For patients with muscle-invasive bladder cancer, neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy remains an important treatment approach. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin, known as ddMVAC, is one of the chemotherapy backbones used in this setting. Still, many patients have residual invasive disease at the time of surgery, underscoring the need for more effective perioperative strategies.
The NEMIO study examined whether adding immune checkpoint inhibition to ddMVAC could increase pathologic response while maintaining the feasibility of radical cystectomy in cisplatin-eligible patients with localized muscle-invasive bladder cancer.
The original article, titled “Neoadjuvant Durvalumab ± Tremelimumab in Combination With Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Muscle-Invasive Bladder Carcinoma: Results of the Phase I/II NEMIO Study,” was published in the Journal of Clinical Oncology on May 26, 2026.
Authors: Constance Thibault, Mostefa Bennamoun, Aude Fléchon, Gwenaelle Gravis, Damien Pouessel, Pierre Combe, Delphine Borchiellini, Yohann Loriot, Brigitte Laguerre, Philippe Barthélémy, Olivier Huillard, Marine Gross-Goupil, Audrey Le Roy, Loic Jaffrelot, Mathilde Cancel, François Audenet, Houda Belhouari, Ghalia Kaci, Eve Lepicard, Dewi Vernerey, Julie Henriques, and Stéphane Oudard.
Why This Study Matters
Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is a standard treatment strategy for localized muscle-invasive bladder cancer, but outcomes remain variable. A considerable proportion of patients continue to have residual muscle-invasive disease after surgery.
Because immune checkpoint inhibitors are active in urothelial cancer, combining PD-L1 blockade with chemotherapy may offer a way to improve response before surgery. NEMIO tested this approach using ddMVAC plus durvalumab, with or without tremelimumab. The trial also addressed a practical question for the field: whether adding CTLA-4 blockade meaningfully improves efficacy, or mainly adds toxicity.
Read more about Durvalumab (Imfinzi) on OncoDaily.
Study Design
NEMIO was a multicenter, open-label, randomized, noncomparative phase II trial with a safety run-in phase. Eligible patients had cT2-T4a N0-1 muscle-invasive bladder cancer with a predominant urothelial component. Patients had to be eligible for cisplatin, have an ECOG performance status of 0 or 1, and be planned for radical cystectomy. Patients with metastatic disease were excluded.
Patients were randomly assigned to receive one of two neoadjuvant regimens:
- ddMVAC plus durvalumab
- ddMVAC plus durvalumab and tremelimumab.
ddMVAC was given every 2 weeks for 4 cycles. Durvalumab was administered at 1,500 mg every 4 weeks for 2 doses, on Cycle 1 Day 1 and Cycle 3 Day 1. In the triplet arm, tremelimumab 75 mg was given on the same schedule. Radical cystectomy was planned 4 to 8 weeks after completion of neoadjuvant treatment.
The coprimary endpoints were pathologic complete response, defined as ypT0N0, and grade 3 or higher treatment-related adverse events. The study was considered positive if the pCR rate was at least 45% and the rate of grade 3 or higher treatment-related adverse events was 30% or lower.
Patient Population
Between November 2018 and April 2022, 121 patients were enrolled across 16 centers in France. Overall, 119 patients received at least one dose of treatment and were included in the safety population. Of these patients, 60 received ddMVAC plus durvalumab, and 59 received ddMVAC plus durvalumab and tremelimumab.
The median age was 64 years. Most patients were male, and most had an ECOG performance status of 0. The majority had cT2 disease at diagnosis. Five patients had cN1 disease. Overall, 113 patients underwent radical cystectomy. Six patients did not proceed to surgery because of refusal, progressive disease, or COVID-19 disease.
Treatment Exposure and Surgical Feasibility
Most patients were able to complete the planned systemic treatment. In the ddMVAC plus durvalumab arm, 88% of patients completed the full planned course. In the ddMVAC plus durvalumab plus tremelimumab arm, 75% completed all planned systemic therapy. The neoadjuvant chemoimmunotherapy approach did not appear to compromise the timing of surgery. The median time from randomization to radical cystectomy was 12.4 weeks, and the median time from the last treatment injection to surgery was 6.3 weeks.
