May 2015, Vol. 2, No. 3

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PD-L1: Promising MIUC Therapy for cNAC Nonresponders

Uncategorized

There’s hope for patients with muscle-invasive urothelial carcinoma (MIUC) who do not respond to cisplatin-based neoadjuvant chemotherapy (cNAC). According to data presented at the 2015 Genitourinary Cancers Symposium, patients with MIUC who are nonresponders to cNAC fare worse than patients undergoing radical cystectomy (RC) alone, but both groups exhibited similar rates of programmed death ligand 1 (PD-L1) positivity.

“Our results demonstrate that nonresponders to cNAC exhibit frequent PD-L1 tumoral staining,” noted Jen-Jane Liu, MD, Instructor of Urology at the Johns Hopkins School of Medicine in Baltimore, MD. “This suggests that neoadjuvant or adjuvant anti–PD-L1 therapy represents an attractive treatment alternative in MIUC patients whose tumors do not respond to cisplatin-based chemotherapy or in patients who cannot tolerate the therapy.”

As Liu explained, the 5-year cancer-specific survival (CSS) for nonresponders to cNAC is poor (27%) compared with the CSS in MIUC patients treated with RC alone (50%).

“The response rate to cNAC is 40% to 50%,” she reported, “which means that less than half of MIUC patients will benefit from cNAC. However, alternative systemic therapies are lacking.”

PD-L1 Shows Promise

According to Liu, anti–PD-L1 therapy has shown promising results in tumors with proven PD-L1 expression, including advanced-stage MIUC, by suppressing the immune response via T cells. To test the hypothesis that anti–PD-L1 therapy is a rational therapeutic option for patients nonresponsive to cNAC, researchers evaluated PD-L1 expression in MIUC in a cohort categorized by pathologic response to cNAC.

“We studied 150 patients who received cNAC followed by open radical cystectomy from 2000 to 2013,” said Liu. “Pathologic response (<pT1 N0 at RC) and CSS were compared to patients who had RC without cNAC.”

Tissue microarrays of MIUC specimens representing patients with and without response to cNAC were stained with PD-L1 and FOXP3, a marker for regulatory T cells, which help downregulate the immune system. A blinded pathologist then scored the degree of tumoral PD-L1 and tumoral lymphocyte FOXP3 staining. The primary outcome of the study was to determine the percentage of nonresponders to cNAC staining positive for PD-L1. Tumors with 5% and >15/hpf staining were considered positive for PD-L1 and FOXP3, respectively.

“Overall PD-L1 positivity was 38% (25 of 68) in patients receiving cNAC,” Liu observed, “and approximately 40% of both responders and nonresponders to cNAC were PD-L1 positive” (42% vs 37%, respectively).

As Liu noted, the similar rates of positivity between the 2 groups suggest that this mechanism is a potential therapeutic target for patients with MIUC.

PD-L1 also positively corresponded to FOXP3 positivity on tumor lymphocytes, implying that tumoral PD-L1 acts to circumvent the immune system by downregulating the T-cell immune response.

For Liu and colleagues, these findings indicate that anti–PD-L1 therapy could be effective in settings other than metastatic disease and is a reasonable therapeutic consideration for patients who do not respond to cNAC.

“It’s worthy of prospective clinical trial testing,” she concluded. “Further studies are needed to evaluate the efficacy of anti–PD-L1 therapy in this context.”

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