Pembrolizumab As Second-Line Therapy For Advanced .

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new englandjournal of medicineTheestablished in 1812March 16, 2017vol. 376no. 11Pembrolizumab as Second-Line Therapy for AdvancedUrothelial CarcinomaJ. Bellmunt, R. de Wit, D.J. Vaughn, Y. Fradet, J.-L. Lee, L. Fong, N.J. Vogelzang, M.A. Climent, D.P. Petrylak,T.K. Choueiri, A. Necchi, W. Gerritsen, H. Gurney, D.I. Quinn, S. Culine, C.N. Sternberg, Y. Mai, C.H. Poehlein,R.F. Perini, and D.F. Bajorin, for the KEYNOTE-045 Investigators* a bs t r ac tBACKGROUNDPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.METHODSIn this open-label, international, phase 3 trial, we randomly assigned 542 patients withadvanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotypeantibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or theinvestigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessedamong all patients and among patients who had a tumor PD-1 ligand (PD-L1) combinedpositive score (the percentage of PD-L1–expressing tumor and infiltrating immune cellsrelative to the total number of tumor cells) of 10% or more.RESULTSThe authors’ full names, academic degrees,and affiliations are listed in the Appendix.Address reprint requests to Dr. Bellmuntat the Dana–Farber Cancer Institute, 450Brookline Ave., Dana Bldg. 1230, Boston,MA 02215, or at j oaquim bellmunt@ dfci . harvard . edu.* A complete list of investigators in theKEYNOTE-045 trial is provided in theSupplementary Appendix, available atNEJM.org.This article was published on February 17,2017, at NEJM.org.N Engl J Med 2017;376:1015-26.DOI: 10.1056/NEJMoa1613683Copyright 2017 Massachusetts Medical Society.The median overall survival in the total population was 10.3 months (95% confidenceinterval [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, 0.59to 0.91; P 0.002). The median overall survival among patients who had a tumor PD-L1combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in thepembrolizumab 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 totalpopulation (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% ormore (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P 0.24). Fewer treatment-related adverseevents 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%).CONCLUSIONSPembrolizumab 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.)n engl j med 376;11nejm.orgMarch 16, 2017The New England Journal of MedicineDownloaded from nejm.org at UW-Madison on September 14, 2018. For personal use only. No other uses without permission.Copyright 2017 Massachusetts Medical Society. All rights reserved.1015

