John Sfakianos, MD, on dual immune checkpoint inhibition in NMIBC

In a recent interview with Urology Times®, John P. Sfakianos, MD, shares the background/rationale for the phase 2 ENHANCE trial (NCT06503614), evaluating the combination of durvalumab plus monalizumab, dual immune checkpoint inhibitors, in non–muscle invasive bladder cancer (NMIBC).¹

Sfakianos is a urological oncologist in the department of urology at the Icahn School of Medicine at Mount Sinai in New York, New York.

During the discussion, Sfakianos explains why dual targeting of PD-1/PD-L1 and the HLA-E/NKG2A pathway is of interest in this disease setting. Drawing on more than a decade of translational research conducted at his institution with collaborator Amir Horowitz, PhD, he explains that these patients exhibit elevated expression of multiple immune checkpoints beyond PD-1/PD-L1, including the HLA-E/NKG2A pathway. Prior studies in other malignancies, such as lung and ovarian cancer, have shown that combining PD-1/PD-L1 blockade with NKG2A inhibition can significantly improve outcomes. He specifically cites the COAST trial (NCT03822351) in lung cancer, where response rates nearly doubled compared with PD-L1 inhibition alone.²

Notably, NIH-supported translational work from Dr. Sfakianos’ group demonstrated increased HLA-E and NKG2A expression specifically in high-risk NMIBC, providing a strong biologic rationale for testing this combination in bladder cancer.

Building on this work, the phase 2 ENHANCE trial is aiming to enroll 60 patients across 2 cohorts. Arm A will evaluate the combination in 43 patients with carcinoma in situ (CIS) with or without high-grade papillary tumors, and Arm B will assess the combination in 17 patients who without CIS but who have high-grade papillary disease.

Participants in the study will receive durvalumab plus monalizumab intravenously every 28 days for up to 13 cycles. Primary completion of the study is expected in December 2026.

REFERENCES

1. A Trial of Durvalumab (MEDI4736) Plus Monalizumab in Non-Muscle-Invasive Bladder Cancer (ENHANCE). ClinicalTrials.gov. Last updated January 13, 2026. Accessed January 29, 2026. https://clinicaltrials.gov/study/NCT06503614

2. Herbst RS, Majem M, Barlesi F, et al. COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2022 Oct 10;40(29):3383-3393. doi:10.1200/JCO.22.00227