established in 1812
`
`November 5, 2015
`
`vol. 373 no. 19
`
`Nivolumab versus Everolimus in Advanced Renal-Cell
`Carcinoma
`R.J. Motzer, B. Escudier, D.F. McDermott, S. George, H.J. Hammers, S. Srinivas, S.S. Tykodi, J.A. Sosman,
`G. Procopio, E.R. Plimack, D. Castellano, T.K. Choueiri, H. Gurney, F. Donskov, P. Bono, J. Wagstaff, T.C. Gauler,
`T. Ueda, Y. Tomita, F.A. Schutz, C. Kollmannsberger, J. Larkin, A. Ravaud, J.S. Simon, L.-A. Xu, I.M. Waxman,
`and P. Sharma, for the CheckMate 025 Investigators*
`
`The authors’ full names, academic degrees,
`and affiliations are listed in the Appendix.
`Address reprint requests to Dr. Motzer at
`Memorial Sloan Kettering Cancer Center,
`Memorial Hospital, 1275 York Ave., New
`York, NY 10021, or at motzerr@ mskcc . org;
`or to Dr. Sharma at M.D. Anderson Cancer
`Center, 1515 Holcombe Blvd., Houston, TX
`77030, or at padsharma@ mdanderson . org.
`
`* A complete list of investigators in the
`CheckMate 025 study is provided in the
`Supplementary Appendix, available at
`NEJM.org
`
`This article was published on September
`25, 2015, and updated on January 14,
`2016, at NEJM.org.
`
`N Engl J Med 2015;373:1803-13.
`DOI: 10.1056/NEJMoa1510665
`Copyright © 2015 Massachusetts Medical Society.
`
`abs tr act
`
`BACKGROUND
`Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with en-
`couraging overall survival in uncontrolled studies involving previously treated patients with
`advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared
`nivolumab with everolimus in patients with renal-cell carcinoma who had received previous
`treatment.
`METHODS
`A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had
`received previous treatment with one or two regimens of antiangiogenic therapy were ran-
`domly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight
`intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end
`point was overall survival. The secondary end points included the objective response rate
`and safety.
`RESULTS
`The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not
`estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The
`hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93;
`P = 0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective re-
`sponse rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98
`[95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months
`(95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus
`(hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P = 0.11). Grade 3 or 4 treatment-related adverse
`events occurred in 19% of the patients receiving nivolumab and in 37% of the patients re-
`ceiving everolimus; the most common event with nivolumab was fatigue (in 2% of the
`patients), and the most common event with everolimus was anemia (in 8%).
`CONCLUSIONS
`Among patients with previously treated advanced renal-cell carcinoma, overall survival was
`longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with
`everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number,
`NCT01668784.)
`
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`1803
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`The new england
`journal of medicine
`
`The New England Journal of Medicine
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Each year, an estimated 338,000 new
`
`cases of renal-cell carcinoma are diag-
`nosed worldwide,1 and approximately 30%
`of patients present with metastatic disease at the
`time of diagnosis.2 A number of targeted thera-
`pies have been approved for the treatment of
`advanced or metastatic renal-cell carcinoma.
`These agents include vascular endothelial growth
`factor (VEGF) pathway inhibitors and mamma-
`lian target of rapamycin (mTOR) inhibitors.3,4
`Everolimus is an mTOR inhibitor that is recom-
`mended for the treatment of advanced renal-cell
`carcinoma after treatment with sorafenib or
`sunitinib has failed.3-6 Although everolimus and
`other agents have changed the therapeutic land-
`scape for this disease, these treatments are asso-
`ciated with limited overall survival after a given
`agent is no longer effective.
`Nivolumab is a fully human IgG4 pro-
`grammed death 1 (PD-1) immune checkpoint
`inhibitor antibody that selectively blocks the in-
`teraction between PD-1, which is expressed on
`activated T cells, and PD-1 ligand 1 (PD-L1) and 2
`(PD-L2), which are expressed on immune cells
`and tumor cells. Interaction between PD-1 and
`PD-L1 or PD-L2 normally results in inhibition of
`the cellular immune response.7-9 Previous studies
`have shown that PD-L1 expression is associated
`with a poor prognosis in renal-cell carcinoma,
`presumably because of its immunosuppressive
`function.10-12 It has been postulated that PD-L1
`expression would be associated with improved
`overall survival in response to nivolumab therapy,
`because disruption of PD-1–PD-L1 signaling me-
`diated by nivolumab leads to restored antitumor
`immunity.13,14
`In a phase 2 dose-ranging trial involving pre-
`viously treated patients with metastatic renal-cell
`carcinoma, nivolumab was found to produce ob-
`jective responses in 20 to 22% of the patients
`and overall survival ranging from 18.2 to 25.5
`months.15 Here, we report results from a phase 3
`study comparing nivolumab with everolimus in
`the treatment of patients with previously treated
`advanced renal-cell carcinoma.