Then e w e ng l a n d j o u r na lUA Quick Takeis available atNEJM.orgrothelial cancer is highly lethalin the metastatic state.1 Platinum-basedcombination chemotherapy remains thestandard first-line treatment for metastatic disease. Carboplatin-based combinations are associated with a median overall survival of 9 months,2and cisplatin-based combinations with a medianoverall survival of 12 to 15 months.3 However,after platinum-based chemotherapy, there is nointernationally accepted standard of care. Singleagent paclitaxel and docetaxel are commonlyused worldwide,4,5 and in Europe, vinflunine hasbeen approved on the basis of an overall survivaladvantage of 2 months over best supportivecare.6,7 Because the median overall survival withsecond-line therapy is only 6 to 7 months, effective options are needed in patients with previously treated advanced urothelial carcinoma.Monoclonal antibodies against programmeddeath 1 (PD-1) and its ligands (PD-L1 and PD-L2)have shown robust antitumor activity and a manageable safety profile in many advanced malignant conditions,8 including urothelial cancer.9-14Pembrolizumab, a highly selective, humanizedmonoclonal IgG4κ isotype antibody against PD-1,can disrupt the engagement of PD-1 with itsligands and impede inhibitory signals in T cells.Pembrolizumab showed antitumor activity in patients with advanced urothelial carcinoma in thephase 1b KEYNOTE-012 study9 and the phase 2KEYNOTE-052 study.12 In the international, randomized, open-label, phase 3 KEYNOTE-045 trial,we compared pembrolizumab with investigator’schoice of chemotherapy with paclitaxel, docetaxel,or vinflunine as second-line therapy in patientswith advanced urothelial carcinoma that progressed during or after the receipt of platinumbased chemotherapy.Me thodsPatientsPatients who were 18 years of age or older wereeligible for enrollment if they had histologicallyor cytologically confirmed urothelial carcinoma ofthe renal pelvis, ureter, bladder, or urethra thatshowed predominantly transitional-cell featureson histologic testing, had progression afterplatinum-based chemotherapy for advanced disease or recurrence within 12 months after thereceipt of platinum-based adjuvant or neoadjuvanttherapy for localized muscle-invasive disease, hadreceived two or fewer lines of systemic chemo1016n engl j med 376;11ofm e dic i n etherapy for advanced disease previously, had atleast one measurable lesion according to theResponse Evaluation Criteria in Solid Tumors(RECIST), version 1.1,15 and had an Eastern Cooperative Oncology Group (ECOG) performancestatus score of 0, 1, or 2 (on a 5-point scale, with0 indicating no symptoms and higher numbersindicating greater disability). Patients who hadan ECOG performance-status score of 2 (indicating that the patient is ambulatory and capable ofall self-care but is unable to carry out any workactivities and is out of bed more than 50% ofwaking hours) and had one or more of the established poor prognostic factors for second-linetherapy (i.e., hemoglobin concentration of 10 gper deciliter, presence of liver metastases, andreceipt of the last dose of most recent chemotherapy 3 months before enrollment)16,17 wereexcluded from enrollment. Patients were ineligible if they had received anti–PD-1, anti–PD-L1,or anti–CTLA-4 therapy previously. Full eligibility criteria are listed in the trial protocol, available with the full text of this article at NEJM.org.Trial Design and TreatmentPatients were randomly assigned in a 1:1 ratio toreceive pembrolizumab (at a dose of 200 mg) orinvestigator’s choice of paclitaxel (at a dose of175 mg per square meter of body-surface area),docetaxel (at a dose of 75 mg per square meter),or vinflunine (at a dose of 320 mg per square meter), all administered intravenously every 3 weeks.Randomization was stratified according to ECOGperformance-status score (0 or 1 vs. 2), presenceof liver metastases (yes vs. no), hemoglobin concentration ( 10 g per deciliter vs. 10 g per deciliter), and time since the last dose of chemotherapy ( 3 months vs. 3 months). Treatmentassignment was not blinded. Treatment wascontinued until RECIST-defined disease progression,15 development of an unacceptable level oftoxic effects, withdrawal of consent, decision bythe investigator to discontinue treatment, or thecompletion of 2 years of pembrolizumab therapy.Patients with disease progression, accordingto the investigator’s assessment of radiographicresults, and a clinically stable status could continue to receive the therapy at the discretion ofthe investigator. Patients in the pembrolizumabgroup who had a complete response could discontinue treatment if they had received pembrolizumab for at least 24 weeks and for at least twodoses beyond the time of initial complete re-nejm.orgMarch 16, 2017The New England Journal of MedicineDownloaded from nejm.org at UW-Madison on September 14, 2018. For personal use only. No other uses without permission.Copyright 2017 Massachusetts Medical Society. All rights reserved.

