Patritumab Deruxtecan (HER3-DXd) in Active Brain Metastases (BM) from Metastatic Breast (mBC) and Non–small Cell Lung Cancers (aNSCLC), and Leptomeningeal Disease (LMD) from Advanced Solid Tumors: Results from the TUXEDO-3 Phase II Trial 

Dr. Mathias Preusser

Introduction

Brain metastases and LMD are common and serious complications of advanced cancers, especially breast and non-small cell lung cancer (NSCLC). HER3 is expressed in ~75% of brain metastases from breast and NSCLC. HER3-DXd is an antibody-drug conjugate (ADC) targeting HER3, linked to a topoisomerase I inhibitor. It has shown CNS penetration and potential efficacy. Previous trials investigated HER3-DXd in systemic settings (e.g., HERTHENA-Lung01); however, its CNS activity in active brain mets or LMD was unknown.

Study Design

• Trial Type: Phase 2, single-arm, open-label, non-comparative
• Three cohorts:
  1. Cohort 1: Breast cancer with active brain metastases
  2. Cohort 2: NSCLC with active brain metastases
  3. Cohort 3: LMD from any solid tumor
• Treatment: HER3-DXd at 5.6 mg/kg IV every 3 weeks
• Endpoints:
  1. Primary
     • Cohorts 1 & 2: Intracranial ORR, by RANO-BM criteria
     • Cohort 3: 3-month OS rate
  2. Secondary: Extracranial ORR, PFS, OS, safety, QoL, neurocognitive and neurological function

Patient Characteristics

• Enrolled: 60 patients between Dec 2023–Sep 2024 across 8 sites (Austria & Spain)
• Median age: 50–60 years
• ~30% had treatment-naive with active brain metastases
• Cohort 3: All newly diagnosed, no prior LMD treatment
• Tumor Subtypes
  1. Cohort 1 (Breast cancer): HER2+, luminal, and triple-negative
  2. Cohort 2 (NSCLC): Squamous and non-squamous histology, EGFR WT and mutant
  3. Cohort 3 (LMD): Mostly breast or lung primary, 50% with CSF+ (type 1)

Results 

Efficacy

• Cohort 1 – Breast Cancer with Brain Mets
  1. Intracranial ORR: 23.8%
  2. Responses across subtypes, including deep responses in triple-negative BC
  3. Activity noted even in patients with prior ADC exposure
• Cohort 2 – NSCLC with Brain Mets
  1. Intracranial ORR: 30%
  2. Majority of responders had EGFR WT tumors and non-squamous histology
  3. Effective in both newly diagnosed and previously treated brain metastases
• Cohort 3 – LMD from any Solid Tumors
  1. 3-month OS rate: 65%
  2. 10-month OS: ~60%
  3. No difference between LMD type 1 and 2
  4. Suggests meaningful activity and durable survival in this poor-prognosis population

Secondary Outcomes

• Intracranial responses > extracranial responses
• DcR and clinical benefit rate (≥6 months) were encouraging despite prior heavy treatment

Safety Profile

• Grade ≥3 treatment-emergent AEs: ~33%
• No HER3-DXd related deaths
• Permanent discontinuation in ~5% of patients
• Common AEs: Neutropenia, nausea, diarrhoea

Quality of Life & Neurocognition Function

• Assessed via standardized tools
• QoL and cognitive function remained stable or improved across treatment period

Conclusion

• HER3-DXd demonstrated CNS activity in: Brain metastases from breast and lung cancers, Leptomeningeal disease (LMD) with significant survival benefit
• Effective across subtypes, including:
  1. Triple-negative BC
  2. EGFR-WT NSCLC
  3. After prior ADC use

No new safety signals; well-tolerated with preserved QoL and function

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