# Therapeutic Intensification Based on Immune Checkpoint Inhibitors in Non-Muscle Invasive Bladder Cancer: State of the Art and Future Perspectives

## TL;DR

Systemic immunotherapy is becoming a key treatment for non-muscle invasive bladder cancer, with promising results in both BCG-unresponsive and high-risk patients.

## Contribution

The paper highlights new combination therapies targeting PD-1/PD-L1 and HLA-E/NKG2A pathways in bladder cancer treatment.

## Key findings

- PD-1/PD-L1 inhibitors as monotherapy showed complete response rates of 12% to 43% in BCG-unresponsive NMIBC.
- Combining BCG with systemic immunotherapy showed positive results in CREST and POTOMAC trials for high-risk NMIBC.
- A new phase II trial is testing a combination targeting both PD-1/PD-L1 and HLA-E/NKG2A pathways.

## Abstract

Systemic immunotherapy is now playing an increasingly important therapeutic role in the treatment option of non-muscle invasive bladder cancer (NMIBC), either alone or in combination with BCG instillations. Four phase II studies evaluating PD-1/PD-L1 inhibitors as monotherapy in BCG-unresponsive NMIBC reported complete response rates ranging from 12% to 43%, with durable responses in nearly half of patients at 12 months. A new phase II trial tests a combination therapy targeting both the PD-1/PD-L1 axis and the emerging HLA-E/NKG2A pathway. In BCG-naïve high-risk NMIBC, four phase III trials are evaluating the combination of BCG with systemic immunotherapy, with positive results reported in the CREST and POTOMAC trials, marking a potential therapeutic breakthrough. The main future challenge lies in selecting patients most likely to benefit from this intensified strategy, while avoiding overtreatment, and to find predictive biomarkers for personalized therapy.

Background/Objectives: Systemic immunotherapy, previously used mainly for advanced urothelial carcinoma, now plays an important role in the treatment of non-muscle invasive bladder cancer (NMIBC), either alone or combined with intravesical BCG instillations. Methods: We conducted a collaborative, comprehensive review to summarize the key evidence and future perspectives on therapeutic intensification strategies involving immune checkpoint inhibitors in NMIBC. A total of 51 references published between 2000 and 2025 were included. Results: Four phase II studies evaluated pembrolizumab, atezolizumab, durvalumab, and cetrelimab as monotherapy in 28 to 132 BCG-unresponsive NMIBC patients. They reported complete response rates ranging from 12% to 43% after 3 to 12 months of treatment, with a durable response rate ranging from 49% to 57.4% at 12 months. To improve these results, a phase II trial launched this year tests a new systemic combination targeting both the PD-1/PD-L1 axis and the emerging HLA-E/NKG2A pathway. Regarding BCG-naïve high-risk (HR) NMIBC, four phase III studies are evaluating BCG instillations combined with systemic immunotherapy: sasanlimab (CREST), durvalumab (POTOMAC), atezolizumab (ALBAN), and pembrolizumab (KEYNOTE-676), with significant results reported for the CREST and POTOMAC trials. The key challenge remains selecting patients most likely to benefit from this combination therapy while avoiding overtreatment. Identifying predictive biomarkers of tumor aggressiveness and response to immunotherapy also represents a major future challenge. Conclusions: Therapeutic intensification using systemic immunotherapy applies to both BCG-unresponsive NMIBC, with a new target pathway (HLA-E/NKG2A), and BCG-naïve HR NMIBC, where the combination of BCG instillations and immunotherapy represents a major breakthrough.