Efficacy Results
Among the 113 patients who underwent radical cystectomy, the overall pCR rate was 47.8%. The pCR rate was 49.1% with ddMVAC plus durvalumab and 46.6% with ddMVAC plus durvalumab plus tremelimumab. Bayesian posterior mean pCR rates were 48.70% in the doublet arm and 46.27% in the triplet arm.
An additional 17.7% of patients achieved pathologic downstaging. Pathologic downstaging occurred in 21.8% of patients treated with ddMVAC plus durvalumab and 13.8% of patients treated with the tremelimumab-containing regimen. In the safety population, where patients who did not undergo surgery were counted as nonresponders, the pCR rate was 45%.
PD-L1 Exploratory Analysis
In an exploratory analysis, patients with PD-L1–high tumors had higher pCR rates than those with PD-L1–low or PD-L1–negative tumors. The observed pCR rate was 69.6% in PD-L1–high tumors, compared with 33.3% in PD-L1–low or negative tumors. PD-L1 status remained significantly associated with pCR in multivariable analysis. However, this result should be interpreted with caution because the analysis was exploratory and PD-L1 data were not available for all patients.
Survival Outcomes
At a median follow-up of 27.0 months, early survival outcomes were encouraging. In the safety population, the 2-year event-free survival rate was 74.8% with ddMVAC plus durvalumab and 77.2% with ddMVAC plus durvalumab plus tremelimumab.
The 2-year overall survival rate was 84.9% in the doublet arm and 87.9% in the triplet arm. Among patients who underwent radical cystectomy, the 2-year disease-free survival rate was 81.6% with ddMVAC plus durvalumab and 75.3% with the tremelimumab-containing regimen. Among patients who achieved pCR, only 3 patients relapsed after surgery.
Safety Results
All treated patients experienced at least one treatment-related adverse event. Grade 3 or higher treatment-related adverse events occurred in 42.0% of patients overall. These events were more frequent in the tremelimumab-containing arm.
Grade 3 or higher treatment-related adverse events occurred in 31.7% of patients treated with ddMVAC plus durvalumab and 52.5% of patients treated with ddMVAC plus durvalumab plus tremelimumab. The most common treatment-related adverse events included fatigue, nausea, and anemia. The most common grade 3 or higher treatment-related adverse events included neutropenia and anemia.
Immune-related adverse events related to treatment occurred in 26.9% of patients, with grade 3 or higher immune-related events reported in 4.2%. No treatment-related deaths were reported. Although the pCR benchmark was met, the prespecified safety threshold was not fully satisfied because grade 3 or higher treatment-related adverse events exceeded 30%, particularly in the tremelimumab arm.
Interpretation
NEMIO showed that neoadjuvant ddMVAC plus durvalumab was associated with substantial pathologic responses and encouraging early survival outcomes in cisplatin-eligible patients with localized muscle-invasive bladder cancer. The addition of tremelimumab produced similar pCR rates to ddMVAC plus durvalumab and was associated with substantially higher toxicity. These findings suggest that adding CTLA-4 blockade to this regimen may not provide a clear clinical advantage in this setting.
The study also supports the feasibility of combining ddMVAC with durvalumab before radical cystectomy, as the treatment approach did not appear to delay surgery.
Limitations
NEMIO was open-label and noncomparative, without a ddMVAC-only control arm. As a result, the study cannot definitively determine the added contribution of durvalumab over chemotherapy alone. Follow-up was limited to approximately 2 years, and longer-term outcomes remain important. The PD-L1 analysis was exploratory and should be validated in larger prospective studies.
Comparisons with other perioperative regimens should also be made cautiously because of differences in trial design, chemotherapy backbone, adjuvant treatment strategies, and patient populations.
Takeaway
The NEMIO study supports neoadjuvant ddMVAC plus durvalumab as a promising chemoimmunotherapy strategy for cisplatin-eligible localized muscle-invasive bladder cancer. The regimen produced substantial pathologic responses, encouraging early survival outcomes, and did not appear to compromise surgical feasibility.
Adding tremelimumab resulted in similar pCR rates but higher toxicity, limiting the value of CTLA-4 blockade in this regimen. Further comparative studies are needed to define the role of ddMVAC plus durvalumab within the evolving perioperative treatment landscape for muscle-invasive bladder cancer.
The full article is available in the Journal of Clinical Oncology.
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