Immunotherapy for Patients with Advanced Urothelial Cancer: Current Evidence and Future Perspectives

Table 1

Clinical trials with anti-PD-L1 and anti-PD-1 immune checkpoint inhibitors in metastatic urothelial cancer.

Drug	Trial	Phase	Indication	Sample size ()	Control arm	Results in all pts	Results according to PDL1
Atezolizumab 1200 mg IV	ImVigor 210	II	Cohort A: 1° line, cisplatin ineligible [24]	123		IR-ORR 23% (95% CI 16–31); IA-ORR: 25% (18–34); DOR not reached (range 3.7–21.0+); PFS 2.7 months (95% CI 2.1–4.2); OS 15.9 m (95% CI 10.4 to N.E.)	IR-ORR 28% (14–47) in IC2/3, 24% (15–35) in IC1/2/3, 21% (95% CI 10–35) in IC1, and 21% (95% CI 9–36) in IC0; IA-ORR: 31% (16–36) in IC2/3, 25% (16–36) in IC1/2/3, 21% (95% CI 11–35) in IC1, and 26% (95% CI 13–42) in IC0; PFS 4.1 m (2.3–11.8) in IC2/3, 2.1 m (2.1–5.4) in IC1, and 2.6 m (2.1–5.7) in IC0; OS 12.3 m (6.0 to N.E.) in IC2/3, and 19.1 m (9.8 to N.E.) in IC0/1
			Cohort B: postplatinum [23]	310		IR-ORR: 15% (95% CI 11–20); IA-ORR: 19% (95% CI 15–24); DOR: not reached (range 2.0–13.7 m); IR-PFS: 2.1 m (95% CI 2.1-2.1); IA-PFS: 2.7 m (95% CI 2.1–3.9); OS: 7.9 m (95% CI 6.6–9.3); OS at 12 m: 36% (95% CI 30–41); Safety: Any grade TRAE 215 (69%), serious TRAE 50 (16%)	IR-ORR: 26% (95% CI 18–36) in IC2/3,; 18% (95% CI 13–24) in IC1/2/3; IR-ORR: 27% (95% CI 19–37) in IC2/3,; 22% (95% CI 16–28) in IC1/2/3; DOR: IC-PFS: 2.1 m (95% CI 2.1–4.1) in IC2/3, 2.1 m (95% CI 2.1-2.1) in IC1/2/3; IA-PFS: 4.0 m (95% CI 2.6–5.9) in IC2/3, 2.9 m (95% CI 2.1–4.1) in IC1/2/3; OS: 11.4 m (95% CI 9.0–N.E.) in IC2/3, 8.8 m (95% CI 7.1–10.6) in IC1/2/3; OS at 12 m: 48% (95% CI 38–58) in IC2/3, 39% (95% CI 32–46) in IC1/2/3
Durvalumab 10 mg/kg q2w [25]	NCT01693562.	I/II	Unresectable or metastatic	61		Safety: Any grade AE 39 (63.9%), serious AE 3 (4.9%); IA-ORR 31.0%; (95% CI, 17.6 to 47.1) in all pts	IA-ORR: 46.4% in PD-L1+ and 0% in PD-L1−; DCR at 12 w: 57.1% in PD-L1+ and 28.6% in PD-L1−
Avelumab 10 mg/kg q2w [27]	NCT01772004	I	Postplatinum or cisplatin ineligible	44		Safety: Any grade AE 29 (65.9%), serious AE 3 (6.8%); IR-ORR: 18.2% (95% CI, 8.2%–32.7%); OS: 13.7 m (95% CI, 8.5–N.E.); PFS: 11.6 w (95% CI, 6.1–17.4)	ORR: 53.8% in PD-L1 ≥ 5% versus 4.2% in PD-l1 < 5%