`
`Methods
`
`Patients
`Eligible patients were 18 years of age or older,
`had histologic confirmation of advanced or
`metastatic renal-cell carcinoma with a clear-cell
`component and measurable disease according to
`
`the Response Evaluation Criteria in Solid Tumors
`(RECIST version 1.1),16 and had received one or
`two previous regimens of antiangiogenic therapy.
`Additional inclusion criteria were no more than
`three total previous regimens of systemic ther-
`apy, including cytokines and cytotoxic chemo-
`therapy drugs, and disease progression during
`or after the last treatment regimen and within
`6 months before study enrollment. All patients
`had a Karnofsky performance status of at least
`70 at the time of study entry (Karnofsky perfor-
`mance status scores range from 0 to 100, with
`higher scores indicating better functioning).17
`Key exclusion criteria were metastasis to the
`central nervous system, previous treatment with
`an mTOR inhibitor, or a condition requiring
`treatment with glucocorticoids (equivalent to
`>10 mg of prednisone daily).
`
`Study Design
`This was a randomized, open-label, phase 3 study
`of nivolumab in comparison with everolimus.
`Randomization (in a 1:1 ratio) was performed with
`a block size of 4, with stratification according to
`region (United States or Canada, Western Europe,
`and the rest of the world), Memorial Sloan Ketter-
`ing Cancer Center (MSKCC) prognostic risk group,
`and the number of previous antiangiogenic
`therapy regimens (one or two) for advanced renal-
`cell carcinoma. The MSKCC prognostic risk is
`based on the presence of zero (favorable risk), one
`(intermediate risk), or two or three (poor risk) of
`the following prognostic factors: anemia, hyper-
`calcemia, and poor performance status.18
`Nivolumab and everolimus were provided by the
`sponsor, except in cases in which everolimus was
`procured as a local commercial product in certain
`countries. Nivolumab was administered at a dose
`of 3 mg per kilogram of body weight as a 60-min-
`ute intravenous infusion every 2 weeks. Evero-
`limus was administered orally as a daily dose of
`10 mg. Dose modifications were not permitted
`for nivolumab but were permitted for everolimus.
`
`Study Oversight
`This study was approved by the institutional re-
`view board or an independent ethics committee
`at each center and was conducted in accordance
`with Good Clinical Practice guidelines, as de-
`fined by the International Conference on Harmo-
`nisation. All the patients provided written in-
`formed consent that was based on the principles
`of the Declaration of Helsinki. A data and safety
`
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`
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`Nivolumab vs. Everolimus in Renal-Cell Carcinoma
`
`monitoring committee reviewed efficacy and
`safety during the study.
`The study was designed by the authors in
`collaboration with the sponsor (Bristol-Myers
`Squibb). The authors vouch for the accuracy and
`completeness of the analyses reported and for
`the fidelity of the study to the protocol, which is
`available with the full text of this article at
`NEJM.org. The development of the first draft of
`the manuscript was led by the first author. All
`the authors contributed to the drafting of the
`manuscript and provided final approval to sub-
`mit the manuscript for publication. Medical-
`writing support, funded by the sponsor, was
`provided by PPSI.
`
`End Points and Assessments
`The primary end point was overall survival,
`which was defined as the time from randomiza-
`tion to the date of death. Secondary end points
`included the objective response rate, progression-
`free survival, the association between overall
`survival and tumor expression of PD-L1, and the
`incidence of adverse events. Disease assessments
`were performed with the use of computed tomog-
`raphy or magnetic resonance imaging at base-
`line, every 8 weeks for the first year, and then
`every 12 weeks until disease progression or dis-
`continuation of treatment. Imaging data were
`evaluated by the investigator to assess tumor
`response (according to RECIST version 1.1). Pa-
`tients were allowed to continue the study ther-
`apy after initial disease progression if a clinical
`benefit as assessed by the investigator was noted
`and the study drug had an acceptable side-effect
`profile. Safety assessments were conducted at each
`clinic visit. After discontinuation of treatment,
`patients were followed every 3 months for as-
`sessment of survival and subsequent anticancer
`therapy.
