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Neoadjuvant Dual Checkpoint Blockade for High-Risk Urothelial Carcinoma

By: Julia Fiederlein
Posted: Friday, November 20, 2020

According to Padmanee Sharma, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues, neoadjuvant combination therapy with the anti–CTLA-4 antibody tremelimumab and the anti–PD-1 antibody durvalumab appeared to be well tolerated in patients with high-risk localized muscle-invasive urothelial carcinoma who were ineligible to receive cisplatin-based chemotherapy. The results of this early-phase trial, which were published in Nature Medicine, also showed early signs of activity in certain patients after treatment with this dual checkpoint blockade.

“Immune checkpoint therapy has clearly revolutionized cancer care for patients with metastatic disease in multiple tumor types, but we continue to work toward moving these therapies into earlier disease settings for patients in need,” Dr. Sharma commented in an MD Anderson press release. “By combining these therapies, we felt we could take advantage of the distinct biologic mechanisms and stimulate a more robust antitumor immune response for these patients.”

A total of 28 patients underwent transurethral resection and were administered a combination of durvalumab and tremelimumab every 4 weeks prior to cystectomy. Blood and tumor tissue samples were obtained before and after treatment.

Immune-related adverse events of grade 3 or higher (asymptomatic elevation of lipase and amylase levels, asymptomatic hyponatremia, hepatitis, and colitis) were observed in 21% of patients. Of the 24 patients who completed surgery, 58% experienced downstaging to pT1 or less; the pathologic complete response rate was 37.5%. After 1 year, the rate of relapse-free survival was 82.8%. Among all patients, the overall survival rate was 88.8% at 1 year. Compared with nonresponders, responders to combination therapy had a higher density of tertiary lymphoid structures in their pretreatment tumor samples (P = .01). This increased prevalence of specialized immune-cell clusters seemed to correlate with longer durations of overall survival and relapse-free survival.

Disclosure: For full disclosures of the study authors, visit www.nature.com.



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