Prolonged Survival in HER2 Mutant Metastatic NSCLC with Leptomeningeal Metastases Treated with Intrathecal Trastuzumab and Methotrexate: A Case Report

Abstract

Leptomeningeal metastasis (LM) is a devastating complication of any solid organ malignancy, including nonsmall cell lung cancer (NSCLC). Human Epidermal Growth Factor Receptor2 HER2 mutant NSCLC is a rare subtype detected in only 2 to 4% cases. The occurrence of LM in HER2 mutant NSCLC is an extremely rare event. This case report describes a HER2 mutant NSCLC patient who developed LM during treatment with maintenance intravenous (IV) pemetrexed 500 mg/m² following four cycles of pemetrexed 500 mg/m² and carboplatin area under the curve 5. He was treated with a combination of twice-weekly intrathecal (IT) methotrexate (12.5 mg), trastuzumab (75 mg), and hydrocortisone (50 mg) with continued 3-weekly maintenance IV Pemetrexed. Patient improved clinically after the first week of initiation of IT therapy. Cerebrospinal fluid (CSF) was negative for malignant cells after seven doses of IT therapy, after which IT therapy was switched to once weekly. After 3 months, IT therapy was continued at 3 weekly intervals with IV Pemetrexed. Patient is still progression-free after 12 months of initiation of IT therapy. Toxicities were minimal and conservatively manageable. This is the first reported case of HER2 mutant NSCLC with LM treated with IT trastuzumab, methotrexate, and hydrocortisone, along with maintenance IV chemotherapy, and the patient has remained progression-free after 12 months of initiation of IT therapy. This regimen can be considered as a novel treatment of choice for HER2 mutant NSCLC with LM, especially in resource limited setting.

Keywords

NSCLC - HER2 mutant - CSF - leptomeningeal - trastuzumab - methotrexate

Introduction

Lung cancer is the second most common cancer in males in India by both incidence and mortality.[1] Leptomeningeal metastases (LM) are an uncommon and clinically devastating complication of lung cancer, especially in the absence of common targetable driver mutations. LM is detected in about 3 to 5% of non-small cell lung cancer (NSCLC) patients. The overall prognosis of LM is very poor, with overall survival ranging from weeks to a few months.[2]

Erb-B2 Receptor Tyrosine Kinase2, also known as Human Epidermal Growth Factor2 HER2, mutations are very rarely detected in NSCLC in only about 2 to 4% cases.[3] The presence of LM in the background of HER2 mutation in lung cancer is extremely rare. Frontline clinical trial (Destiny Lung 02) in HER2-mutated NSCLC excluded patients with active brain metastases, including LM.[4] Treatment guidelines in this setting are lacking, and few isolated individualized treatment approaches were found on literature search. Here, we present a case of adenocarcinoma of the lung having an HER2 mutation developing LM during treatment.

Case Report

A 53-year-old male smoker presented with cough and right-sided chest pain for 1 month in August 2023. Chest X-ray showed a right lower zone mass with nodules in the contralateral lung. He then underwent whole body 18 fluoro deoxy glucose (FDG) positron emission computed tomography (PET-CT) scan which revealed FDG avid enhancing spiculated parahilar mass encasing right middle and upper lobar bronchi abutting right main pulmonary artery and partially encasing its descending branch, metastatic right lower lobe lung nodule, extensive bilateral lung nodules and septal thickening, metabolically active involved prevascular, right upper and bilateral lower paratracheal, subcarinal, left hilar and intra thoracic para-aortic nodes, metastatic right cervical level IVB and perigastric nodes and D11 vertebra and right nineth rib lesions. ([Fig. 1])

Fig. 1 PET CT scan on initial diagnosis.

Patient underwent CT-guided biopsy from the lung lesion, which revealed adenocarcinoma of the lung with solid and lepidic patterns. Immunohistochemistry (IHC) showed diffuse strong positivity for thyroid transcription factor-1. IHC for programmed death ligand-1) on SP-263 Ventana platform showed tumor positivity score-0%. Next-generation sequencing (NGS) was done, which showed HER2 Exon 20 insertion.