Pembrolizumab for Advanced Urothelial Carcinomasponse. There was no planned crossover on disease progression. Full information about guidance regarding the treatment decisions is providedin the protocol.AssessmentsPD-L1 expression was assessed in formalin-fixedtumor samples at a central laboratory with the useof the commercially available PD-L1 IHC 22C3pharmDx assay (Dako North America). The kitswere purchased at full cost. Archival tumorsamples and newly obtained core or excisionalbiopsy samples from nonirradiated sites werepermitted. There were no restrictions on the ageof the archival samples or on the number of intervening therapies received after the sample wasobtained. All samples, regardless of whetherthey were archival or newly obtained, were analyzed by the central laboratory during the screening process, and only the patients whose samples could be evaluated for PD-L1 expression werepermitted to enroll in the study. PD-L1 expressionwas categorized as the PD-L1 combined positivescore, defined as the percentage of PD-L1–expressing tumor and infiltrating immune cells relativeto the total number of tumor cells.12Tumor imaging was scheduled for week 9,followed by every 6 weeks during the first yearand every 12 weeks thereafter. Response totreatment was assessed according to RECIST15 bymeans of blinded, independent, central radiologicreview. During follow-up for survival, patientswere contacted every 12 weeks for survival assessment. The full assessment schedule is providedin the trial protocol. All the adverse events andabnormalities were graded according to the National Cancer Institute Common TerminologyCriteria for Adverse Events, version 4.0.End PointsAt the second interim analysis, the coprimaryend points were overall survival and progressionfree survival, which were assessed in the totalpopulation and in the population of patientswho had a tumor PD-L1 combined positive scoreof 10% or more. Overall survival was defined asthe time from randomization to death from anycause. Progression-free survival was defined asthe time from randomization to disease progression or death from any cause.Secondary efficacy end points, which were assessed in the total population and in the population of patients who had a tumor PD-L1 comn engl j med 376;11bined positive score of 10% or more, includedthe objective response rate, defined as the percentage of patients who had a confirmed complete or partial response, and the duration ofconfirmed response, defined as the time from thefirst documented complete or partial responseto disease progression or death. Safety in thetotal population was also a secondary end point.The full list of end points is provided in theprotocol.Efficacy was assessed in the intention-to-treatpopulation, which included all the patients whowere assigned to a treatment group. Safety wasassessed in the as-treated population, whichincluded all the patients who received at leastone dose of study treatment.Trial OversightThe trial was designed by academic advisors andemployees of the sponsor (Merck). Data were collected by investigators and their site personneland analyzed by statisticians who were employeesof the sponsor. Results were interpreted by theacademic authors, by authors who were employees of the sponsor, and by other employees ofthe sponsor who did not fulfill all the authorshipcriteria as outlined by the International Committee of Medical Journal Editors. An external dataand safety monitoring committee oversaw thetrial and assessed efficacy and safety at the timeof prespecified interim analyses that were performed by statisticians from QuintilesIMS, withfunding by the sponsor.The trial protocol and all the amendmentswere approved by the appropriate ethics body ateach center. The trial was conducted in accordance with the protocol and its amendments,with Good Clinical Practice guidelines, and withthe provisions of the Declaration of Helsinki. Allthe patients provided written informed consentbefore enrollment.All the authors attest that the trial was conducted in accordance with the protocol and allthe amendments, attest that they had access tothe data used for the writing of the manuscript,and vouch for the accuracy and completeness ofthe data and analyses. The first draft of themanuscript was written by the first and last authors, with input from authors who were employees of the sponsor. Assistance with manuscriptpreparation was provided by a medical writeremployed by the sponsor. All the authors participated in reviewing and editing the manuscriptnejm.orgMarch 16, 2017The New England Journal of MedicineDownloaded from nejm.org at UW-Madison on September 14, 2018. For personal use only. No other uses without permission.Copyright 2017 Massachusetts Medical Society. All rights reserved.1017

