT recommendation: after biopsy, local radiotherapy was given to the progressing right upper lobe lesion, with a prescribed dose of 60 Gy to the GTV (right lung lesion) and 50 Gy to the PGTV (GTV plus a 5 mm margin). The patient tolerated radiotherapy well, with no radiation pneumonitis.

Key question 3: How to choose subsequent systemic therapy? MDT recommendation: subsequent systemic therapy options included targeted therapy (pyrotinib, zongertinib), novel ADC drugs (trastuzumab rezetecan) and immunotherapy combined with second-line chemotherapy. However, pyrotinib has limited overall efficacy as later-line therapy (ORR 35.3%); zongertinib, as a novel targeted drug, has significantly improved efficacy (ORR 71%) but at that time had only just been launched domestically and was not yet accessible; and trastuzumab rezetecan is in the same class as trastuzumab deruxtecan, with no clinical trial clearly defining its efficacy in sequential therapy. After weighing these, the MDT team recommended immunotherapy combined with second-line chemotherapy as the first choice, while awaiting the clinical availability of zongertinib as a subsequent option. Decision: after full informed discussion, the patient had clear concerns about chemotherapy and, worrying that the side effects would affect quality of life, declined the immunotherapy plus second-line chemotherapy regimen. Although the later-line efficacy of pyrotinib is limited, based on the patient's strong preference, treatment was finally adjusted to pyrotinib targeted therapy.

Treatment response: the patient started pyrotinib targeted therapy on September 28, 2025. After 3 months of treatment, repeat tumour markers showed CEA higher than before and chest CT showed the lung lesions slightly larger than before, indicating that pyrotinib monotherapy had limited efficacy in this pretreated HER2-mutant patient and failed to effectively control tumour progression; head MRI showed new brain metastases, consistent with previous literature reporting a later-line ORR of about 30% for pyrotinib, and with the MDT's prediction.

Fourth MDT: Adjusting to a Different Targeted Drug

Core topic: with suboptimal pyrotinib efficacy and zongertinib now available, should treatment be switched?

Basis for decision: on August 29, 2025 zongertinib received conditional approval from the National Medical Products Administration (NMPA) for adult patients with unresectable locally advanced or metastatic NSCLC harbouring a HER2 mutation who have received at least one prior systemic therapy. The Beamion LUNG-1 study showed that zongertinib achieved an ORR of 71% in pretreated patients with HER2-mutant advanced NSCLC, and an intracranial ORR of 43% in patients with brain metastases.

Decision: pyrotinib was discontinued and switched to zongertinib 120 mg once daily.

Treatment response: the patient started zongertinib on January 13, 2026. The first repeat assessment on February 12, 2026 showed stable lung lesions and a markedly slowed rise in CEA, assessed as SD, and treatment was continued. However, the assessment on April 13, 2026 showed that multiple intracranial metastases were smaller than before, but the right upper lobe primary lesion and intrapulmonary metastases were larger, with a new nodule-like lesion in the mid-portion of the left kidney; PET-CT showed hypermetabolism of the lung lesions and a new metabolically active nodule in the left kidney, confirming a "brain-lung dissociation" phenomenon — effective intracranially but progressing extracranially. The PFS of zongertinib was about 3 months.

Fifth MDT: Treatment Choice After Targeted Therapy Resistance

Core topic: after "brain-lung dissociation" on zongertinib, how should the deadlock be broken?

Key question 1: The causes of zongertinib "brain-lung dissociation" and countermeasures. Analysis: zongertinib was effective against intracranial lesions but poorly controlled the lung primary lesion and pulmonary metastases. Possible reasons include that concomitant variants such as MYC amplification and INI1 loss may mediate bypass resistance, along with tumour heterogeneity and pharmacokinetic differences.

