A 67-year-old man, a former smoker, presented with gross hematuria. His initial workup revealed normal renal function, iron deficiency anemia, and increased alkaline phosphatase levels. A CT urogram showed a bladder tumor in the anterior wall and multiple enlarged retroperitoneal lymph nodes. Two vertebral metastases (at T10 and L2) were seen on a bone scan. He underwent a transurethral resection of the bladder, and the pathology report revealed muscle-invasive urothelial carcinoma.
He was treated upfront with cisplatin and gemcitabine. After receiving the first 3 cycles of this regimen, imaging studies demonstrated stable disease. However, upon completion of 6 cycles, he developed mild bone pain; follow-up CT and bone scans revealed an increase in the number and size of the enlarged retroperitoneal lymph nodes, a new right adrenal gland metastasis, and a new bone lesion in the 10th rib compatible with disease progression.
Immunohistochemistry (IHC) of paraffin-embedded bladder tumor tissue revealed > 10% expression of programmed death ligand 1 (PD-L1) in tumor cells and infiltrating immune cells. His performance status was good (Eastern Cooperative Oncology Group [ECOG] performance status score, 1), so he was started on pembrolizumab every 3 weeks as second-line treatment. After 3 cycles, he was found to have a partial response, with his follow-up CT scan showing a 50% decrease in size of the right adrenal gland metastasis and the retroperitoneal lymph node conglomerate (Figure 1). Additionally, the bone scan showed decreased radiotracer uptake in bone lesions (Figure 2). The patient will continue on treatment with pembrolizumab until further assessment.
Which of the following biomarkers indicated that this patient was a good candidate to receive immunotherapy as a second-line therapy after his disease had progressed following platinum therapy—and can be used to make treatment decisions in other patients with metastatic urothelial carcinoma in this setting?
A. PD-L1 expression assessed by IHC on infiltrating immune cells > 5%
B. PD-L1 expression assessed by IHC on tumor cells and infiltrating immune cells > 5%
C. PD-L1 expression assessed by IHC on tumor cells and infiltrating immune cells > 10%
D. There is currently no reliable biomarker
- Five immune checkpoint inhibitors have recently been approved for second-line treatment of urothelial carcinoma based on their good response rates and toxicity profiles. Pembrolizumab has demonstrated an overall survival benefit compared with investigator's choice of chemotherapy in a phase III randomized trial.
- Currently, there is no reliable biomarker for selecting candidates for anti–PD-1/PD-L1 agents in this setting. Patients must be considered eligible based on their performance status and prognostic risk factors; PD-1/ PD-L1 testing is not needed.
Correct Answer: D
There is currently no reliable biomarker for selecting candidates for programmed death 1 (PD-1)/PD-L1–targeted immunotherapy as second-line therapy in metastatic urothelial carcinoma. Patients are eligible for immune checkpoint inhibitor therapy regardless of their PD-L1 status. The IHC assay, and whether testing should be performed in tumor cells, infiltrating immune cells, or both, have not yet been standardized; the optimal cutoff point for determining PD-L1 status also remains to be defined.
Urothelial carcinoma is the second most common malignancy of the genitourinary system and the sixth most common cancer in the United States. Stage IV metastatic disease is associated with a poor prognosis, with only a 5% survival rate at 5 years.[1,2] Platinum-based chemotherapy leads to high response rates in patients with advanced urothelial carcinoma and has remained the standard of care for first-line systemic treatment, with an expected survival of 9 to 15 months.
Like the patient in this case, most patients will ultimately experience disease progression after platinum-based chemotherapy and will need further therapy. However, there is a lack of effective second-line therapies in this setting. Single-agent chemotherapies used in the second-line setting, such as paclitaxel, docetaxel, gemcitabine, and pemetrexed, have only been tested in phase II studies, in which they have demonstrated low response rates and considerable toxicities. Vinflunine is the only cytotoxic agent to have demonstrated a benefit in a placebo-controlled randomized phase III trial. Nevertheless, the drug showed a disappointing overall response rate (ORR; 8.6%); was not compared against other commonly used chemotherapies, such as taxanes; was never approved in the United States; and in the most recent intention-to-treat analysis, the overall survival (OS) difference (6.9 vs 4.6 months) did not reach statistical significance.
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