Then e w e ng l a n d j o u r na lofm e dic i n eand made the decision to submit the manuscript able at NEJM.org). All the data reported hereinfor publication.are those from the second interim analysis. Thefull statistical analysis plan is available in theStatistical Analysisprotocol.Overall survival, progression-free survival, andduration of response were estimated with the useR e sult sof the Kaplan–Meier method. In the analysis ofoverall survival, patients who were alive or lost to Patients and Treatmentfollow-up had their data censored at the time of A total of 748 patients were screened for enrolllast contact. In the analysis of progression-free ment at 120 sites in 29 countries. Between Nosurvival, patients who were alive and without dis- vember 5, 2014, and November 13, 2015, a totalease progression or who were lost to follow-up of 542 patients were randomly assigned to pemhad their data censored at the time of last tumor brolizumab (270 patients) or investigator’s choiceassessment. Between-group differences in overall of chemotherapy (272). Of these, 266 patients insurvival and progression-free survival were calcu- the pembrolizumab group and 255 in the chemolated with the use of a stratified log-rank test. therapy group received treatment (Fig. S1 in theHazard ratios and associated 95% confidence in- Supplementary Appendix). In the chemotherapytervals were calculated with the use of a stratified group, 84 patients received docetaxel, 84 receivedCox proportional-hazards model and Efron’s meth- paclitaxel, and 87 received vinflunine. The demood of handling ties. Differences in the response graphic and disease characteristics of the patientsrate were calculated with the stratified Miettinen at baseline were generally balanced between theand Nurminen method. The same stratification two treatment groups (Table 1, and Table S2 infactors that were used for randomization were the Supplementary Appendix). A total of 164 paapplied to all stratified efficacy analyses.tients (30.3%), including 74 patients in the pemThe overall family-wise type I error rate was brolizumab group and 90 in the chemotherapystrictly controlled at a one-sided alpha level of group, had a tumor PD-L1 combined positive2.5%. We calculated that enrollment of 470 pa- score of 10% or more (Table S3 in the Suppletients would provide the study with 88% power mentary Appendix).to show a hazard ratio for death of 0.781 or betThe median duration of follow-up, defined aster in the analysis of overall survival in the pem- the time from randomization to September 7,brolizumab group versus the chemotherapy group 2016, was 14.1 months (range, 9.9 to 22.1). Inin the total population and 86% power to show the as-treated population, the median duration ofa hazard ratio of 0.625 or better in the pembro- study treatment was 3.5 months (range, 0.1 tolizumab group versus the chemotherapy group 20.0) in the pembrolizumab group and 1.5 monthsamong patients who had a tumor PD-L1 combined (range, 0.1 to 14.2) in the chemotherapy group.A total of 49 patients (18.4%) in the pembrolizu positive score of 10% or more.The protocol specified two interim analyses mab group and 3 (1.2%) in the chemotherapybefore the final analysis. After reviewing the group were still receiving study treatment at thefirst interim analysis, the data and safety moni- time of data cutoff (Fig. S1 in the Supplementarytoring committee recommended continuing the Appendix). In the intention-to-treat population,study as planned. The second interim analysis 68 patients (25.2%) in the pembrolizumab groupwas based on a cutoff date of September 7, 2016, and 91 (33.5%) in the chemotherapy group reand was performed after 334 deaths had oc- ceived subsequent therapy, including 2 patientscurred in the total population and 104 deaths (0.7%) and 35 patients (12.9%), respectively, whohad occurred in the population of patients who received subsequent immunotherapy.had a tumor PD-L1 combined positive score of10% or more. The data and safety monitoring Overall Survivalcommittee reviewed the results of the second As of September 7, 2016, a total of 334 deathsinterim analysis on October 18, 2016, and recom- had occurred in the intention-to-treat population.mended early termination of the trial because Overall survival was significantly longer in thepembrolizumab met the superiority thresholds pembrolizumab group than in the chemotherapyfor overall survival in the coprimary populations group (hazard ratio for death, 0.73; 95% con (Table S1 in the Supplementary Appendix, avail- fidence interval [CI], 0.59 to 0.91; P 0.002)1018n engl j med 376;11nejm.orgMarch 16, 2017The New England Journal of MedicineDownloaded from nejm.org at UW-Madison on September 14, 2018. For personal use only. No other uses without permission.Copyright 2017 Massachusetts Medical Society. All rights reserved.

Pembrolizumab for Advanced Urothelial CarcinomaTable 1. Demographic and Disease Characteristics at Baseline in the Intention-to-Treat Population.*CharacteristicPembrolizumab Group(N 270)Chemotherapy Group(N 272)6765Age — yrMedianRange29–8826–84200 (74.1)202 (74.3)0119 (44.1)106 (39.0)1143 (53.0)158 (58.1)22 (0.7)4 (1.5)Male sex — no. (%)ECOG performance-status score — no. (%)†6 (2.2)4 (1.5)Current or former smoker — no./total no. (%)Missing data165/269 (61.3)186/269 (69.1)Pure transitional-cell features in histologic testing — no./total no. (%)186/270 (68.9)197/270 (73.0)74/260 (28.5)90/266 (33.8)Site of primary tumor in bladder or urethra — no./total no. (%)232/270 (85.9)234/271 (86.3)Visceral disease — no./total no. (%)240/269 (89.2)233/271 (86.0)Liver metastases — no./total no. (%)91/270 (33.7)95/271 (35.1)Hemoglobin concentration 10 g/dl — no./total no. (%)43/262 (16.4)44/267 (16.5)054 (20.0)44 (16.2)196 (35.6)97 (35.7)266 (24.4)80 (29.4)3 or 445 (16.7)45 (16.5)Tumor PD-L1 combined positive score 10% — no./total no. (%)‡No. of risk factors — no. (%)§Missing dataCompletion or discontinuation of most recent therapy 3 mo previously— no./total no. (%)9 (3.3)6 (2.2)103/269 (38.3)104/271 (38.4)* The intention-to-treat population included all the patients who underwent randomization. There were no significant differences between thetwo treatment groups. For the characteristics of current or former smoker, pure transitional-cell features on histologic testing, a tumor PD-L1combined positive score of 10% or more, site of primary tumor in bladder

tients with advanced urothelial carcinoma in the phase 1b KEYNOTE-012 study9 and the phase 2 KEYNOTE-052 study.12 In the international, ran-domized, open-label, phase 3 KEYNOTE-045 trial, we compared pembrolizumab with investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine as second-line therapy in patients

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