Utilization of Circulating Tumor DNA as a Biomarker of Response in a Case of Metastatic Urothelial Carcinoma Treated with Efortumab Vedotin and Pembrolizumab

Background

Though the standard of care for metastatic urothelial carcinoma (mUC) patients is cisplatin-based chemotherapy, many are deemed “unfit.” The FDA recently granted approval for frontline use of enfortumab vedotin (EV), an antibody-drug conjugate (ADC), with pembrolizumab (immune checkpoint inhibitor, ICI) for cisplatin-ineligible mUC. However, with such a novel therapy, optional treatment duration remains unclear. Furthermore, a key challenge to ICI-containing treatment is the lack of reliable predictive biomarkers of response. Circulating tumor DNA (ctDNA) is emerging as a noninvasive biomarker that may assess ICI response.

Case Discussion

A 73-year-old woman presented with gross hematuria. A transurethral resection of bladder tumor revealed T2b papillary UC. Genetic sequencing noted elevated PD-L1 expression and tumor mutational burden (TMB). Computed tomography (CT) showed an osteolytic lesion of the right inferior pubic ramus concerning for metastasis, confirmed by nuclear medicine bone scan and bone biopsy. Since the patient’s glomerular filtration rate was less than 50 mL/min, she was started on EV/pembrolizumab. Serial ctDNA measurements following treatment initiation were undetectable. After her sixth cycle, with undetectable ctDNA and restaging scans showing complete response, the decision was made to stop treatment and remove the primary tumor. She underwent a radical cystourethrectomy, with complete pathologic response. The patient has remained on observation without treatment for over two years, with continued complete response on CT scans and undetectable serial ctDNA.

Conclusion

Frontline EV/pembrolizumab is being evaluated against the conventional cisplatin-based regimen for mUC in the EV-302 phase III trial. The investigation for optimal treatment duration and biomarkers of response are being studied given the novelty of these agents. In this case of de novo oligometastatic UC with elevated PD-L1 expression and high TMB, the utilization of ctDNA in monitoring response to EV/pembrolizumab was helpful in the decision for consolidative surgery and early treatment discontinuation.