KEYTRUDA® in locally advanced or metastatic urothelial carcinoma (UC)1 following platinum-containing chemotherapy
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EXPLORE KEYTRUDA® in the KEYNOTE-045 trial as monotherapy for patients who progressed during or following platinum-containing chemotherapy or within 12 months of completing neoadjuvant or adjuvant platinum-containing chemotherapy, with locally advanced or metastatic urothelial carcinoma (UC)
KEYNOTE-045 trial: A randomized, active-controlled phase 3 trial for the treatment of locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy
Trial overview
- Multicentre, randomized active-controlled trial
- Patients must have experienced disease progression or have previously been treated with platinum-containing chemotherapy
- 542 patients with locally advanced or metastatic urothelial carcinoma
- Patient demographics:
- 66 years old median age (range: 26 to 88); 58% age 65 or older
- 57% had ECOG performance status ≥1
- 96% M1 disease
- 87% had visceral metastases, including 34% with liver metastases
- 86% had a primary tumor in the lower tract
- 15% of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy as the most recent line of therapy
- 21% of patients received ≥2 prior systemic regimens in the metastatic setting
- 76% of patients received prior cisplatin, 23% had prior carboplatin, 1% were treated with other platinum-based regimens
- Patients with an autoimmune disease or a medical condition that required immunosuppression were excluded from the study
Treatment arms
KEYTRUDA® 200 mg Q3W
via intravenous administration
(n=270)Chemotherapy Q3W
via intravenous administration
(n=272)Investigator’s choice of any of the following: paclitaxel 175 mg/m2 (n=84); docetaxel 75 mg/m2 (n=84); or vinflunine 320 mg/m2 (n=87)
Patients received KEYTRUDA® until unacceptable toxicity or disease progression. Patients without disease progression were treated for up to 24 months.
Primary endpoints
- overall survival (OS)
- progression-free survival (PFS), assessed by BICR per RECIST v1.1
Secondary endpoints
- overall response rate (ORR), assessed by BICR per RECIST v1.1
- duration of response (DoR)
BICR= blinded independent central review; CI=confidence interval; HR=hazard ratio; IC= investigator’s choice; ITT= intend-to-treat; ORR=overall response rate; OS= overall survival; PD-L1=programmed death-ligand 1; PFS= progression-free survival; Q3W=every three weeks; RECIST=response evaluation criteria in solid tumours.
† Based on stratified Log rank test
£ p-value is compared with 0.0123 of the allocated alpha for the interim analysis
€ p-value is compared with 0.0151 of the allocated alpha for the interim analysis
¥p-value is compared with 0.0170 of the allocated alpha for the interim analysisITT population (interim analysis)
Overall Survival
27% reduction in the risk of death with KEYTRUDA® monotherapy vs. IC chemotherapy (HR=0.73 [95% CI: 0.59, 0.91]; p†=0.002£; # of deaths 155/270 and 179/272, respectively)
Median Overall Survival
Median overall survival was 10.3 months (95% CI: 8.0, 11.8) for KEYTRUDA® and 7.4 months (95% CI: 6.1, 8.3) for IC chemotherapy.
Objective Response Rate
1.9X improvement in objective response rate with KEYTRUDA® monotherapy (21%, 95% CI:16,27; p=0.001¥) vs IC chemotherapy (11%, 95% CI:8,16; p=0.001)
ITT population (final descriptive analysis)
Overall Survival
30% reduction in the risk of death with KEYTRUDA® monotherapy vs. IC chemotherapy (HR=0.70 [95% CI: 0.57, 0.85]; p<0.001; # of deaths 200/270 and 219/272, respectively)
Kaplan-Meier Curve for overall survival in the KEYNOTE-045 trial (final descriptive analysis, intent-to-treat population)
Median Overall Survival
Median overall survival was 10.1 months (95% CI: 8.0, 12.3) for KEYTRUDA® and 7.3 months (95% CI: 6.1, 8.1) for chemotherapy.
Progression Free Survival
In the interim analysis and final descriptive analysis of progression-free survival there was no statistically significant difference between KEYTRUDA® and IC chemotherapy
BICR= blinded independent central review; CI=confidence interval; HR=hazard ratio; IC= investigator’s choice; ITT= intend-to-treat; ORR=overall response rate; OS= overall survival; PD-L1=programmed death-ligand 1; PFS= progression-free survival; Q3W=every three weeks; RECIST=response evaluation criteria in solid tumours.
† Based on stratified Log rank test
£ p-value is compared with 0.0123 of the allocated alpha for the interim analysis
€ p-value is compared with 0.0151 of the allocated alpha for the interim analysis
¥p-value is compared with 0.0170 of the allocated alpha for the interim analysisKEYTRUDA® demonstrated safety profile in locally advanced or metastatic UC in KEYNOTE-045
The most common grades 3 to 5 treatment-related adverse events (reported in ≥2 of patients) were:
Adverse ReactionKEYTRUDA® 200 mg
every 3 weeks
% (n=266)Chemotherapy
% (n=255)Pneumonitis1.50Diarrhea1.10.8Fatigue1.14.3Aspartate aminotransferase increased1.10- 15% of patients had ≥ Grade 3 adverse reactions.
- KEYTRUDA® was discontinued for treatment-related adverse events in 5.6% of patients
- The most common treatment-related adverse event leading to study drug discontinuation (occurring in more than 2 patients) was: pneumonitis (n=5)
- The median time to discontinuation for treatment-related adverse events was 0.7 months.
The most common treatment-related adverse events (any grade, reported in ≥10% of patients) were:
Adverse ReactionKEYTRUDA® 200 mg
every 3 weeks
% (n=266)Chemotherapy
% (n=255)Pruritus19.52.7Fatigue13.927.8Nausea10.924.3For the complete list of treatment-related adverse events, please consult the Product Monograph
BICR= blinded independent central review; CI=confidence interval; HR=hazard ratio; IC= investigator’s choice; ITT= intend-to-treat; ORR=overall response rate; OS= overall survival; PD-L1=programmed death-ligand 1; PFS= progression-free survival; Q3W=every three weeks; RECIST=response evaluation criteria in solid tumours.
† Based on stratified Log rank test
£ p-value is compared with 0.0123 of the allocated alpha for the interim analysis
€ p-value is compared with 0.0151 of the allocated alpha for the interim analysis
¥p-value is compared with 0.0170 of the allocated alpha for the interim analysis
References:
1. Merck Canada Inc. KEYTRUDA® Product Monograph. December 29, 2022.
2.Warren Canadian Urological Association (CUA)/Genitourinary Medical Oncologists of Canada (GMOC) consensus statement: Management of unresectable locally advanced and metastatic urothelial carcinoma. April 2019
CA-PDO-00146