`The objective response rate (investigator-
`assessed) was defined as the number of patients
`with a complete response or a partial response
`divided by the number of patients who under-
`went randomization. The best overall response
`was defined as the investigator-assessed best
`response (complete response, partial response,
`stable disease, or progressive disease) from the
`time of randomization to objectively documented
`disease progression or subsequent therapy, which-
`ever occurred first. Progression-free survival was
`defined as the time from randomization to first
`documented RECIST-defined tumor progression
`
`or death from any cause. Tumor PD-L1 membrane
`expression (≥1% vs. <1% and ≥5% vs. <5%) was
`assessed at a central laboratory in sections that
`had at least 100 tumor cells that could be evalu-
`ated and were positive for PD-L1 expression, as
`assessed with Dako PD-L1 immunohistochemi-
`cal staining in accordance with the manufactur-
`er’s instructions.19
`Adverse events were graded according to the
`National Cancer Institute Common Terminol-
`ogy Criteria for Adverse Events, version 4.0.20
`Quality of life was assessed with the use of the
`Functional Assessment of Cancer Therapy Kid-
`ney Symptom Index–Disease-Related Symptoms
`(FKSI-DRS) scoring algorithm.21 The FKSI-DRS
`questionnaire consists of nine symptom-specific
`questions that address lack of energy, pain,
`weight loss, bone pain, fatigue, dyspnea, cough,
`fevers, and hematuria. A summary score ranges
`from 0 to 36, with 36 as the best possible score
`(no symptoms) and 0 as the worst possible score
`(all the worst symptoms).21 Additional details are
`provided in the Supplementary Appendix, avail-
`able at NEJM.org.
`
`Statistical Analysis
`This planned interim analysis was conducted
`after 398 of the 569 deaths (70%) required for
`the final analysis had occurred; the stopping
`boundary was derived on the basis of the num-
`ber of deaths with the use of an O’Brien–Flem-
`ing alpha-spending function that provided 90%
`power to detect a hazard ratio of 0.76 with an
`overall type I error rate of 0.05 (two-sided).22
`Interim overall survival was projected at a 0.0148
`nominal significance level; if the results for over-
`all survival were significant at that level, the study
`could be stopped at the recommendation of the
`data monitoring committee and declared to be
`positive for efficacy. The interim analysis would
`then be considered the final analysis. In July
`2015, the study was stopped early because an
`assessment conducted by the independent data
`monitoring committee concluded that the study
`had met its end point with regard to significant
`results for overall survival.
`All patients who underwent randomization
`were included in the efficacy analyses; patients
`who received one or more doses of study drug
`were included in the safety analyses. Overall
`survival, progression-free survival, and the dura-
`tion of response were estimated with the use of
`Kaplan–Meier methods.16 Medians and corre-
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 1. Baseline Demographic and Clinical Characteristics of the Patients Who Underwent Randomization.
