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Pembrolizumab is currently a standard first-line treatment option in stage IV non-small cell lung cancer (NSCLC) patients without targetable mutations. Discrepancies between pembrolizumab registration and its application in daily practice exist due to lack of clinical data in specific patient populations. Pharmacokinetic monitoring of pembrolizumab concentrations might provide more insight in the impact of certain conditions on immunotherapy exposure. In this report, we describe a 55-year-old male with metastasized programmed death ligand 1 (PD-L1)-high NSCLC and clinically diagnosed nephrotic syndrome with widespread edema, proteinuria, and severe hypoalbuminemia. The patient was treated with first-line 200 mg pembrolizumab every 3 weeks. Nephrotic syndrome is reported to be a potential source of therapeutic antibody loss during immunotherapy, due to increased protein turnover and excretion. Serum and urine pembrolizumab levels were measured to assess pembrolizumab exposure. Despite severe hypoalbuminemia and proteinuria, treatment was successful. The patient achieved therapeutic exposure and had an impressive clinical response with a vast improvement of edema and hypoalbuminemia, a radiological partial tumor response and ECOG performance status improving from 2 to 0.