By Dr. Evanguelos Xylinas
Neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy is the standard of care for non-metastatic muscle-invasive bladder cancer (MIBC). However, 60-75% of the patients harbor residual disease after neoadjuvant cisplatin-gemcitabin or ddMVAC regimen. Pathological complete response (pCR) after NAC has been shown to be correlated with overall survival (OS). Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe in urothelial carcinoma (UC) in fit patients. The emergence of immune checkpoint inhibitors (ICI) in the metastatic setting raises the question of the added value of a combination of NAC plus ICI on pCR rates achieved.
NEMIO is a French open-label randomized phase II trial assessing in the neoadjuvant setting the combination ddMVAC plus durvalumab (D) alone or in combination with tremelimumab (T): 4 cycles of ddMVAC every 2 weeks + 2 cycles of D (1500 mg) +/- T (75 mg) every 4 weeks. Radical cystectomy is performed within 4-8 weeks after administration of the last dose of ddMVAC. As no safety data are available on the ICI plus ddMVAC combination, 6 pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate of the 2 regimens. Each arm will be expanded to a maximum of 60 pts according to a Bayesian stopping rule based on grade 3/4 treatment-related adverse events (G 3/4 TRAE). The primary endpoint of the safety run-in phase will be the rate of G3/4 TRAE. The primary endpoint of the phase II will be the pCR rate and G3/4 TRAE. The authors hypothesized that pCR after ddMVAC + D +/- T will be > or = 45%. Exploratory endpoints will include biomarkers of response and resistance to the combination treatment. Molecular analyses will be conducted on tumor, blood (ctDNA) and urine samples (uDNA). Immunological and metabolomics profile will also be analyzed. 10 French participating centers are open and the expected end of recruitment period is 2021.
Expert’s comment:
The NEMIO trial is of great interest in the onco-urology community evaluating for the first time the combination of immune check point inhibitors and chemotherapy in the neoadjuvant setting prior to radical cystectomy. The latter comes after the success of immune check point inhibitors in this setting as a monotherapy in the PURE-01 and ABACUS trials.
Read the abstract of the NEMIO trial here.