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atezolizumab alone (n=406) vs. no additional treatment (n=403)
randomized controlled trial
atezolizumab
1200 mgintravenous atezolizumab fora total of 16 cycles or 1 year, Dose reductions ofatezolizumab were not permitted.
observation
Crossover was not permitted
MIBC - NA - all population
selction regardless of PDL1 status
opan-label
192 hospitals, academic centres, and community oncology practices across 24 countries or regions
P3/ two sided with two interim analysis (OS). If results from the disease-freesurvival analysis were significant at an α value of 0·05,the analysis of overall survival was to be performed at anα level of 0·05,
IMvigor010 study evaluating Tecentriq ® (atezolizumab) as an adjuvant (after surgery) monotherapy treatment did not meet its primary endpoint of disease-free survival (DFS) compared to observation in people with muscle-invasive urothelial cancer (MIUC)
nivolumab alone (n=353) vs. placebo (n=356)
randomized controlled trial
nivolumab
nivolumab (240 mg intravenously) every 2 weeks for up to 1 year
placebo
placebo every 2 weeks for up to 1 year
Dose delaysor discontinuations were allowed to managetoxic effects.
MIBC - NA - all population
Neoadjuvant cisplatin-based chemotherapybefore trial entry was allowed
double blind
156 sites in 29 countries in North and South America, Europe, Asia, and Australia
The alpha level(0.01784 for the intention-to-treat populationand 0.01282 for the group of patients with a PD-L1expression level of ≥1%) for disease-free survivalwas adjusted for the planned interim analysis.The secondary end point of overall survivalwas planned to be formally compared withthe use of a hierarchical procedure in eachpopulation and will be assessed with longerfollow-up,
In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more.
nivolumab alone (n=140) vs. placebo (n=142)
randomized controlled trial
nivolumab
nivolumab (240 mg intravenously) every 2 weeks for up to 1 year
placebo
placebo every 2 weeks for up to 1 year
Dose delays or discontinuations were allowed to manage toxic effects.
MIBC - NA - PDL1 positive
Neoadjuvant cisplatin-based chemotherapybefore trial entry was allowed
double blind
156 sites in 29 countries in North and South America, Europe, Asia, and Australia
The alpha level(0.01784 for the intention-to-treat populationand 0.01282 for the group of patients with a PD-L1expression level of ≥1%) for disease-free survivalwas adjusted for the planned interim analysis.The secondary end point of overall survivalwas planned to be formally compared withthe use of a hierarchical procedure in eachpopulation and will be assessed with longerfollow-up,
In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more.
atezolizumab alone (n=360) vs. gemcitabine plus platin (n=400)
randomized controlled trial
atezolizumab (B)
atezolizumab (1200 mg administered intravenously on day 1 of each cycle
chemotherapy (C) gemcitabine plus platine
21-day cycles of gemcitabine (1000 mg/m² body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m² body surface area administered intravenously) on day 1 of each cycle
mUC - L1 - all population
open-design
221 sites in 35 countries
P3/ one sided 0,025 and interim analysis (resultats rentrés = AI1). Repartition and hierarchy OS / PFS (A vs C) then OS (B vs C)
Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma.
atezolizumab plus SoC (n=451) vs. placebo plus SoC (n=400)
randomized controlled trial
atezolizumab (A) plus gemcitabine and platine
atezolizumab (1200 mg administered intravenously on day 1 of each cycle with 21-day cycles of gemcitabine (1000 mg/m² body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m² body surface area administered intravenously
placebo (C) plus gemcitabine and platine
atezolizumab matched-placebo and 21-day cycles of gemcitabine (1000 mg/m² body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m² body surface area administered intravenously
No crossover will be allowed from the control arm to either experimental arm
mUC - L1 - all population
open-design
221 sites in 35 countries
P3/ one sided 0,025 and interim analysis (resultats rentrés = AI1). Repartition and hierarchy OS / PFS (A vs C) then OS (B vs C)
Addition of atezolizumab to platinum-based chemotherapy as first-line treatment significantly prolonged progression-free survival in patients with metastatic urothelial carcinoma.
durvalumab alone (n=346) vs. gemcitabine plus platin (n=344)
randomized controlled trial
durvalumab
durvalumab monotherapy (at a fixed dose of 1500 mg, administered intravenously every 4 weeks) Dose reductions were not permitted for durvalumab or durvalumab plus tremelimumab.
platine based chemotherpy (SOC) cisplatine plus gemcitabine
IV infusions of cisplatin at a dose of 70 mg/m2 on day 2 of each 28-day cycle plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle, for up to six cycles; OR IV infusions of cisplatin at 70 mg/m2 on day 1 of each 21-day cycle plus gemcitabine at 1000–1250 mg/m2 on days 1 and 8 of each 21-day cycle, for up to six cycles
3 arms : durvalumab alone or with tremelimumab vs SOC; crossover from the chemotherapy group to either the durvalumab or durvalumab plus tremelimumab groups was not allowed
mUC - L1 - all population
Patients who had received adjuvant or neoadjuvant treatment for locally advanced disease and had progressed within 6 months of their last therapy or surgery were also excluded.
