Metastatic lung adenocarcinoma: pembrolizumab response complicated by pulmonary arterial hypertension

What happened, in summary

This 71-year-old man, a former smoker who had quit more than 24 years earlier, first sought care after a lump in his right armpit enlarged over about 2 months. Ultrasound showed a 3.7 cm abnormal right axillary lymph node, and biopsy showed carcinoma with CK7 and TTF-1 positivity and focal p40 staining. PET imaging found FDG-avid lymph nodes in the right hilum, thoracic inlet, mediastinum, and right axilla, while brain MRI showed no intracranial metastases. The findings supported Stage IV metastatic lung adenocarcinoma with a possible squamous component. Next-generation sequencing showed high tumor mutational burden but no other targetable mutations, so there was no driver alteration to guide targeted therapy. Because his disease burden was low and he did not want chemotherapy, he started single-agent pembrolizumab. His cancer responded well for 17 months. He then developed progressive shortness of breath. PET imaging did not show cancer progression or lung inflammation, but echocardiography and right-heart catheterization showed severe pulmonary arterial hypertension with right-heart strain, including markedly elevated right ventricular systolic pressure and high pulmonary vascular resistance. Ventilation-perfusion scanning was normal. Autoimmune and connective-tissue testing did not reveal another cause, so pembrolizumab-related pulmonary arterial hypertension was considered the most likely explanation, and pembrolizumab was stopped. He started riociguat and macitentan, and his exertional fatigue and dyspnea improved; repeat echocardiography showed normalized right ventricular size. His cancer treatment was changed to single-agent pemetrexed. As of April 2025, he was tolerating pemetrexed well, had improved exercise tolerance, and had no evidence of lung cancer progression.