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Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.

ABSTRACT: BACKGROUND:Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. METHODS:In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4? isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. RESULTS:The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). CONCLUSIONS:Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).

SUBMITTER: Bellmunt J

PROVIDER: S-EPMC5635424 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.

Bellmunt Joaquim J de Wit Ronald R Vaughn David J DJ Fradet Yves Y Lee Jae-Lyun JL Fong Lawrence L Vogelzang Nicholas J NJ Climent Miguel A MA Petrylak Daniel P DP Choueiri Toni K TK Necchi Andrea A Gerritsen Winald W Gurney Howard H Quinn David I DI Culine Stéphane S Sternberg Cora N CN Mai Yabing Y Poehlein Christian H CH Perini Rodolfo F RF Bajorin Dean F DF

The New England journal of medicine 20170217 11

<h4>Background</h4>Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.<h4>Methods</h4>In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 ...[more]

PMID: 28212060

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Project description:ImportanceImmune checkpoint inhibitors have been approved for use as a second-line therapy for hepatocellular carcinoma (HCC) in patients who previously received sorafenib. Pembrolizumab has shown substantial antitumor activity and a favorable toxicity profile as a second-line treatment of HCC. However, considering the high cost of pembrolizumab, there is a need to assess its value by considering both the clinical efficacy and cost.ObjectiveTo evaluate the cost-effectiveness of pembrolizumab vs placebo as second-line therapy in patients with HCC from the US payer perspective.Design, setting, and participantsA Markov model was developed to compare the lifetime cost and efficacy of pembrolizumab as a second-line treatment of HCC with those of placebo using outcome data from the KEYNOTE-240 randomized placebo-controlled trial, which included 413 patients with advanced HCC previously treated with sorafenib and randomized patients to receive pembrolizumab plus best supportive care or placebo plus best supportive care in a 2:1 ratio.Main outcomes and measuresLife-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were estimated at a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed to account for the parameter of uncertainty. A cost-threshold analysis was also performed. The study was conducted from January 31 to July 29, 2020.ResultsThe base-case model found that treatment with pembrolizumab was associated with increased overall cost by $47 057 and improved effectiveness by 0.138 QALYs compared with placebo, leading to an ICER of $340 409 per QALY. The model was most sensitive to the hazard ratio of overall survival (range, 0.61-1.00), health utility of placebo (range, 0.59-0.93), price of pembrolizumab (range, $5531-$8297), and price of postprogression therapies (range, $5596-$7944 for pembrolizumab and $4770-$7156 for placebo). The ICER of pembrolizumab was larger than $150 000 per QALY in most of the sensitivity and subgroup analyses. The price of pembrolizumab needed to be reduced by 57.7% to $2925 per cycle to achieve cost-effectiveness.Conclusions and relevanceThe findings of this cost-effectiveness analysis suggest that, at its current price, pembrolizumab is not a cost-effective second-line therapy for HCC in the US, with a willingness-to-pay threshold of $150 000 per QALY.

Project description:IntroductionKEYNOTE-240 investigated the efficacy and safety of pembrolizumab plus best supportive care (BSC) in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). Results for the subgroup of patients from Asia are described.MethodsAdults with advanced HCC previously treated with sorafenib were randomized 2:1 to pembrolizumab or placebo plus BSC. Here, the Asian subgroup comprised patients enrolled in Hong Kong, Japan, Korea, the Philippines, Taiwan, and Thailand. Primary endpoints were progression-free survival (PFS) per blinded central imaging review and overall survival (OS). Secondary endpoints included objective response rate (ORR) per blinded central imaging review, duration of response (DOR), and safety.ResultsThe Asian subgroup included 157 patients. As of January 2, 2019, the median follow-up in this subgroup was 13.8 months for pembrolizumab and 8.3 months for placebo. The median PFS was 2.8 months for pembrolizumab (95% confidence interval [CI] 2.6-4.1) versus 1.4 months (95% CI 1.4-2.4) for placebo (hazard ratio [HR] 0.48; 95% CI 0.32-0.70). The median OS was 13.8 months (95% CI 10.1-16.9) for pembrolizumab versus 8.3 months (95% CI 6.3-11.8) for placebo (HR 0.55; 95% CI 0.37-0.80). ORR was 20.6% (95% CI 13.4-29.5) for pembrolizumab versus 2.0% (95% CI 0.1-10.6) for placebo (difference: 18.5%; 95% CI 8.3-27.6). The median DOR was 8.6 and 2.8 months for pembrolizumab and placebo, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 63 patients (58.9%) receiving pembrolizumab and 24 patients (48.0%) receiving placebo; 14 (13.1%) and 2 (4.0%) patients experienced grade 3-5 TRAEs, respectively. No treatment-related deaths occurred.ConclusionPembrolizumab demonstrated antitumor activity and was well tolerated in the Asian subgroup of KEYNOTE-240. A trend toward greater benefit with pembrolizumab in the Asian subgroup was observed compared with the overall cohort, supporting further evaluation of pembrolizumab treatment in this population.

Project description:BackgroundPatients with treatment-naive advanced urothelial cancer (UC) ineligible for cisplatin-based chemotherapy are typically older and have comorbidities, representing a difficult-to-treat population.ObjectiveTo evaluate the safety and antitumor activity of first-line pembrolizumab in subgroups of cisplatin-ineligible older patients (aged ≥65 and ≥75 yr) with advanced UC in KEYNOTE-052 (NCT02335424), including those with poor performance status (Eastern Cooperative Oncology Group performance status score 2 [ECOG PS2]).Design, setting, and participantsPatients were cisplatin ineligible, had treatment-naive, histologically/cytologically confirmed, locally advanced/metastatic UC with measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]), and had ECOG PS0-2. Patient subgroups analyzed were aged ≥65yr (n = 302), ≥75 yr (n = 179), ≥65yr with ECOG PS2 (≥65yr+ECOG PS2; n = 119), and ≥75 yr+ECOG PS2 (n = 78).InterventionAll patients received pembrolizumab 200mg intravenously every 3 wk until confirmed progression, intolerable toxicity, patient withdrawal, or 24 mo of therapy.Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR) as per RECIST v1.1. The key secondary endpoints were overall survival (OS), duration of response (DOR), and safety.Results and limitationsORRs for the ≥65yr, ≥75 yr, ≥65yr+ECOG PS2, and ≥75 yr+ECOG PS2 subgroups were 29%, 27%, 29%, and 31%, respectively; rates of complete and partial responses were similar across subgroups (9%, 5%, 6%, and 6%, and 20%, 22%, 23%, and 24%, respectively). Median DOR and OS were also consistent across the ≥65yr and ≥65yr+ECOG PS2 subgroups and the ≥75 yr and ≥75 yr+ECOG PS2 subgroups. Study limitations included open-label design, lack of a comparator group, and nature of post hoc exploratory analysis.ConclusionsThe clinical benefit of pembrolizumab in advanced UC appeared to be consistent regardless of age and/or poor performance status.Patient summaryThis study looked at whether older age and poorer performance status affect how well patients with previously untreated advanced urothelial cancer ineligible for standard-of-care treatment respond to pembrolizumab. Outcomes with pembrolizumab were not affected by older age or poorer performance status, making it an effective option.

Dataset Information

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.

Publications

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.

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