open label
243 academic research centres, hospitals, and oncology clinics in 23 countries
P3/ two sided and two interim analysis. Splitting alpha between coprimary endpoint and recycling with hierachical testing procedure for OS ITT (D) and PDL1 high (DT)
This study did not meet either of its coprimary endpoints (OS).
durvalumab plus tremelimumab (n=342) vs. gemcitabine plus platin (n=344)
randomized controlled trial
durvalumab plus tremelimumab
durvalumab monotherapy (at a fixed dose of 1500 mg, administered intravenously every 4 weeks) Dose reductions were not permitted for durvalumab or durvalumab plus tremelimumab.
platine based chemotherpy
IV infusions of cisplatin at a dose of 70 mg/m2 on day 2 of each 28-day cycle plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle, for up to six cycles; OR IV infusions of cisplatin at 70 mg/m2 on day 1 of each 21-day cycle plus gemcitabine at 1000–1250 mg/m2 on days 1 and 8 of each 21-day cycle, for up to six cycles
3 arms : durvalumab alone or with tremelimumab vs SOC; crossover from the chemotherapy group to either the durvalumab or durvalumab plus tremelimumab groups was not allowed
mUC - L1 - all population
Patients who had received adjuvant or neoadjuvant treatment for locally advanced disease and had progressed within 6 months of their last therapy or surgery were also excluded
open label
243 academic research centres, hospitals, and oncology clinics in 23 countries
P3/ two sided and two interim analysis. Splitting alpha between coprimary endpoint and recycling with hierachical testing procedure for OS ITT (D) and PDL1 high (DT)
This study did not meet either of its coprimary endpoints.
pembrolizumab alone (n=307) vs. Standard of Care (SoC) (n=352)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg every 3 weeks (Q3W) for a maximum of 35 cycles
chemotherapy alone (cisplatine or carbo plus gemcitabine)
Investigator’s choice of cisplatin 44% [70 mg/m2 Q3W] plus gemcitabine [1000 mg/m2 on days 1 and 8 Q3W] OR carboplatin 56% [AUC 5Q3W] plus gemcitabine if cisplatin ineligible)
3 arms: pembrolizumab ± chemotherapy versus chemotherapy Dose modifications for pembrolizumab were not permitted;
mUC - L1 - all population
open label
201 medical centres in 21 countries
A Bonferroni approachwas used to control the type I error rate at α=0·025(one-sided), with 0·005 allocated to progressionfree survival and 0·02 allocated to overall survival.A sequential testing strategy was used
Results from the trial indicated that the PD-1 inhibitor plus chemotherapy failed to result in a statistically significant improvement in progression-free survival (PFS) or overall survival (OS) over chemotherapy in patients with treatment-naïve advanced urothelial carcinoma
pembrolizumab plus SoC (n=351) vs. gemcitabine plus platin (n=352)
randomized controlled trial
pembrolizumab plus chemotherapy
pembrolizumab 200 mg every 3 weeks (Q3W) for a maximum of 35 cycles, [70 mg/m2 Q3W] plus gemcitabine [1000 mg/m2 on days 1 and 8 Q3W] OR carboplatin [AUC 5Q3W] plus gemcitabine if cisplatin ineligible)
chemotherapy alone (cisplatine or carbo plus gemcitabine)
Investigator’s choice of platin [70 mg/m2 Q3W] plus gemcitabine [1000 mg/m2 on days 1 and 8 Q3W] OR carboplatin [AUC 5Q3W] plus gemcitabine if cisplatin ineligible)
3 arms: pembrolizumab ± chemotherapy versus chemotherapy Dose modifications for pembrolizumab were notpermitted;
mUC - L1 - all population
open label
201 medical centres in 21 countries
A Bonferroni approachwas used to control the type I error rate at α=0·025(one-sided), with 0·005 allocated to progressionfree survival and 0·02 allocated to overall survival.A sequential testing strategy was used
Results from the trial indicated that the PD-1 inhibitor plus chemotherapy failed to result in a statistically significant improvement in progression-free survival (PFS) or overall survival (OS) over chemotherapy in patients with treatment-naïve advanced urothelial carcinoma
durvalumab alone (n=209) vs. gemcitabine plus platin (n=207)
randomized controlled trial
durvalumab
durvalumab monotherapy (at a fixed dose of 1500 mg, administered intravenously every 4 weeks) Dose reductions were not permitted for durvalumab or durvalumab plus tremelimumab.