`
`Characteristic
`
`Median age (range) — yr
`
`Sex — no. (%)
`
`Male
`
`Female
`
`Race — no. (%)*
`
`White
`
`Asian
`
`Black
`
`Other
`
`MSKCC risk group — no. (%)†
`
`Favorable
`
`Intermediate
`
`Poor
`
`Karnofsky performance status — no. (%)‡
`
`<70
`
`70
`
`80
`
`Nivolumab Group
`(N = 410)
`
`Everolimus Group
`(N = 411)
`
`Total
`(N = 821)
`
`62 (23–88)
`
`62 (18–86)
`
`62 (18–88)
`
`315 (77)
`
`95 (23)
`
`353 (86)
`
`42 (10)
`
`1 (<1)
`
`14 (3)
`
`145 (35)
`
`201 (49)
`
`64 (16)
`
`2 (<1)
`
`22 (5)
`
`110 (27)
`
`150 (37)
`
`304 (74)
`
`107 (26)
`
`619 (75)
`
`202 (25)
`
`367 (89)
`
`720 (88)
`
`32 (8)
`
`4 (1)
`
`8 (2)
`
`148 (36)
`
`203 (49)
`
`60 (15)
`
`1 (<1)
`
`30 (7)
`
`116 (28)
`
`130 (32)
`
`74 (9)
`
`5 (1)
`
`22 (3)
`
`293 (36)
`
`404 (49)
`
`124 (15)
`
`3 (<1)
`
`52 (6)
`
`226 (28)
`
`280 (34)
`
`90
`
`100
`
`Disease sites that could be evaluated — no. (%)
`
`1
`
`≥2
`
`Site of metastasis — no. (%)
`
`Lung
`
`Liver
`
`Bone
`
`Previous nephrectomy — no. (%)
`
`Yes
`
`No
`
`Median time from initial diagnosis to randomization
`(range) — mo
`
`Previous antiangiogenic regimens for treatment of ad-
`vanced renal-cell carcinoma — no. (%)
`
`1
`
`2
`
`Previous systemic cancer therapy for metastatic renal-cell
`carcinoma — no. (%)§
`
`Sunitinib
`
`Pazopanib
`
`Axitinib
`
`126 (31)
`
`134 (33)
`
`260 (32)
`
`68 (17)
`
`341 (83)
`
`278 (68)
`
`100 (24)
`
`76 (19)
`
`364 (89)
`
`46 (11)
`
`71 (17)
`
`338 (82)
`
`273 (66)
`
`87 (21)
`
`70 (17)
`
`359 (87)
`
`52 (13)
`
`139 (17)
`
`679 (83)
`
`551 (67)
`
`187 (23)
`
`146 (18)
`
`723 (88)
`
`98 (12)
`
`31 (1–392)
`
`31 (2–372)
`
`31 (1–392)
`
`294 (72)
`
`116 (28)
`
`246 (60)
`
`119 (29)
`
`51 (12)
`
`297 (72)
`
`114 (28)
`
`242 (59)
`
`131 (32)
`
`50 (12)
`
`591 (72)
`
`230 (28)
`
`488 (59)
`
`250 (30)
`
`101 (12)
`
`1806
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`The New England Journal of Medicine
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`Downloaded from nejm.org on June 4, 2017. For personal use only. No other uses without permission.
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`Nivolumab vs. Everolimus in Renal-Cell Carcinoma
`
`Table 1. (Continued.)
`
`Characteristic
`
`Nivolumab Group
`(N = 410)
`
`Everolimus Group
`(N = 411)
`
`Patients with quantifiable PD-L1 expression — no. (%)
`
`370 (90)
`
`386 (94)
`
`PD-L1 expression level¶
`
`≥1%
`
`<1%
`
`≥5%
`
`<5%
`
`Patients without quantifiable PD-L1 expression — no. (%)
`
`94 (25)
`
`276 (75)
`
`44 (12)
`
`326 (88)
`
`40 (10)
`
`87 (23)
`
`299 (77)
`
`41 (11)
`
`345 (89)
`
`25 (6)
`
`Total
`(N = 821)
`
`756 (92)
`
`181 (24)
`
`575 (76)
`
`85 (11)
`
`671 (89)
`
`65 (8)
`
`* Race was self-reported.
`† The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups are based on the presence of 0 (favorable),
`1 (intermediate), or 2 or 3 (poor) of the following prognostic factors: anemia, hypercalcemia, and poor performance status.
`‡ Karnofsky performance status scores range from 0 to 100, with higher scores indicating better functioning. All patients
`had a Karnofsky performance status of 70 or higher at time of study entry, which may have decreased at randomization.
`§ Therapeutic agents that were received by more than 10% of all patients who underwent randomization are included.
`¶ The expression level is expressed as the percentage of membrane immunohistochemical staining in 100 or more tumor cells.
