Open-label phase II to evaluate the efficacy of NEoadjuvant dose-dense MVAC In cOmbination with durvalumab and tremelimumab in muscle-invasive urothelial carcinoma: NEMIO.

Neoadjuvant cisplatin-based chemotherapy (NAC) is the standard of care in localized muscle-invasive bladder cancer (MIBC). However, 60-70% of patients have residual tumor after NAC. Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe. The emergence of immune checkpoint inhibitor (ICI) in the metastatic setting raises the question if the combination of chemo plus ICI could increase the pCR rate. NEMIO is a French open-label randomized phase I/II trial assessing in the neoadjuvant setting the combination of ddMVAC plus durvalumab alone or with tremelimumab: 4 cycles of ddMVAC/2 weeks + 2 cycles of Durvalumab +/- Tremelimumab/4 weeks. Cystectomy is performed 4-8 weeks after the last dose of ddMVAC. Six pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate. Each arm will be expanded to a maximum of 60 pts. The primary endpoint of the safety run-in phase will be the rate of grade 3/4 treatment-related adverse events G3/4 TRAE. The primary endpoint of the phase II will be the pathological response rate and G 3/4 TRAE. Exploratory endpoints will include biomarkers of response and resistance to the combo. A total of 120 patients will be included in 15 French centers and we expect the recruitment to be completed in 2021. NEMIO trial will assess for the first time the tolerance and the efficacy of ddMVAC regimen associated with checkpoints inhibitors as neoadjuvant treatment in localized MIBC. NCT number: NCT03549715. Registered on June 8, 2018.

Thibault C ，Elaidi R ，Vano YA ，Rouabah M ，Braychenko E ，Helali I ，Audenet F ，Oudard S ... -  《-》

Phase II study of neoadjuvant chemotherapy with four cycles of dose-dense MVAC followed by radical cystectomy in Korean patients with muscle-invasive or locally advanced urothelial carcinoma of bladder.

While previous retrospective or phase II studies in Western populations showed that dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as neoadjuvant chemotherapy (NAC) was beneficial, no studies have been reported in Asian populations. This prospective phase II study aimed to evaluate efficacy and safety of ddMVAC in Korean patients with muscle-invasive bladder cancer (MIBC) or locally advanced urothelial cancer (UC). Patients with MIBC (cT2-4aN0M0) or locally advanced UC (cTanyN1-3M0) eligible for radical cystectomy (RC) were enrolled prospectively. The participants were treated with four cycles of ddMVAC with pegfilgrastim every 2 weeks. The primary endpoint was pathologic response rate (≤ypT1N0). Secondary endpoints were pathologic complete response (pCR, ypT0N0), relapse-free survival (RFS), overall survival (OS), and safety. Among 24 patients enrolled between December 2019 and August 2021, 23 were evaluable (52%, cT2-4aN0; 48%, cTanyN1-3). Eighteen patients (78%) completed four cycles of ddMVAC, while remaining five patients experienced early discontinuation. Dose modification (91%) and dose delay (70%) occurred, and the dose intensity of ddMVAC was 79%. Nineteen patients underwent RC and four patients declined. Of 19 patients who underwent RC, eight patients (42%) achieved ≤ypT1N0. With a median follow-up of 22.8 months, the median RFS was 13.5 months (95% CI, not yet evaluable) and the median OS was 28.9 months (95% confidence interval, 19.9-37.9). Our study showed substantial efficacy and safety of ddMVAC, even in patients with locally advanced UC. The ddMVAC still should be a promising option as NAC in Asian patients with UC.

Park K ，Lee HJ ，Kim TU ，Ryu H ，Ki YK ，Hong YJ ，Nam JK ... -  《-》

Randomized Phase III Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin, or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with Muscle-invasive Bladder Cancer. Analysis of the GETUG/AFU V05 VESPER Trial Seconda