platine based chemotherapy (gemcitabine)
IV infusions of cisplatin at a dose of 70 mg/m2 on day 2 of each 28-day cycle plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle, for up to six cycles; OR IV infusions of cisplatin at 70 mg/m2 on day 1 of each 21-day cycle plus gemcitabine at 1000–1250 mg/m2 on days 1 and 8 of each 21-day cycle, for up to six cycles
3 arms : durvalumab alone or with tremelimumab vs SOC; crossover from the chemotherapy group to either the durvalumab or durvalumab plus tremelimumab groups was not allowed
mUC - L1 - PDL1 positive
Patients who had received adjuvant or neoadjuvant treatment for locally advanced disease and had progressed within 6 months of their last therapy or surgery were also excluded
open label
243 academic research centres, hospitals, and oncology clinics in 23 countries
P3/ two sided and two interim analysis. Splitting alpha between coprimary endpoint and recycling with hierachical testing procedure for OS ITT (D) and PDL1 high (DT)
This study did not meet either of its coprimary endpoints.
durvalumab plus tremelimumab (n=205) vs. gemcitabine plus platin (n=207)
randomized controlled trial
durvalumab plus tremelimumab
durvalumab monotherapy (at a fixed dose of 1500 mg, administered intravenously every 4 weeks) Dose reductions were not permitted for durvalumab or durvalumab plus tremelimumab.
platine based chemotherpy (SOC)
IV infusions of cisplatin at a dose of 70 mg/m2 on day 2 of each 28-day cycle plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle, for up to six cycles; OR IV infusions of cisplatin at 70 mg/m2 on day 1 of each 21-day cycle plus gemcitabine at 1000–1250 mg/m2 on days 1 and 8 of each 21-day cycle, for up to six cycles
3 arms : durvalumab alone or with tremelimumab vs SOC; crossover from the chemotherapy group to either the durvalumab or durvalumab plus tremelimumab groups was not allowed
mUC - L1 - PDL1 positive
Patients who had received adjuvant or neoadjuvant treatment for locally advanced disease and had progressed within 6 months of their last therapy or surgery were also excluded
open label
243 academic research centres, hospitals, and oncology clinics in 23 countries
P3/ two sided and two interim analysis. Splitting alpha between coprimary endpoint and recycling with hierachical testing procedure for OS ITT (D) and PDL1 high (DT)
This study did not meet either of its coprimary endpoints.
atezolizumab alone (n=467) vs. Standard of Care (SoC) (n=464)
randomized controlled trial
atezolizumab
atezolizumab 1200 mg intravenously every 3 weeks
chemotherapy
chemotherapy (vinflunine 320 mg/m² (54.6%), paclitaxel 175 mg/m² (33.4%), or docetaxel 75 mg/m²(12.0%) intravenously every 3 weeks
No prespecified crossover was planned per protocol.
mUC - L2 - all population
open label
217 academic medical centres and community (results from 198 sites)
P3/two sided no AI planned. Tested with a hierarchical fixed-sequence procedure based on a stratified log-rank test at a two-sided level of 5% significance
The sponsor has revealed that its phase III IMVigor 211 failed to meet the primary endpoint of extending overall survival compared with chemotherapy. Roche withdraws Atezolizumab in platinum refractory UC after FDA discussions
pembrolizumab alone (n=270) vs. Standard of Care (SoC) (n=272)
randomized controlled trial
pembrolizumab
pembrolizumab at dose of 200 mg every 3 weeks
chemotherapy (ICC) : paclitaxel, docetaxel, or vinflunine
investigator's choice of chemotherapy with paclitaxel (30.9%), docetaxel (30.9%), or vinflunine(32.0%) : paclitaxel (at a dose of 175 mg per square meter of body-surface area), docetaxel (at a dose of 75 mg per square meter), or vinflunine (at a dose of 320 mg per square meter), all administered intravenously every 3 weeks.
There was no planned crossover on disease progression.
mUC - L2 - all population
open-label
120 sites in 29 countries
P3 / one sided and two interim analysis. Repartition and hierachical testing procedure between coprimary endpoints
Pembrolizumab was associated with significantly longer overall survival (by approximately3 months) and with a lower rate of treatment-related adverse events than chemotherapyas second-line therapy for platinum-refractory advanced urothelial carcinoma.
atezolizumab alone (n=116) vs. Standard of Care (SoC) (n=118)
randomized controlled trial
atezolizumab
atezolizumab 1200 mg intravenously every 3 weeks
chemotherapy
chemotherapy (vinflunine 320 mg/m², paclitaxel 175 mg/m², or docetaxel 75 mg/m²) intravenously every 3 weeks (no % for this sub-population)
No prespecified crossover was planned per protocol.