`
`sponding 95% confidence intervals were deter-
`mined with Brookmeyer and Crowley methods23;
`95% confidence intervals were constructed by
`means of a log–log transformation. A stratified
`log-rank test was performed to compare the
`nivolumab group with the everolimus group
`with respect to overall survival and progression-
`free survival. We obtained a stratified hazard
`ratio and confidence interval for nivolumab ver-
`sus everolimus by fitting a stratified Cox model
`with the group variable as a single covariate. The
`difference in response rates between the nivolu-
`mab group and the everolimus group along with
`the two-sided 95% confidence interval were esti-
`mated with the Cochran–Mantel–Haenszel method
`of weighting, with adjustment for the stratification
`factors.24 Survival was compared between the treat-
`ment groups with the use of the interim analysis
`monitoring feature of East software, version 5.4
`(Cytel), which is based on the Lan–DeMets error-
`spending-function approach, with an O’Brien–
`Fleming stopping boundary used to reject the
`null hypothesis (i.e., that there is no treatment
`difference), while maintaining a two-sided over-
`all alpha level of 0.05.22 If superiority with regard
`to the primary end point was demonstrated, a
`hierarchical statistical testing procedure was fol-
`lowed for the objective response rate (estimated
`along with the exact 95% confidence interval
`with the use of the Clopper–Pearson method25)
`and progression-free survival at an alpha level of
`0.05. For quality-of-life assessments, descriptive
`statistics were used to assess completion rates
`
`and changes in quality of life. Wilcoxon–Mann–
`Whitney tests were used to evaluate the between-
`group differences in the median change from
`baseline in quality-of-life scores.
`
`R esults
`
`Patients
`From October 2012 through March 2014, a total
`of 821 patients were randomly assigned to a
`treatment group at 146 sites in 24 countries in
`North America, Europe, Australia, South Amer-
`ica, and Asia; 803 of the 821 patients who under-
`went randomization were treated — 406 in the
`nivolumab group and 397 in the everolimus
`group. At data cutoff (June 2015), 67 of the 406
`patients (17%) in the nivolumab group and 28 of
`the 397 patients (7%) in the everolimus group
`continued to receive treatment (Fig. S1 in Supple-
`mentary Appendix). The minimum follow-up
`period was 14 months. The primary reason for
`discontinuation of treatment was disease pro-
`gression (285 of 406 patients [70%] in the
`nivolumab group and 273 of 397 patients [69%]
`in the everolimus group) (Fig. S1 in Supplemen-
`tary Appendix). The demographic and clinical
`characteristics of the patients were balanced be-
`tween the treatment groups; the majority of pa-
`tients (72%) had received one previous regimen
`of antiangiogenic therapy for advanced renal-cell
`carcinoma (Table 1).
`
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`tial responses were observed in 99 patients
`(24%) in the nivolumab group and in 20 patients
`(5%) in the everolimus group. Complete re-
`sponses were observed in 4 patients (1%) in the
`nivolumab group and in 2 patients (<1%) in the
`everolimus group. The median time to response
`was 3.5 months (range, 1.4 to 24.8) among the
`103 patients with a response in the nivolumab
`group and 3.7 months (range, 1.5 to 11.2)
`among the 22 patients with a response in the
`everolimus group; the median duration of re-
`sponse was 12.0 months (range, 0 to 27.6) with
`nivolumab and 12.0 months (range, 0 to 22.2)
`with everolimus (Table S1 in the Supplementary
`Appendix). Among the patients with a treatment
`response, 49 patients (48%) in the nivolumab
`group and 10 (45%) in the everolimus group had
`an ongoing response; 32 patients (31%) in the
`nivolumab group and 6 (27%) in the everolimus
`group had an ongoing response for 12 months
`or longer (Fig. S2 in Supplementary Appendix).
`The median progression-free survival was 4.6
`months (95% CI, 3.7 to 5.4) in the nivolumab
`group and 4.4 months (95% CI, 3.7 to 5.5) in the
`everolimus group (hazard ratio, 0.88; 95% CI,
`0.75 to 1.03; P = 0.11) (Fig. 2B). To explore the
`apparent delayed separation of the curves, we
`performed an ad hoc sensitivity analysis of pro-
`gression-free survival in patients who had not
`had disease progression or died at 6 months
`(145 patients [35%] in the nivolumab group and
`129 patients [31%] in the everolimus group). The
`analysis of this subgroup of patients yielded a
`median progression-free survival of 15.6 months
`(95% CI, 11.8 to 19.6) in the nivolumab group
`and 11.7 months (95% CI, 10.9 to 14.7) in the
`everolimus group (hazard ratio, 0.64; 95% CI,
`0.47 to 0.88).