Patient was started on intravenous (IV) pemetrexed 500 mg/m² and carboplatin area under the curve 5 every 3 weeks. After four cycles, PET CT was done in November 2023, which showed a completely resolved right parahilar mass and D11 lesion, a metabolically mildly active small residual nodule in the right lung lower lobe, active bilateral hilar lymphadenopathy with a few mediastinal lymph nodes, overall partial metabolic response compared to the previous PET-CT ([Fig. 2]). Patient was continued on IV Pemetrexed 500 mg/m² maintenance every 3 weeks.

Fig. 2 PET CT scan after four cycles of chemotherapy.

After the 10th cycle of Pemetrexed, repeat PET CT in March 2024, and in October 2024, showed a partial response. Patient was continued on 3 weekly pemetrexed. However, in November 2024, the patient was admitted with a headache and diminished vision in both eyes for 15 days. The patient also had a few episodes of generalized tonic-clonic convulsions. The patient was treated with levetiracetam, lacosamide, and other supportive measures. Contrast-enhanced magnetic resonance imaging of the brain showed generalized cerebral and cerebellar atrophic changes. CSF analysis showed the presence of malignant cells in CSF with slightly elevated protein (63 mg/dL).

Patient was then started on intrathecal (IT) hydrocortisone (50 mg), methotrexate (12.5 mg), along with trastuzumab (75 mg) twice weekly. Patient improved neurologically after the first week of IT therapy, and his headache and dimness of vision improved significantly. After the sixth dose, he had prolonged grade 3 mucositis for which IT and IV therapy were interrupted for 3 weeks. Treatment was resumed after resolution of mucositis, and since then, leucovorin 15 mg has been administered orally 24 hours after IT therapy. No further episodes of mucositis were documented. CSF was tested weekly for malignant cells, and it tested negative for malignant cells after seven doses of IT therapy. IT therapy was switched to once weekly after CSF tested negative for malignant cells. Pemetrexed was continued 3 weekly as before. After completing 3 months, IT chemotherapy was continued at 3 weekly intervals along with Pemetrexed. CSF cytology at 6 months from initiation of IT therapy was negative for malignant cells.

Patient has remained clinically asymptomatic to date and is continuing 3 weekly IT therapy and IV Pemetrexed. PET CT in April 2025 showed a partial response with a faint FDG-avid residual primary neoplastic lesion ([Fig. 3]). Post-initiation of IT therapy for LM, the patient is progression-free after 12 months.

Fig. 3 PET CT after 5 months of initiation of intrathecal therapy.

Discussion

There is sparse data in the literature with respect to the incidence or treatment of LM in HER2 mutant NSCLC. HER2 aberrations show an association with increased central nervous system (CNS) metastases across different cancers.[5] Till recently, the only approved therapies for patients with HER2 mutant NSCLC were fam-Trastuzumab deruxtecan-nxki (TDXd) and ado-trastuzumab emtansine (TDM-1). However, the Destiny Lung 01 and Destiny Lung 02 trials, which evaluated TDXd in this setting, excluded patients with active symptomatic brain metastases.[4] [6] A phase II basket trial by Li et al evaluating TDM-1 showed progression at the first response assessment itself in the two patients having brain metastases.[7] Pyrotinib and Poziotinib are HER2-specific tyrosine kinase inhibitors (TKI), which are being evaluated for HER2 mutant NSCLC but are not yet approved.[8] Also, data is lacking with respect to their use in LM. A case report of Poziotinib use in the treatment of LM in pretreated HER2 mutant NSCLC showed PFS limited to about 2 months only.[9] Another anti-HER2 TKI Zongertinib is being evaluated and was very recently approved by the Food and Drug Administration for the treatment of NSCLC patients with HER2 tyrosine kinase domain mutation. It has shown promising CNS activity but is still not available in India.[10]

Historically, IT methotrexate has been used in the management of LM in solid organ malignancies, including NSCLC.[11] Several case reports and series have shown the effectiveness of IT trastuzumab in LM in HER2-positive metastatic breast cancer.[12] [13] Furthermore, a phase II clinical trial showed that weekly 150 mg of IT Trastuzumab resulted in clinical neurological response in HER2-positive breast cancer patients with LM.[14]

In spite of an extensive literature search, only two isolated case reports were available to date that addressed HER2-mutated NSCLC patients with LM.[3] [9] In one of those reports, Poziotinib resulted in PFS of only about 2 months and OS of 2.5 months. In the other report, Trastuzumab deruxtecan was started, but no follow-up data after treatment initiation were provided. A list of available data on treatment options in HER2 mutant NSCLC is given in [Table 1] [15] but no data is available for standard of care treatment options in the presence of LM.