mUC - L2 - PDL1 positive
IC2/3 patients as planned as step 1 of the hierarchical testing
open label
217 academic medical centres and community (results from 198 sites)
P3/two sided no AI planned. Tested with a hierarchical fixed-sequence procedure based on a stratified log-rank test at a two-sided level of 5% significance
The sponsor has revealed that its phase III IMVigor 211 failed to meet the primary endpoint of extending overall survival compared with chemotherapy.Roche withdraws Atezolizumab in platinum refractory UC after FDA discussions.
atezolizumab alone (n=316) vs. Standard of Care (SoC) (n=309)
randomized controlled trial
atezolizumab
atezolizumab 1200 mg intravenously every 3 weeks
chemotherapy
chemotherapy (vinflunine 320 mg/m², paclitaxel 175 mg/m², or docetaxel 75 mg/m²) intravenously every 3 weeks (no % for this sub-population)
No prespecified crossover was planned per protocol.
mUC - L2 - PDL1 positive
IC1/2/3 patients as planned as step 1 of the hierarchical testing
open label
217 academic medical centres and community (results from 198 sites)
P3/two sided no AI planned. Tested with a hierarchical fixed-sequence procedure based on a stratified log-rank test at a two-sided level of 5% significance
The sponsor has revealed that its phase III IMVigor 211 failed to meet the primary endpoint of extending overall survival compared with chemotherapy.Roche withdraws Atezolizumab in platinum refractory UC after FDA discussions
pembrolizumab alone (n=74) vs. Standard of Care (SoC) (n=90)
randomized controlled trial
pembrolizumab
pembrolizumab at dose of 200 mg every 3 weeks
chemotherapy (ICC)
investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine : paclitaxel (at a dose of 175 mg per square meter of body-surface area), docetaxel (at a dose of 75 mg per square meter), or vinflunine (at a dose of 320 mg per square meter), all administered intravenously every 3 weeks.(no % for this sub-population)
There was no planned crossover on disease progression.
mUC - L2 - PDL1 positive
open-label
120 sites in 29 countries
P3 / one sided and two interim analysis. Repartition and hierachical testing procedure between coprimary endpoints
Pembrolizumab was associated with significantly longer overall survival (by approximately3 months) and with a lower rate of treatment-related adverse events than chemotherapyas second-line therapy for platinum-refractory advanced urothelial carcinoma.
avelumab alone (n=350) vs. BSC (n=350)
randomized controlled trial
avelumab
avelumab (10 mg/kg IV every 2 weeks)
BSC
other systemic antitumor therapy was not permitted but palliative local radiotherapy for isolated lesions was acceptable.
all patients received best supportive care (will be administered as deemed appropriate by the treating physician, and could include treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including palliative radiotherapy), etc. BSC does not include any active anti-tumor therapy, however local radiotherapy of isolated lesions with palliative intent is acceptable.)
mUC - M - all population
stage IV disease at initiation of first-line chemotherapy; PD-L1 status was defined as expression in ≥25% of tumor cells or in ≥25% or 100% of tumor-associated immune cells if the percentage of immune cells was >1% or ≤1%, respectively (SP263 assay).
open label
197 sites in 29 countries
P3/ one sided and one interim analysis. Splitting alpha between corpimary endpoint (0.015 OS ITT and 0.01 PDL1>25%) no plan for secondary endpoint
IA1 stopped : Avelumab Displays Survival Benefit in JAVELIN Bladder 100 Trial : avelumab was found to have met its primary study endpoint of improved overall survival (OS)
avelumab alone (n=189) vs. BSC (n=169)
randomized controlled trial
avelumab
avelumab (10 mg/kg IV every 2 weeks)
no treatment
other systemic antitumor therapy was not permitted but palliative local radiotherapy for isolated lesions was acceptable.
all patients received best supportive care ( will be administered as deemed appropriate by the treating physician, and could include treatment with antibiotics, nutritional support, correction of metabolic disorders, optimal symptom control and pain management (including palliative radiotherapy), etc. BSC does not include any active anti-tumor therapy, however local radiotherapy of isolated lesions with palliative intent is acceptable.)
mUC - M - PDL1 positive
stage IV disease at initiation of first-line chemotherapy; PD-L1 status was defined as expression in ≥25% of tumor cells or in ≥25% or 100% of tumor-associated immune cells if the percentage of immune cells was >1% or ≤1%, respectively (SP263 assay).
open label
197 sites in 29 countries
P3/ one sided and one interim analysis. Splitting alpha between corpimary endpoint (0.015 OS ITT and 0.01 PDL1>25%) no plan for secondary endpoint
Avelumab Displays Survival Benefit in JAVELIN Bladder 100 Trial : avelumab was found to have met its primary study endpoint of improved overall survival (OS)
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