CDK4/6 inhibition with dual immunotherapy in chemorefractory SMARCA4-deficient undifferentiated tumor: a case report.

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are rare malignancies characterized by resistance to chemotherapy and poor clinical outcomes. While immunotherapy have shown promise, especially in the first-line treatment, effective therapeutic strategies for patients with PD-L1-negative tumors and complex genomic profiles remain undefined. We report a case of chemorefractory SMARCA4-UT in a patient presenting with cervical mass. CGP revealed pathogenic SMARCA4, TP53, and CDKN2A mutations. Despite PD-L1 negativity, the tumor exhibited TMB-H and a dominant smoking signature. Guided by precision oncology targeting both immunogenic profile and cell-cycle dysregulation, the patient was treated with dual immunotherapy (pembrolizumab plus ipilimumab) combined with the CDK4/6 inhibitor palbociclib. This novel regimen elicited a metabolic partial response within 1.5 months, which has been sustained for over 4 months. To our knowledge, this is the first report demonstrating the efficacy of dual checkpoint blockade plus CDK4/6 inhibition in SMARCA4-UT. This case highlights potential of biomarker-driven therapies to overcome resistance in rare thoracic neoplasms.