Targeted Therapy for Metastatic Urothelial Cancer: A Work in Progress

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 64-year-old man presented to the clinic to discuss treatment options for progressive metastatic urothelial carcinoma (UC). At age 57 years, he underwent cystoprostatectomy for bacillus Calmette-Guérin-refractory, high-grade noninvasive UC. He was well until age 61 years, when he developed a left upper-tract UC. He underwent left nephroureterectomy, revealing locally advanced high-grade UC invading the renal parenchyma (pT3). Postoperatively, his renal function precluded adjuvant cisplatin-based chemotherapy. He enrolled onto a clinical trial of autologous cellular immunotherapy targeting human epidermal growth factor receptor 2, for which he was eligible on the basis of human epidermal growth factor receptor 2 positivity (≥ 1+ by immunohistochemistry) in his nephrectomy tumor specimen. He was randomly assigned to observation. Two years later, he developed a left pelvic mass. Biopsy confirmed metastatic high-grade UC. He was briefly treated with gemcitabine and carboplatin, but this was discontinued as a result of rapid symptomatic and radiographic progression at 8 weeks. He underwent palliative radiation to the left pelvic mass to relieve symptoms of pain and leg edema and subsequently elected to enroll onto a clinical trial of a programmed death 1 inhibitor. Concurrently, his previously obtained pelvic mass biopsy sample was sent for panel-based genomic profiling. He now returns for his first restaging evaluation. Imaging shows marked progression on study with new metastases to the liver as well as progressive edema and pain in the left leg, limiting ambulation. Review of his now-available genomic testing results reveals alterations in HRAS (G12D) and ATR (S296, Q257). He elected to enroll onto a single-arm, open-label trial of a farnesyl transferase inhibitor for patients with HRAS mutations.