Table 2.
Key clinical trials of PD1/PDL1 inhibitors in advanced bladder cancer
| Study | Design | n | Key patient selection | Treatment regimen | Efficacy outcomes (PD1/PDL1 vs comparator) | AE rate (PD1/PDL1 vs comparator) |
|---|---|---|---|---|---|---|
| Pembrolizumab | ||||||
| KEYNOTE-01227 | Phase IB, open-label, single-arm, multicenter, international | 33 | Advanced UC PDL1 ≥1% ECOG 0 or 1 |
10 mg/kg IV every 2 weeks | ORR 26% (7/27) mPFS 2 months mOS 13 months DoR 10 months |
Tx-related AEs 61% Tx-related grade 3–4 AEs 15% Immunomediated AEs 18% Tx-related deaths 0 |
| KEYNOTE-04526 | Phase III, open-label, randomized, multicenter, international | 542 | Advanced UC Progression or recurrence after platinum or recurrence within 12 months after receipt of platinum- based adjuvant or neoadjuvant Tx ≤2 lines of chemotherapy ECOG 0–2 |
200 mg IV every 3 weeks vs investigator- choice single-agent chemotherapy | ORR 21% vs 11.4%, P=0.001 ORR PDL1 ≥10% 21.6% vs 6.7% mPFS 2.1 vs 3.3 months, P=0.42 mOS 10.3 vs 7.4 months, HR 0.73, P=0.002 mOS PDL1 ≥10% 8.0 months vs 5.2 months; HR 0.57, P=0.005 |
Tx-related AEs 61% vs 90% Tx-related grade 3–4 AEs 15% vs 49% Immunomediated AEs 16.9% vs 7.5% Tx-related deaths 1 (pneumonitis) |
| KEYNOTE-05228 | Phase II, open-label, single arm, multicenter, international | 370 | Advanced UC Untreated Cisplatin-ineligible ECOG 0–2 |
200 mg IV every 3 weeks | ORR 29% ORR PDL1 ≥10% 51% mPFS 2 months mOS not reported |
Tx-related AEs 62% Tx-related grade 3–4 AEs 16% Immunomediated AEs 17% Tx-related deaths 1 (myositis) |
| Atezolizumab | ||||||
| IMvigor 210 cohort 132 | Phase II, open-label, single-arm, two-cohort, multicenter, international | 119 | Advanced UC Untreated Cisplatin-ineligible ECOG 0–2 |
1,200 mg IV every 3 weeks | ORR 23% (RECIST 1.1) ORR PDL1 IC ≥5% 28% mDoR not reached mPFS 2.7 months mPFS PDL1 IC ≥5% 4.1 months mOS 15.9 months mOS PDL1 IC ≥5% 12.3 months |
Tx-related AEs 66% Tx-related grade 3–4 AEs 16% Immunomediated AEs 12% Tx-related deaths 1 (sepsis) |
| IMvigor 210 cohort 219 | Phase II, open-label, single-arm, two-cohort, multicenter, international | 310 | Advanced UC Progression or recurrence after platinum or recurrence within 12 months after receipt of platinum- based adjuvant or neoadjuvant Tx ECOG 0–1 |
1,200 mg IV every 3 weeks | ORR 15% (RECIST 1.1) ORR 19% (immunomodified RECIST) ORR PDL1 IC ≥5% 26% (RECIST 1.1) mDoR not reached mPFS 2.1 months mPFS PDL1 IC ≥5% 2.1 months mOS 7.9 months mOS PDL1 IC ≥5% 11.4 months |
Tx-related AEs 69% Tx-related grade 3–4 AEs 16% Immunomediated AEs 7% Tx-related deaths 0 |
| IMvigor 211 cohort 334 | Phase III, open label, randomized, two-arm, multicenter, international | 931 | Advanced UC Progression or recurrence after platinum or recurrence within 12 months after receipt of platinum- based adjuvant or neoadjuvant Tx ≤2 lines of chemotherapy ECOG 0–1 |
1,200 mg IV every 3 weeks vs investigator- choice single-agent chemotherapy | ORR (PDL1 IC ≥5%) 23.0% vs 21.6% (RECIST 1.1) ORR (ITT) 13.4% vs 13.4% (RECIST 1.1) PFS (ITT) 2.1 vs 4.0 months mPFS (PDL1 IC >5%) 2.4 vs 4.2 months mOS (PDL1 IC >5%) 11.1 vs 10.6 months, HR 0.87, 95% CI 0.63–1.21; P=0.41 mOS 12 months (ITT) 8.6 vs 8.0 months, HR 0.85, 95% CI 0.73–0.99, OR (ITT) 21.7 vs 7.4 months mDoR (PDL1 IC >5%) 15.9 vs 8.3 months |