`
`PD-L1 Expression
`Of the 821 patients who underwent randomiza-
`tion, 756 (92%) had quantifiable tumor PD-L1
`expression in pretreatment samples: 370 of the
`410 patients (90%) in the nivolumab group and
`386 of the 411 patients (94%) in the everolimus
`group (Table 1). In total, 181 of the 756 patients
`(24%) with quantifiable PD-L1 expression had
`1% or greater PD-L1 expression, and 575 (76%)
`had less than 1% PD-L1 expression (Table 1).
`Among patients with 1% or greater PD-L1 ex-
`pression, the median overall survival was 21.8
`months (95% CI, 16.5 to 28.1) in the nivolumab
`group and 18.8 months (95% CI, 11.9 to 19.9) in
`
`No.of
`Patients
`
`Nivolumab
`Everolimus
`
`410
`411
`
`MedianOverall
`Survival(95%CI)
`mo
`25.0 (21.8–NE)
`19.6 (17.6–23.1)
`
`No.of
`Deaths
`
`183
`215
`
`Hazard ratio, 0.73 (98.5% CI, 0.57–0.93)
`P=0.002
`
`Nivolumab
`
`Everolimus
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`18
`Months
`
`21
`
`24
`
`27
`
`30
`
`33
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`ProbabilityofOverallSurvival
`
`00
`
`32
`
`410
`411
`
`389
`366
`
`359
`324
`
`337
`287
`
`305
`265
`
`275
`241
`
`213
`187
`
`139
`115
`
`73
`61
`
`29
`20
`
`No.atRisk
`Nivolumab
`Everolimus
`
`Figure 1. Kaplan–Meier Curve for Overall Survival.
`CI denotes confidence interval, and NE not estimable.
`
`Efficacy
`Overall Survival
`The median overall survival was 25.0 months
`(95% confidence interval [CI], 21.8 to not esti-
`mable) in the nivolumab group and 19.6 months
`(95% CI, 17.6 to 23.1) in the everolimus group
`(Fig. 1). Death occurred in 183 of the 410 patients
`(45%) randomly assigned to receive nivolumab
`and in 215 of the 411 patients (52%) randomly
`assigned to receive everolimus. The hazard ratio
`for death (from any cause) with nivolumab ver-
`sus everolimus was 0.73 (98.5% CI, 0.57 to 0.93;
`P = 0.002), which met the prespecified criterion
`for superiority. The overall survival benefit with
`nivolumab was observed across prespecified sub-
`groups, including subgroups defined according
`to region, MSKCC prognostic score, and number
`of previous regimens of antiangiogenic therapy
`(Fig. 2A). The heterogeneity of the treatment ef-
`fect within each subgroup shown in Figure 2A
`was tested with the use of an interaction test in
`a Cox proportional-hazards model with treatment,
`subgroup, and treatment-by-subgroup interaction
`as covariates. None of the interaction terms were
`significant at the 0.05 level.
`
`Tumor Response and Progression-free Survival
`The objective response rate was higher with
`nivolumab than with everolimus (25% vs. 5%;
`odds ratio 5.98; 95% CI, 3.68 to 9.72; P<0.001)
`(Table S1 in the Supplementary Appendix). Par-
`
`1808
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`n engl j med 373;19 nejm.org November 5, 2015
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`West-Ward Exhibit 1106
`Motzer-Escudier 2015
`Page 006
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`

`

`Nivolumab vs. Everolimus in Renal-Cell Carcinoma
`
`A SubgroupAnalysesofOverallSurvival
`Everolimus
`Subgroup
`Nivolumab
`no. of events/total no.