Perioperative chemotherapy (neoadjuvant or adjuvant) has been developed to increase overall survival for nonmetastatic muscle-invasive bladder cancer (MIBC). Retrospective studies or prospective phase II trials have been reported to use dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC). As dd-MVAC has shown higher response rates in metastatic disease, better efficacy is expected in the perioperative setting. We designed a randomized phase III trial to compare the efficacy of dd-MVAC or GC in MIBC perioperative (neoadjuvant or adjuvant) setting. A total of 500 patients were randomized from February 2013 to March 2018 in 28 centers and received either six cycles of dd-MVAC every 2 wk or four cycles of GC every 3 wk. The primary endpoint (progression-free survival at 3 yr) was not reported. We focused on secondary endpoints: chemotherapy toxicity and pathological responses. In the neoadjuvant group, 218 patients received dd-MVAC and 219 received GC. Of the patients, 60% received six cycles in the dd-MVAC arm and 84% received four cycles in the GC arm; 199 (91%) and 198 (90%) patients underwent surgery, respectively. Complete pathological response (ypT0pN0) was observed in 84 (42%) and 71 (36%) patients, respectively (p=0.2). An organ-confined status (<ypT3pN0) was obtained in 154 (77%) and 124 (63%) patients, respectively (p=0.001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm and 60% received four cycles in the GC arm. Most of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 toxicities concerned hematological toxicities, reported for 129 (52%) patients in the dd-MVAC group and 134 (55%) patients in the GC group. Gastrointestinal (GI) grade ≥3 disorders were more frequently observed in the dd-MVAC arm (p=0.003), as well as asthenia of grade ≥3 (p<0.001). The toxicity of dd-MVAC was manageable with more severe asthenia and GI side effects than that of GC in perioperative chemotherapy. A higher local control rate (complete pathological response, tumor downstaging, or organ confined) was observed in the dd-MVAC arm (p=0.021). However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021. The authors have designed a randomized phase III controlled study comparing the efficacy of gemcitabine and cisplatin, and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) in patients for whom chemotherapy has been decided, before or after radical cystectomy. Higher toxicity regarding asthenia and gastrointestinal side effects along with a better bladder control rate were observed in the dd-MVAC arm. However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.

Pfister C ，Gravis G ，Fléchon A ，Soulié M ，Guy L ，Laguerre B ，Mottet N ，Joly F ，Allory Y ，Harter V ，Culine S ，VESPER Trial Investigators ... -  《-》

Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer.

Gemcitabine plus cisplatin (GC) has been adopted as a neoadjuvant regimen for muscle-invasive bladder cancer despite the lack of Level I evidence in this setting. Data were collected using an electronic data-capture platform from 28 international centers. Eligible patients had clinical T-classification 2 (cT2) through cT4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) before undergoing cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC versus GC given their baseline characteristics. These propensity scores were then included in a new logistic regression model to estimate an adjusted odds ratio comparing the odds of attaining a pathologic complete response (pCR) between patients who received MVAC and those who received GC. In total, 212 patients (146 patients in the GC cohort and 66 patients in the MVAC cohort) met criteria for inclusion in the analysis. The majority of patients in the MVAC cohort (77%) received dose-dense MVAC. The median age of patients was 63 years, they were predominantly men (74%), and they received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate was 29% in the MVAC cohort and 31% in the GC cohort. There was no significant difference in the pCR rate when adjusted for propensity scores between the 2 regimens (odds ratio, 0.91; 95% confidence interval, 0.48-1.72; P = .77). In an exploratory analysis evaluating survival, the hazard ratio comparing hazard rates for MVAC versus GC adjusted for propensity scores was not statistically significant (hazard ratio, 0.78; 95% confidence interval, 0.40-1.54; P = .48). Patients who received neoadjuvant GC and MVAC achieved comparable pCR rates in the current analysis, providing evidence to support what has become routine practice.

Galsky MD ，Pal SK ，Chowdhury S ，Harshman LC ，Crabb SJ ，Wong YN ，Yu EY ，Powles T ，Moshier EL ，Ladoire S ，Hussain SA ，Agarwal N ，Vaishampayan UN ，Recine F ，Berthold D ，Necchi A ，Theodore C ，Milowsky MI ，Bellmunt J ，Rosenberg JE ，Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators ... -  《-》

Dose dense MVAC prior to radical cystectomy: a real-world experience.

Zargar H ，Shah JB ，van de Putte EEF ，Potvin KR ，Zargar-Shoshtari K ，van Rhijn BW ，Daneshmand S ，Holzbeierlein JM ，Spiess PE ，Winquist E ，Horenblas S ，Dinney C ，Black PC ，Kassouf W ... -  《-》