Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study
Menés respectivement dans 21 et 14 pays sur 1 010 patients atteints d'un carcinome urothélial de stade avancé et sur 334 patients atteints d'un cancer de la vessie sans envahissement musculaire, à haut risque de récidive et ne répondant pas à une injection intravésicale de BCG, ces deux essais évaluent l'efficacité et la toxicité du pembrolizumab, seul ou combiné avec une chimiothérapie
Background : Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethralresection of bladder tumour followed by intravesical BCG immunotherapy. However, despitehigh initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive.PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study,we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasivebladder cancer.
Methods : We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitalsand cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 yearsor older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder,with or without papillary tumours, with an Eastern Cooperative Oncology Group performancestatus of 0–2, and who were ineligible for or declined radical cystectomy were enrolled.All enrolled patients were assigned to receive pembrolizumab 200 mg intravenouslyevery 3 weeks for up to 24 months or until centrally confirmed disease persistence,recurrence, or progression; unacceptable toxic effects; or withdrawal of consent.The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasivebladder cancer or progressive disease), assessed by cystoscopy and urine cytologyapproximately 3 months after the first dose of study drug. Patient follow-ups weredone every 3 months for the first 2 years and every 6 months thereafter for up to5 years. Efficacy was assessed in all patients who received at least one dose of thestudy drug and met BCG-unresponsive criteria. Safety was assessed in all patientswho received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.
Findings : Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186patients did not meet inclusion criteria, and 47 patients were assigned to cohortB (patients with BCG-unresponsive high grade Ta or any grade T1 papillary diseasewithout carcinoma in situ; results will be reported separately). 101 eligible patientswere enrolled and assigned to receive pembrolizumab. All 101 patients received atleast one dose of the study drug and were included in the safety analysis. Five patientshad disease that did not meet the US Food and Drug Administration definition of BCG-unresponsivenon-muscle-invasive bladder cancer and were therefore not included in the efficacyanalysis (n=96). Median follow-up was 36·4 months (IQR 32·0–40·7). 39 (41%; 95% CI30·7–51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder withor without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-relatedadverse events occurred in 13 (13%) patients; the most common were arthralgia (intwo [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-relatedadverse events occurred in eight (8%) patients. There were no deaths that were consideredtreatment related.
Interpretation : Pembrolizumab monotherapy was tolerable and showed promising antitumour activity inpatients with BCG-unresponsive non-muscle-invasive bladder cancer who declined orwere ineligible for radical cystectomy and should be considered a a clinically activenon-surgical treatment option in this difficult-to-treat population.
The Lancet Oncology , résumé, 2020