Table 1 Drugs used in HER2-mutated NSCLC

Setting	Drug(s)	Reference	Year	ORR (%)	mPFS (mo)	mOS (mo)
Monoclonal antibodies ± chemotherapy
≥2 L	Trastuzumab + Pertuzumab	Van Berge HJM	2022	8.3	4	10
≥1 L	Trastuzumab + Pertuzumab + Docetaxel	Mazieres IFCT-1703R2D2 Trial	2022	29	6.8	17.6
Antibody drug conjugates
≥2 L	Trastuzumab emtansine	Hotta Phase II	2018	14.3	2	10.9
≥2 L	Trastuzumab emtansine	Iwama Phase II	2022	38.1	2.8	8.1
≥2 L	Trastuzumab deruxtecan	Li-(6.4 mg/kg) DESTINY lung 01 phase II	2022	55	8.2	17.8
≥2 L	Trastuzumab deruxtecan	Goto (5.4 mg/kg) Janne (6.4 mg/kg) DESTINY lung 02 phase II	2023 2024	50 (IC-50) 56 (IC-30)	10 12.9	19 17.3
≥2 L	Trastuzumab rezetecan	Li HORIZON lung phase II	2025	73	11.5	NE
Tyrosine kinase inhibitors
≥1 L	Neratinib	Gandhi PUMA-Ner 4201. Phase-II	2017	0	2.9	10
≥2 L	Afatinib	Dziadziuszko NICHE trial phase II	2019	7.7	3.7	13.1
≥2 L	Pyrotinib	Wang Phase II	2019	53	6.4	12.9
≥2 L	Pyrotinib	Liu Phase II	2023	37.5	7.3	14,3
≥2 L	Poziotinib	Elamin Phase II	2022	27	5.5	15
1 L	Poziotinib	Cornellisen ZENITH 20-4 trial, phase-II	2023	39	5.6	–
≥2 L	Sevabertinib	Le SOHO1 trial (phase I/II)	2024	72.1	7.5	–
≥2 L	Zongertinib	Heymach BEAMION lung 1 phase-Ia/Ib	2025	71	12.4	–

Abbreviations: 1 L, first line; 2 L, second line; IC, intracranial objective response rate; mOS, median overall survival; mPFS, median progression-free survival; ORR, objective response rate.

Based on these extrapolated data, we initiated our patient on combined IT methotrexate and trastuzumab therapy. He is progression-free even after 12 months of initiation of therapy. Use of this combination can be considered as a novel approach in the treatment of LM in HER2 mutant NSCLC. To the best of our knowledge, this will be the first reported case of HER2 mutant NSCLC with LM showing sustained pathological and clinical neurological response with a combination of IT methotrexate, trastuzumab, and hydrocortisone. Though we could not perform NGS on CSF when LM was detected due to logistic constraints, therapy based on the initial tissue NGS results produced a clinically meaningful response. In a resource-limited setting, where newer TKIs and antibody drug conjugates (ADCs) may not be available or have prohibitive costs, this combination used in our patient can be considered as a clinically useful option in the given subset of patients. Also, serious adverse effects of ADCs and newer TKIs, like interstitial lung disease, could be avoided with this regimen. It also highlights the importance of continuing systemic therapy in this group of patients.

Conclusion

Our case highlights the clinical effectiveness of IT methotrexate, trastuzumab, and hydrocortisone combined with continuing IV maintenance chemotherapy in control of LM disease in HER2 mutant NSCLC. We suggest that the regimen used in our case can be considered for evaluation in further clinical research as the treatment of choice in the given subgroup of patients, especially in resource limited setting.

Conflict of Interest

None declared.

Authors' Contributions

The article has been read and approved by all the authors, that the requirements for authorship have been met, and that each author believes that the article represents honest work. All the authors have contributed to patient management and preparation of the article.

Patient Consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal.

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Publication History

Article published online:
28 February 2026