The STAT3/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report

Joaquim Bosch-Barrera^1,2,3*Elia Sais^1,2,3Eduard Teixidor-Vilà^1,2Carmen Vásquez-Dongo^3,4Alejandro Hernandez-Martínez^1,2Alvaro Romera^1,2Mel.lina Pinsach-Abuin⁵Bernat del Olmo⁵Glòria Oliveras⁴Emma Polonio-Alcalá²Sara Verdura Martinez²Miriam Soriano-Gamero²Victor Pineda⁶Hugo Rosales⁷Javier A Menendez^2,8

• ¹Department of Medical Oncology, Catalan Institute of Oncology, Girona, Catalonia, Spain
• ²Institute of Biomedical Research of Girona, Girona, Catalonia, Spain
• ³Department of Medical Sciences, University of Girona, Girona, Catalonia, Spain
• ⁴Department of Pathology, Doctor Josep Trueta Girona University Hospital, Girona, Spain
• ⁵Molecular Diagnostics and Precision Medicine Unit. Girona Territorial Clinical Laboratory - Dr. Josep Trueta University Hospital, Girona, Spain
• ⁶Department of Radiology, Hospital Universitari de Girona Doctor Josep Trueta, Girona, Catalonia, Spain
• ⁷Department of Radiotherapy, Catalan Institute of Oncology, Girona, Spain
• ⁸Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, Girona, Spain

Background: Approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastases (BM), which are associated with poor prognosis. Pembrolizumab has shown promising results in advanced NSCLC with PD-L1≥50%, including patients with BM. Silibinin is a flavonolignan with known blood-brain barrier permeability and anti-BM activity associated with inhibition of the STAT3/TIMP1 signaling axis. To the best of our knowledge, this is the first clinical evidence of combining silibinin with pembrolizumab to achieve a durable partial response in BM, lasting over nine months. Case Report: We present the case of a 72-year-old male with stage IVB lung adenocarcinoma and BM, who achieved durable intracranial tumor control with a combination of pembrolizumab and silibinin supplementation. Initial treatment with brain hypofractionated stereotactic radiotherapy and pembrolizumab led to a 14-month partial response. Progression occurred with a new jejunal metastasis and increasing temporal brain lesion. After declining whole-brain radiotherapy, the patient continued pembrolizumab with silibinin (630 mg/day), on a compassionate basis. At two months, a partial response in the temporal lobe lesion was observed, and at nine months, nearly complete intracranial response was achieved with no extracranial progression. Molecular analysis revealed high PD-L1 expression and a METex14, potentially enhancing the response to immunotherapy. Conclusions: This case highlights the potential of silibinin as an adjuvant therapy to enhance anti-PD-1 efficacy in brain metastases, possibly by targeting STAT3/TIMP1-driven immunosuppressive astrocytes. Further investigation of the role of silibinin in improving immunotherapy outcomes in advanced lung cancer patients with BM is required.