`183/410
`215/411
`
`Overall
`MSKCC prognostic score
`Favorable
`Intermediate
`Poor
`Previous antiangiogenic regimens
`
`1 2
`
`Region
`United States or Canada
`Western Europe
`Rest of the world
`Age
`<65 yr
`≥65 to <75 yr
`≥75 yr
`Sex
`Female
`Male
`
`UnstratifiedHazardRatioforDeath(95%CI)
`
`0.76 (0.62–0.92)
`
`0.89 (0.59–1.32)
`0.76 (0.58–0.99)
`0.47 (0.30–0.73)
`
`0.71 (0.56–0.90)
`0.89 (0.61–1.29)
`
`0.66 (0.48–0.91)
`0.86 (0.63–1.16)
`0.78 (0.51–1.20)
`
`0.78 (0.60–1.01)
`0.64 (0.45–0.91)
`1.23 (0.66–2.31)
`
`0.84 (0.57–1.24)
`0.73 (0.58–0.92)
`
`45/145
`101/201
`37/64
`
`128/294
` 55/116
`
` 66/174
` 78/140
`39/96
`
`111/257
` 53/119
`19/34
`
`48/95
`135/315
`
` 52/148
`116/203
`47/60
`
`158/297
` 57/114
`
` 87/172
` 84/141
`44/98
`
`118/240
` 77/131
`20/40
`
` 56/107
`159/304
`
`B Kaplan–MeierCurveforProgression-freeSurvival
`
`0.25
`
`0.50
`
`0.75 1.00
`
`1.50
`
`2.25
`
`Nivolumab
`Better
`
`Everolimus
`Better
`
`No.of
`Patients
`
`Nivolumab
`Everolimus
`
`410
`411
`
`MedianProgression-
`freeSurvival
`(95%CI)
`mo
`4.6 (3.7–5.4)
`4.4 (3.7–5.5)
`
`No.of
`Progression
`Events
`
`318
`322
`
`Hazard ratio, 0.88 (95% CI, 0.75–1.03)
`P=0.11
`
`Nivolumab
`
`Everolimus
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`18
`Months
`
`21
`
`24
`
`27
`
`30
`
`33
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Survival
`
`ProbabilityofProgression-free
`
`00
`
`00
`
`40
`
`410
`411
`
`230
`227
`
`145
`129
`
`116
`97
`
`81
`61
`
`66
`47
`
`48
`25
`
`29
`16
`
`11
`3
`
`No.atRisk
`Nivolumab
`Everolimus
`
`Figure 2. Overall Survival in Subgroup Analyses and Kaplan–Meier Curve for Progression-free Survival.
`The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups are based on the presence of 0 (fa-
`vorable), 1 (intermediate), or 2 or 3 (poor) of the following prognostic factors: anemia, hypercalcemia, and poor
`performance status. The analyses in Panel A are based on data collected with the use of an interactive voice re-
`sponse system.
`
`the everolimus group (hazard ratio, 0.79; 95%
`CI, 0.53 to 1.17) (Fig. 3A). Among patients with
`less than 1% PD-L1 expression, the median over-
`all survival was 27.4 months (95% CI, 21.4 to not
`estimable) in the nivolumab group and 21.2
`months (95% CI, 17.7 to 26.2) in the everolimus
`
`group (hazard ratio, 0.77; 95% CI, 0.60 to 0.97)
`(Fig. 3B). Similar results were observed among
`patients with 5% or greater PD-L1 expression, as
`compared with patients with less than 5% PD-L1
`expression, although the interpretation of these
`data is limited by the small numbers of patients
`
`n engl j med 373;19 nejm.org November 5, 2015
`
`1809
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
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`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`397 patients treated with everolimus (66%) had
`dose delays (including interruptions). A total of
`102 of the 397 patients in the everolimus group
`(26%) had at least one dose reduction; dose re-
`ductions were not allowed with nivolumab.
`Treatment-related adverse events of any grade
`occurred in 319 of the 406 patients (79%) treat-
`ed with nivolumab and in 349 of the 397 pa-
`tients (88%) treated with everolimus (Table 2).
`The most common treatment-related adverse
`events among patients who received nivolumab
`were fatigue (134 patients, 33%), nausea (57
`patients, 14%), and pruritus (57 patients, 14%);
`among patients who received everolimus, the
`most common events were fatigue (134 pa-
`tients, 34%), stomatitis (117 patients, 29%),
`and anemia (94 patients, 24%). Grade 3 or 4
`treatment-related adverse events occurred in 76
`of the 406 patients (19%) treated with nivolum-
`ab and in 145 of the 397 patients (37%) treated
`with everolimus; the most common grade 3 or
`grade 4 event was fatigue (10 patients, 2%) with
`nivolumab and anemia (31 patients, 8%) with
`everolimus.