Key question 2: Continue HER2 targeting or switch strategy? Controversy: after continuous targeted therapy with trastuzumab deruxtecan → pyrotinib → zongertinib, the tumour had developed complex resistance to the HER2-targeted pathway. Now that PD-L1 had risen from 15% at initial diagnosis to 75%, should the treatment direction shift to immunotherapy? Basis for decision: the MDT team had considered zongertinib combined with chemotherapy. However, given that it took only 3 months from zongertinib response to "brain-lung dissociation", the expected effect of adding chemotherapy in the context of rapid resistance would also be poor, so a complete change in treatment strategy was needed. Ivonescimab is a PD-1/VEGF bispecific antibody that targets both PD-1 and VEGF. Phase II clinical trials are currently exploring the efficacy of ivonescimab in advanced NSCLC with HER2 aberrations. This patient had a PD-L1 TPS as high as 75% and would in theory respond well to ivonescimab combined with chemotherapy. Decision: zongertinib was discontinued and switched to an immunotherapy plus chemotherapy regimen — ivonescimab + nab-paclitaxel + carboplatin.

Treatment response: the ivonescimab plus chemotherapy regimen was started in May 2026, and after 2 cycles the assessment was partial response (PR). After four cycles the lesions were further controlled, and tumour markers such as CEA fell essentially to normal levels.

III. Insights from This Case

1. The treatment landscape of HER2-mutant NSCLC is being redefined. From ADCs to highly selective targeted drugs and then to immunotherapy-based regimens, treatment options for HER2-mutant NSCLC have moved from "no drugs available" to "multiple available lines". The full-course management of this patient verified the feasibility of the multi-line treatment path "chemo-immunotherapy → ADC → TKI → novel immunotherapy plus chemotherapy".

2. "Re-biopsy" is the key to cracking resistance. In this case, timely re-biopsy after trastuzumab deruxtecan resistance revealed key information such as INI1 loss, MYC amplification and a PD-L1 surge, directly changing the treatment direction. This suggests that re-biopsy after resistance should not be an "optional action" but a "standard action".

3. Reshaping the role of immunotherapy in the HER2-mutant population. HER2-mutant NSCLC has traditionally been regarded as a "cold tumour" that responds poorly to immunotherapy. But here, under treatment pressure, PD-L1 rose from 15% to 75% and the patient achieved a PR-level response to ivonescimab plus chemotherapy. This shows that the immune phenotype of a tumour is not fixed, and that dynamic monitoring during treatment may reveal new treatment opportunities.

4. MDT is the core safeguard for full-course management of advanced HER2-mutant lung cancer. This patient received full-course MDT management, and more effective individualized strategies were formulated at multiple key nodes. MDT ensured the scientific rigour of treatment while balancing efficacy and safety, ultimately achieving long-term survival for the patient — fully reflecting the core value of MDT in the diagnosis and treatment of complex tumours.

Expert Commentary

Prof. Zhang Shucai

Chief Physician, Professor, Doctoral Supervisor, Beijing Chest Hospital, Capital Medical University.

The treatment journey of this patient with advanced HER2-mutant lung adenocarcinoma is a vivid microcosm of the rapid development in the field of HER2-mutant NSCLC in recent years — "from nothing to something, from later lines to the first line". HER2 mutation is a refractory subtype of advanced NSCLC: conventional chemotherapy has limited efficacy, the immunotherapy response rate is low, and effective precision treatment options have long been lacking. Trastuzumab deruxtecan is the world's first targeted drug approved for HER2-mutant NSCLC, opening the door to precision therapy. The approval of highly selective oral HER2 TKIs such as zongertinib has pushed this field to a new height, marking that advanced HER2-mutant NSCLC has officially entered a new era of precision targeting. The successive entry of multiple targeted drugs into clinical practice has also brought new challenges — namely how to optimize the treatment sequence of different classes of drugs; the optimal sequential order of ADCs and TKIs still requires more clinical data to determine. In addition, resistance to targeted therapy is inevitable, and how to detect resistance in time and appropriately adjust subsequent treatment regimens has become a key issue urgently to be solved in clinical practice; this patient provides valuable practical experience precisely in this respect. Today, with the treatment landscape of HER2-mutant NSCLC changing rapidly, the complexity of the decisions facing clinicians is unprecedented, and comprehensive MDT assessment has become an indispensable tool, which is expected to find the best balance between the latest therapies and the patient's actual situation, ensuring the greatest benefit for the patient.