Nivolumab 3 mg/kg IV q2w	Checkmate 032 NCT01928394. [30]	I/II	Postplatinum or refusing it	78		IA-ORR: 19 (24.4%, 95% CI 15.3–35.4); DOR: 1.5 m (1.2–4.1); PFS: 2.8 m (95% CI 1.5–5.9); OS: 9.7 m (95% CI 7.3–16.2); Safety: Any grade TRAE 63 (81%), serious TRAE 17 (22%)	IA-ORR: 24% (95% CI 9–45) in PD-L1 ≥ 1%, 26% (14–42) in PD-L1 < 1%, 24.5 (13.8–38.3) in PD-L1 < 5%, 28.6 (8.4–58.1) in PD-L1 ≥ 5%; PFS: 5.5 m (95% CI 1.4–11.2) in PD-L1 ≥ 1%, 2.8 m (1.4–6.5) in PD-L1 < 1%, 2.8 (1.5–7.0) in PD-L1 < 5%, 5.5 (1.2–11.2) in PD-L1 ≥ 5%; OS: 16.2 m (95% CI 7.6–N.E.) in PD-L1 ≥ 1%, and 9.9 m (7.0–N.E.) in PD-L1 < 1%, 10.4 (7.0–N.E.) in PD-L1 < 5%, 12.9 (2.8–N.E.) in PD-L1 ≥ 5%
	Checkmate 275 NCT02387996 [31]	II	Postplatinum (no liver metastasis if ≥2 CT lines)	270		IR-ORR: 19.6% (95% CI 15.0–24.9); IA-ORR: N.A.; PFS: 2.00 m (95% CI 1.87–2.63); OS: 8.74 m (95% CI 6.05–N.E.)	IR-ORR: 28.4% (95% CI 18.9–39.5) in PD-L1 ≥ 5%, 23.8% (95% CI 16.5–32.3) in PD-L1 ≥ 1%, 16.1% (95% CI 10.5–23.1) in PD-L1 < 1%; IA-ORR: N.A.; PFS: N.A.; OS: 11.30 m (8.74–N.E) in PD-L1 ≥ 1%, 5.95 m (4.30–8.08) in PD-L1 < 1%
Nivo 240 mg q2w Nivo 3 mg/kg + Ipi 1 mg/kg q3w, then Nivo 240 mg q2w	CA209-; 260; NCT02553642; [32]	2	Metastatic, option of treatment with the combination if confirmed PD with Nivo	40 (10 treated with Nivo + Ipi)		DCR: 4/10 (1 partial response and 3 stable diseases)
Pembrolizumab 200 mg q3w	Keynote 012 NCT01848834 [33]	Ib	Unresectable or metastatic	33		IR-ORR: 26% (95% CI 11–46); Safety: Any grade TRAE 20 (61%), serious TRAE 5 (15%); IA-ORR: PFS: 2 m (95% CI 2–4); DOR: 10 m (range 4–22+); OS: 13 m (95% CI 5–20)	Patients were required to have ≥1% PD-L1 expression
	Keynote 052 NCT02335424 [34]	II	Cisplatin ineligible	370		IR-ORR: 27% (22–32); DOR: (1+ to 14+ m); PFS 6 m: 31%; OS 6 m: 67%
	Keynote 045 NCT02256436 [36]	III	Postplatinum	542	Investigator’s choice CT with paclitaxel, docetaxel, or vinflunine	OS: 10.3 versus 7.4 m (HR: 0.73; ); PFS: 2.1 versus 3.m (HR: 0.98; ); ORR: 21.1 versus 11.4%; DOR: not reached versus 4.3 m	OS: 8 versus 5.2 (HR: 0.57; ) in PD-L1 ≥ 10%; PFS: HR: 0.89; ORR: N.A.; DOR: N.A.

AE: adverse events, CT: chemotherapy, DOR: duration of response, IA: investigator-assessed, IC: immune cells, IR: independently reviewed, m: months, N.A.: not available, N.E.: not estimable, ORR: overall response rate, OS: overall survival, PFS: progression free survival, TRAE: treatment-related adverse events, w: weeks; bold refers to primary endpoint; italics refers to secondary endpoint; PD-L1 expression status was defined by the percentage of PD-L1+ IC: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%).