KEYNOTE-045: trial | Bending the Curve: Trial by Trial

KEYNOTE-045

Pembrolizumab versus investigator's choice of paclitaxel, docetaxel or vinflunine in advanced urothelial carcinoma that recurred or progressed after platinum-based chemotherapy

Phase 3N = 542NCT02256436

Population

Advanced urothelial carcinoma that recurred or progressed after platinum-based chemotherapy

Design

Open-label, international phase 3 trial; 1:1 to pembrolizumab 200 mg every 3 weeks or investigator's choice of paclitaxel, docetaxel or vinflunine. Coprimary endpoints overall survival and progression-free survival, assessed in all patients and in patients with a PD-L1 combined positive score of 10% or more.

Primary endpoint

OS, PFS

Arms

Pembrolizumab (experimental, n = 270): Pembrolizumab 200 mg every 3 weeks
Investigator's choice chemotherapy (control, n = 272): Paclitaxel 175 mg/m2, docetaxel 75 mg/m2 or vinflunine 320 mg/m2 every 3 weeks

People

Bellmunt J, KEYNOTE-045 Investigators

OSHR 0.73 (95% CI 0.59–0.91)Δ median OS+2.9 monthsOSHR 0.57 (95% CI 0.37–0.88)Δ median OS+2.8 monthsPFSHR 0.98 (95% CI 0.81–1.19)PFSHR 0.89 (95% CI 0.61–1.28)

Show the numbers

Results reported for KEYNOTE-045
Endpoint	Analysis	Pembrolizumab	Investigator's choice chemotherapy	Effect
OSTotal population (n = 542)	primaryBellmunt 2017	median 10.3 months (8.0–11.8)	median 7.4 months (6.1–8.3)	HR 0.73 (95% CI 0.59–0.91)P=0.002
OSPD-L1 combined positive score of 10% or more	primaryBellmunt 2017	median 8 months (5.0–12.3)	median 5.2 months (4.0–7.4)	HR 0.57 (95% CI 0.37–0.88)P=0.005
PFSTotal population (n = 542)	primaryBellmunt 2017	—	—	HR 0.98 (95% CI 0.81–1.19)P=0.42No significant between-group difference in PFS.
PFSPD-L1 combined positive score of 10% or more	primaryBellmunt 2017	—	—	HR 0.89 (95% CI 0.61–1.28)P=0.24
OSTotal population (n = 542)	long term-updatemedian follow-up 27.7 monthsFradet 2019	44.2% at 12 mo; 26.9% at 2 y	29.8% at 12 mo; 14.3% at 2 y	The abstract labels these 'median 1- and 2-year OS rates'; read here as Kaplan-Meier survival rates at 12 and 24 months.
ORRTotal population (n = 542)	long term-updatemedian follow-up 27.7 monthsFradet 2019	21.1%	11%	—
DORResponders	long term-updatemedian follow-up 27.7 monthsFradet 2019	—	median 4.4 months	Median duration of response was not reached with pembrolizumab (range 1.6+ to 30.0+ months).

Results reported for KEYNOTE-045
Endpoint	Analysis	Pembrolizumab	Investigator's choice chemotherapy	Effect
OSTotal population (n = 542)	primaryBellmunt 2017	median 10.3 months (8.0–11.8)	median 7.4 months (6.1–8.3)	HR 0.73 (95% CI 0.59–0.91)P=0.002
OSPD-L1 combined positive score of 10% or more	primaryBellmunt 2017	median 8 months (5.0–12.3)	median 5.2 months (4.0–7.4)	HR 0.57 (95% CI 0.37–0.88)P=0.005
PFSTotal population (n = 542)	primaryBellmunt 2017	—	—	HR 0.98 (95% CI 0.81–1.19)P=0.42No significant between-group difference in PFS.
PFSPD-L1 combined positive score of 10% or more	primaryBellmunt 2017	—	—	HR 0.89 (95% CI 0.61–1.28)P=0.24
OSTotal population (n = 542)	long term-updatemedian follow-up 27.7 monthsFradet 2019	44.2% at 12 mo; 26.9% at 2 y	29.8% at 12 mo; 14.3% at 2 y	The abstract labels these 'median 1- and 2-year OS rates'; read here as Kaplan-Meier survival rates at 12 and 24 months.
ORRTotal population (n = 542)	long term-updatemedian follow-up 27.7 monthsFradet 2019	21.1%	11%	—
DORResponders	long term-updatemedian follow-up 27.7 monthsFradet 2019	—	median 4.4 months	Median duration of response was not reached with pembrolizumab (range 1.6+ to 30.0+ months).

Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.

Data table

Endpoint	HR	95% CI
OS	0.73	0.59–0.91
OS	0.57	0.37–0.88
PFS	0.98	0.81–1.19
PFS	0.89	0.61–1.28

Illustrative — modelled from reported values, not trial data. OS, primary.

Show curves

Pembrolizumab (experimental)
Investigator's choice chemotherapy (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Pembrolizumab	Investigator's choice chemotherapy
0	100.0%	100.0%
6	66.8%	57.0%
13	41.7%	29.6%
19	27.8%	16.9%
26	17.4%	8.8%

Illustrative — modelled from reported values, not trial data. OS, primary.

Show curves

Pembrolizumab (experimental)
Investigator's choice chemotherapy (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Pembrolizumab	Investigator's choice chemotherapy
0	100.0%	100.0%
5	64.8%	51.4%
10	42.0%	26.4%
15	27.3%	13.5%
20	17.7%	7.0%

Appears in

2017 KEYNOTE-045: pembrolizumab after platinum in advanced UC

Sources

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11):1015-1026.
PubMed DOI
Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. Ann Oncol. 2019;30(6):970-976.
PubMed DOI