Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study.
Humans
Antibodies, Monoclonal, Humanized
/ therapeutic use
Male
Female
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Aged
Sulfonamides
/ therapeutic use
Cisplatin
/ therapeutic use
Double-Blind Method
Middle Aged
Urologic Neoplasms
/ drug therapy
Aged, 80 and over
Carcinoma, Transitional Cell
/ drug therapy
Adult
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ antagonists & inhibitors
Oximes
Epacadostat
IDO1
Immune checkpoint inhibition
Immunotherapy
PD-L1
PD1
Pembrolizumab
Randomized controlled study
Urinary tract neoplasms
Urothelial carcinoma
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
25 Jul 2024
25 Jul 2024
Historique:
received:
19
08
2022
accepted:
08
03
2023
medline:
26
7
2024
pubmed:
26
7
2024
entrez:
25
7
2024
Statut:
epublish
Résumé
Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC. ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1). A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%). Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted. ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.
Sections du résumé
BACKGROUND
BACKGROUND
Indoleamine 2,3- dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been correlated with shorter disease-specific survival in patients with urothelial carcinoma (UC). IDO1 may counteract the antitumor effects of immune checkpoint inhibitors. Epacadostat is a potent and highly selective inhibitor of IDO1. In the phase I/II ECHO-202/KEYNOTE-037 study, epacadostat plus pembrolizumab resulted in a preliminary objective response rate (ORR) of 35% in a cohort of patients with advanced UC.
METHODS
METHODS
ECHO-307/KEYNOTE-672 was a double-blinded, randomized, phase III study. Eligible adults had confirmed locally advanced/unresectable or metastatic UC of the urinary tract and were ineligible to receive cisplatin-based chemotherapy. Participants were randomly assigned (1:1) to receive epacadostat (100 mg twice daily) plus pembrolizumab (200 mg every 3 weeks) or placebo plus pembrolizumab for up to 35 pembrolizumab infusions. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors (version 1.1).
RESULTS
RESULTS
A total of 93 patients were randomized (epacadostat plus pembrolizumab, n = 44; placebo plus pembrolizumab, n = 49). Enrollment was stopped early due to emerging data from the phase III ECHO-301/KEYNOTE-252 study. The median duration of follow-up was 64 days in both arms. Based on all available data at cutoff, ORR (unconfirmed) was 31.8% (95% CI, 22.46-55.24%) for epacadostat plus pembrolizumab and 24.5% (95% CI, 15.33-43.67%) for placebo plus pembrolizumab. Circulating kynurenine levels numerically increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and decreased in the epacadostat-plus-pembrolizumab arm. Epacadostat-plus-pembrolizumab combination treatment was well tolerated with a safety profile similar to the placebo arm. Treatment discontinuations due to treatment-related adverse events were more frequent with epacadostat (11.6% vs. 4.1%).
CONCLUSIONS
CONCLUSIONS
Treatment with epacadostat plus pembrolizumab resulted in a similar ORR and safety profile as placebo plus pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced/unresectable or metastatic UC. At a dose of 100 mg twice daily, epacadostat did not appear to completely normalize circulating kynurenine levels when administered with pembrolizumab. Larger studies with longer follow-up and possibly testing higher doses of epacadostat, potentially in different therapy settings, may be warranted.
TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov identifier: NCT03361865, retrospectively registered December 5, 2017.
Identifiants
pubmed: 39054491
doi: 10.1186/s12885-023-10727-3
pii: 10.1186/s12885-023-10727-3
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
pembrolizumab
DPT0O3T46P
epacadostat
71596A9R13
Sulfonamides
0
Cisplatin
Q20Q21Q62J
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Oximes
0
Banques de données
ClinicalTrials.gov
['NCT03361865']
Types de publication
Journal Article
Randomized Controlled Trial
Clinical Trial, Phase III
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
1252Informations de copyright
© 2023. The Author(s).
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