Tx-related AEs (PDL1 IC >5%) 74.6% vs 88.4% Tx-related AEs (ITT) 69.5% vs 89.2% Tx-related grade 3–4 AEs (ITT) 19.8% vs 42.7% Tx-related grade 3–4 AEs (PDL1 IC >5%) 22.8% vs 34.8% Tx-related deaths (PDL1 IC >5%) 1.8% vs 1.8% Tx-related deaths (ITT) 0.9% vs 2.0% Tx-related AEs → discontinuation (ITT) 3.5% vs 14.2% Tx-related AEs → discontinuation (PDL1 IC >5%) 6.1% vs 15.2% |
| Nivolumab | ||||||
| CHECKMATE 03235 | Phase I/II, open-label, multiarm, two-stage, multicenter, international | 78 | Advanced UC Progression or recurrence after platinum or recurrence within 12 months after receipt of platinum- based adjuvant or neoadjuvant Tx or refused standard Tx ECOG 0–1 |
3 mg/kg IV every 2 weeks | ORR 24.4% (RECIST 1.1) ORR PDL1 ≥1% 24% mDoR 9.4 months mPFS 2.8 months mPFS PDL1 ≥1% 5.5 months mOS 9.7 mOS PDL1 ≥1% 16.2 months |
Tx-related grade 1–2 AEs 59% Tx-related grade 3–4 AEs 22% Tx-related deaths 2 (pneumonitis and thrombocytopenia) |
| CHECKMATE 27536 | Phase II, open-label, multicenter, single-arm, international | 270 | Advanced UC Progression or recurrence after platinum or recurrence within 12 months after receipt of platinum- based adjuvant or neoadjuvant Tx ECOG 0–1 |
3 mg/kg IV every 2 weeks | ORR 19.6% (RECIST 1.1) ORR PDL1 ≥1% 23.8% ORR PDL1 ≥5% 28.4% mDoR not reached mPFS 2.0 months mOS 8.7 months mOS PDL1 ≥1% 11.3 months |
Tx-related AEs 64% Tx-related grade 3–4 AEs 18% Immunomediated AEs 7% Tx-related deaths 3 (pneumonitis, acute respiratory failure, and cardiovascular failure) |
| Durvalumab | ||||||
| Study 110838,39 | Phase I/II, open-label, multicenter, international dose-escalation, dose-expansion | 191 | Advanced UC Progression or recurrence during prior Tx or ineligible/refused other therapies ECOG 0–1 |
10 mg/kg IV every 2 weeks for up to 12 months | ORR 17.8% (RECIST 1.1) ORR PDL1 ≥25% in TCs or ICs 27.6% mDoR not reached mPFS 1.5 months mPFS PDL1 ≥25% in TCs or ICs 2.1 months mOS 18.2 months mOS PDL1 ≥25% in TCs or ICs 20 months |
Tx-related AEs 60.7% Tx-related grade 3–4 AEs 6.8% Immunomediated AEs 11.5% Tx-related deaths 2 (autoimmune hepatitis and pneumonitis) |
| Avelumab | ||||||
| JAVELIN42 | Phase I, multicenter, expansion cohort | 249 | Advanced UC Relapsed, refractory, or progressive disease following at least one previous line of platinum-based Tx or cisplatin-ineligible/platinum-naïve ECOG 0–1 |
10 mg/kg IV every 2 weeks | ORR 17% (RECIST 1.1) ORR PDL1 ≥5% in TCs 24% mDoR not reached mPFS 1.5 months mPFS PDL1 ≥5% 2.8 months mOS 6.5 months mOS PDL1 ≥5% 8.2 months |
Tx-related AEs 67% Tx-related grade 3–4 AEs 8% Immunomediated AEs 14% Tx-related deaths 1 (pneumonitis) |
Abbreviations: AE, adverse event; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ICs, immune cells; ITT, intent-to-treat; IV, intravenously; mOS, median overall survival; mPFS, median progression-free survival; ORR, objective response rate; RECIST, response-evaluation criteria in solid tumors; TCs, tumor cells; Tx, treatment; UC, urothelial carcinoma; OR, odds ration; HR, hazard ratio.