Targeted Therapy or Tension: A Case of Tyrosine Kinase Inhibitor-Mediated Hypertensive Crisis in a Patient with Advanced Renal Cell Carcinoma

Introduction: Cabozatinib is an oral inhibitor of multiple tyrosine kinases (TKIs) approved for the treatment of advanced renal cell carcinoma (RCC) based on the METEOR trial. We present a case where the patient experienced a Grade 4 adverse effect in the form of a hypertensive crisis. Case Description: A 71-year-old woman with well-controlled hypertension on lisinopril 20 mg daily and prior RCC treated by radical nephrectomy and short-lived pembrolizumab (stopped for immune polyarthritis) began cabozantinib 40 mg daily for progression. After 48 hours, she presented in hypertensive crisis (BP 207/96 mmHg) requiring IV nicardipine; cabozantinib was held, and she was discharged on nifedipine 120 mg qd and lisinopril 40 mg qd. Six weeks later, a rechallenge with cabozantinib 20 mg daily precipitated another hypertensive emergency (BP 260/120 mmHg) within 10 days, again managed with IV nicardipine and drug cessation. Work-up for secondary hypertension (aldosterone renin ratio, renal doppler, plasma/urine metanephrine, thyroid studies) was negative; kidney function remained normal, and she was non-proteinuric. Twelve weeks after stopping cabozantinib, she remained markedly hypertensive despite four agents (lisinopril 40 mg qd, nifedipine 120 mg qd, chlorthalidone 25 mg qd, spironolactone 25 mg qd). Cabozantinib was permanently discontinued. Post discontinuation, 12 weeks, she remained resistant hypertensive on 4 drugs with BP 120-130/80-90 mmHg. Since then, she has been receiving Belzutifan (HIF-2α inhibitor) without adverse effects. (Ref Fig1) Discussion: Grade 1-3 HTN was observed in about 37% of patients in the METEOR Trial (Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma), but frank hypertensive crisis (grade 4) and true resistant hypertension are very uncommon (<1 %). Presentation with hypertensive crisis prompts discontinuation of the TKI therapy.