`Treatment-related adverse events leading to
`treatment discontinuation occurred in 31 of the
`406 patients (8%) treated with nivolumab and
`in 52 of the 397 patients (13%) treated with
`everolimus. No deaths from study-drug toxic
`effects were reported in the nivolumab group,
`and two deaths were reported in the everolimus
`group (one from septic shock and one from
`acute bowel ischemia). A total of 179 of the
`406 patients (44%) who received nivolumab and
`183 of the 397 patients (46%) who received
`everolimus received treatment beyond initial
`RECIST version 1.1–defined progression be-
`cause, as assessed by the investigator, they
`continued to derive clinical benefit from the
`treatment.
`
`Quality of Life
`The FKSI-DRS questionnaire completion rate
`was 80% or higher throughout the first year of
`the study (Table S2 in Supplementary Appendix).
`The median FKSI-DRS quality-of-life score was
`31.0 in both treatment groups at baseline. The
`median changes from baseline in the FKSI-DRS
`score in the nivolumab group increased over
`time and differed significantly from the median
`changes in the everolimus group at each assess-
`ment point through week 104 (P<0.05) (Table S2
`in Supplementary Appendix).
`
`A Patientswith≥1%PD-L1Expression
`
`No.of
`Patients
`
`Nivolumab
`Everolimus
`
`94
`87
`
`MedianOverall
`Survival(95%CI)
`mo
`21.8 (16.5–28.1)
`18.8 (11.9–19.9)
`
`No.of
`Deaths
`
`48
`51
`
`Nivolumab
`
`Everolimus
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`18
`Months
`
`21
`
`24
`
`27
`
`30
`
`33
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`ProbabilityofOverallSurvival
`
`00
`
`11
`
`44
`
`94
`97
`
`86
`77
`
`79
`68
`
`73
`59
`
`66
`52
`
`58
`47
`
`45
`40
`
`31
`19
`
`18
`9
`
`No.atRisk
`Nivolumab
`Everolimus
`
`B Patientswith<1%PD-L1Expression
`
`No.of
`Patients
`
`Nivolumab
`Everolimus
`
`276
`299
`
`MedianOverall
`Survival(95%CI)
`mo
`27.4 (21.4–NE)
`21.2 (17.7–26.2)
`
`No.of
`Deaths
`
`118
`150
`
`Nivolumab
`
`Everolimus
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`18
`Months
`
`21
`
`24
`
`27
`
`30
`
`33
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`ProbabilityofOverallSurvival
`
`00
`
`21
`
`276
`299
`
`265
`267
`
`245
`238
`
`233
`214
`
`210
`200
`
`189
`192
`
`145
`137
`
`94
`92
`
`48
`51
`
`22
`16
`
`No.atRisk
`Nivolumab
`Everolimus
`
`Figure 3. Kaplan–Meier Curve for Overall Survival, According to Pro-
`grammed Death 1 Ligand (PD-L1) Expression Level.
`
`with 5% or greater expression (Fig. S3 in Supple-
`mentary Appendix).
`
`Treatment Administration and Safety
`The median duration of treatment was 5.5 months
`(range, <0.1 to 29.6) with nivolumab and 3.7
`months (range, 0.2 to 25.7) with everolimus. In
`total, 207 of the 406 patients treated with
`nivolumab (51%) had dose delays, and 262 of the
`
`1810
`
`n engl j med 373;19 nejm.org November 5, 2015
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 2015 Massachusetts Medical Society. All rights reserved.
`
`West-Ward Exhibit 1106
`Motzer-Escudier 2015
`Page 008
`
`

`

`Nivolumab vs. Everolimus in Renal-Cell Carcinoma
`
`Subsequent Therapy
`Among the 821 patients who underwent ran-
`domization, 227 of the 410 patients (55%) in the
`nivolumab group and 260 of the 411 patients
`(63%) in the everolimus group received subse-
`quent systemic therapy. The most common
`therapeutic agents used after treatment with
`nivolumab were everolimus (105 patients, 26%),
`axitinib (99 patients, 24%), and pazopanib (37
`patients, 9%); the most common agents used
`after treatment with everolimus were axitinib
`(149 patients, 36%), pazopanib (64 patients,
`16%), and sorafenib (38 patients, 9%). Anti–PD-1
`therapy was given as subsequent therapy to 7
`patients in the everolimus group.
`
`Discussion
`
`Table 2. Treatment-Related Adverse Events Reported in 10%