Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial
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 : PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positiverandomised data supporting their use as a first-line treatment are lacking. In thisstudy we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma.
Methods : KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma,with an Eastern Cooperative Oncology Group performance status of up to 2. Eligiblepatients were enrolled from 201 medical centres in 21 countries and randomly allocated(1:1:1) via an interactive voice-web response system to intravenous pembrolizumab200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine[1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximumof six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice ofplatinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigatorswere masked to the treatment assignment or CPS. At protocol-specified final analysis,sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapyversus chemotherapy alone in the total population (all patients randomly allocatedto a treatment) for the dual primary endpoints of progression-free survival (p valueboundary 0·0019), assessed by masked, independent central review, and overall survival(p value boundary 0·0142), followed by non-inferiority and superiority of overallsurvival for pembrolizumab versus chemotherapy in the patient population with CPSof at least 10 and in the total population (also a primary endpoint). Safety was assessedin the as-treated population (all patients who received at least one dose of studytreatment). This study is completed and is no longer enrolling patients, and is registeredat ClinicalTrials.gov, number NCT02853305.
Findings : Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307),or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumabplus chemotherapy versus chemotherapy did not significantly improve progression-freesurvival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) inthe pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapygroup (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, witha median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapygroup versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407).No further formal statistical hypothesis testing was done. In analyses of overallsurvival with pembrolizumab versus chemotherapy (now exploratory based on hierarchicalstatistical testing), overall survival was similar between these treatment groups,both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the populationwith CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumabplus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%]of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to anadverse event attributed to study treatment; two patients in each treatment group.One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumabplus chemotherapy group, one each due to cardiac failure and malignant neoplasm progressionin the pembrolizumab group, and one each due to myocardial infarction and ischaemiccolitis in the chemotherapy group.
Interpretation : The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantlyimprove efficacy and should not be widely adopted for treatment of advanced urothelialcarcinoma.
The Lancet Oncology , résumé, 2020