Highest Complete Response Rates With Immunotherapy–Chemotherapy in Muscle-Invasive Bladder Cancer

Muscle-invasive bladder cancer is usually treated with radical cystectomy, the complete removal of the bladder. Many patients, however, do not want this procedure because they fear a major decline in quality of life. This study explores new treatments that could preserve the bladder.

Key Study Findings

Dr. Matthew Galsky and colleagues reported in Nature Medicine on October 2, 2023, that the phase II multicenter HCRN GU 16–257 study, using neoadjuvant (tumor-shrinking) gemcitabine and cisplatin chemotherapy plus nivolumab immunotherapy after TURBT (transurethral resection of bladder tumor), achieved clinical complete response (cCR) in 43% of patients with muscle-invasive bladder cancer. Clinical response assessment helped identify patients particularly likely to have favorable outcomes, making bladder preservation possible.

Genomic, imaging, and immunological biomarkers may further refine this treatment approach, but more research is needed. 

Radical Cystectomy and Its Challenges

Radical cystectomy is currently standard treatment for muscle-invasive bladder cancer. It is life-changing, however, because it requires urinary diversion, and its 90-day mortality risk may reach 6-8%. Neoadjuvant cisplatin-based chemotherapy can improve survival in these patients. Although its aim is to eradicate micrometastatic disease, cisplatin-based chemotherapy after TURBT produces pathologic complete response (pCR) at cystectomy in approximately 30% of patients. Paradoxically, pCR can be established only after the bladder has been surgically removed.

New Approaches and Challenges

Challenges to wider use of this treatment model include few prospective studies, no standardized approach to measuring and defining clinical complete response (cCR), and suboptimal systemic treatment regimens.

Single-Agent and Combination Treatments

Single-agent PD-1/PD-L1 immune checkpoint blockade has produced pCR rates of 30-40% after cystectomy in muscle-invasive bladder cancer treatment. In the phase II studies discussed here, neoadjuvant gemcitabine, cisplatin, and PD-1/PD-L1 blockade (nivolumab) showed pCR rates of 40-50%, leading to the launch of several phase III trials.

Genomic Analysis Results

Alterations in certain genes (ATM, RB1, FANCC, and ERCC2), or increased tumor mutational burden (TMB), did not provide positive predictive value for complete clinical response. Exploratory analyses of peripheral blood using mass cytometry and soluble protein analysis also revealed a link between immune status before and during treatment and clinical outcomes.

Conclusion

In this phase II study, patients with muscle-invasive bladder cancer were clinically reassessed after four cycles of gemcitabine, cisplatin, and nivolumab. The main question was whether clinical complete response (cCR) could safely identify patients who did not need immediate cystectomy. A total of 76 patients were enrolled, of whom 33 achieved cCR; 32 of these patients did not require immediate cystectomy.

The authors described this as one of the first prospective studies testing TURBT and cisplatin-based chemotherapy as bladder-preserving treatment for muscle-invasive bladder cancer. It was also the first to define the performance of uniformly assessed and defined cCR as a patient-selection tool for this strategy, and the first to integrate immunotherapy into this approach. The study shows that a rigorously defined cCR is associated with favorable outcomes and that long-term survival with bladder preservation is possible in a large group of patients with muscle-invasive bladder cancer who achieve cCR after TURBT and gemcitabine, cisplatin, and nivolumab.