T h e ne w e ngl a nd jou r na l o f m e dicine
`
`original article
`
`Temsirolimus, Interferon Alfa,
`or Both for Advanced Renal-Cell Carcinoma
`Gary Hudes, M.D., Michael Carducci, M.D., Piotr Tomczak, M.D.,
`Janice Dutcher, M.D., Robert Figlin, M.D., Anil Kapoor, M.D.,
`Elzbieta Staroslawska, M.D., Jeffrey Sosman, M.D., David McDermott, M.D.,
`István Bodrogi, M.D., Zoran Kovacevic, M.D., Vladimir Lesovoy, M.D.,
`Ingo G.H. Schmidt-Wolf, M.D., Olga Barbarash, M.D., Erhan Gokmen, M.D.,
`Timothy O’Toole, M.S., Stephanie Lustgarten, M.S.,
`Laurence Moore, M.D., Ph.D., and Robert J. Motzer, M.D.,
`for the Global ARCC Trial*
`
`ABS TR ACT
`
`Background
`Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited ef-
`ficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of
`rapamycin kinase, may benefit patients with this disease.
`
`Methods
`In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously
`untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intra-
`venous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 mil-
`lion U) subcutaneously three times weekly, or combination therapy with 15 mg of
`temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The pri-
`mary end point was overall survival in comparisons of the temsirolimus group and
`the combination-therapy group with the interferon group.
`
`Results
`Patients who received temsirolimus alone had longer overall survival (hazard ratio for
`death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P = 0.008) and progression-free
`survival (P<0.001) than did patients who received interferon alone. Overall survival in
`the combination-therapy group did not differ significantly from that in the interferon
`group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P = 0.70). Median overall survival times
`in the interferon group, the temsirolimus group, and the combination-therapy group
`were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia,
`and hyperlipidemia were more common in the temsirolimus group, whereas asthenia
`was more common in the interferon group. There were fewer patients with serious
`adverse events in the temsirolimus group than in the interferon group (P = 0.02).
`
`Conclusions
`As compared with interferon alfa, temsirolimus improved overall survival among
`patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of
`temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number,
`NCT00065468.)
`
`From the Fox Chase Cancer Center, Phila-
`delphia (G.H.); Sidney Kimmel Compre-
`hensive Cancer Center, Baltimore (M.C.);
`Klinika Onkologii, Oddzial Chemioterapii,
`Poznań, Poland (P.T.); Our Lady of Mercy
`Medical Center, Bronx, NY (J.D.); Univer-
`sity of California, Los Angeles, Los Ange-
`les (R.F.); McMaster University, Hamilton,
`ON, Canada (A.K.); Lublin Oncological
`Center, Lublin, Poland (E.S.); Vanderbilt
`University Medical Center, Nashville (J.S.);
`Beth Israel Deaconess Medical Center,
`Boston (D.M.); National Institute of On-
`cology, Budapest, Hungary (I.B.); Military
`Medical Academy, Belgrade, Serbia (Z.K.);
`Regional Clinical Center of Urology and Ne-
`phrology, Kharkov, Ukraine (V.L.); Univer-
`sity of Bonn, Bonn, Germany (I.G.H.S.-W.);
`Kemerovo State Medical Academy, Re-
`gional Clinical Hospital, Kemerovo, Russia
`(O.B.); Ege University Medical Faculty,
`Izmir, Turkey (E.G.); Wyeth Research, Cam-
`bridge, MA (T.O., S.L., L.M.); and Memo-
`rial Sloan-Kettering Cancer Center, New
`York (R.J.M.). Address reprint requests to
`Dr. Hudes at the Department of Medical
`Oncology, Rm. 307, Fox Chase Cancer
`Center, 333 Cottman Ave., Philadelphia, PA
`19111, or at gary.hudes@fccc.edu.
`
`*Members of the Global Advanced Renal-
`Cell Carcinoma (ARCC) Trial are listed in
`the Appendix.
`
`N Engl J Med 2007;356:2271-81.
`Copyright © 2007 Massachusetts Medical Society.
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`2271
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 11, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`NPC02237249
`
`NOVARTIS EXHIBIT 2179
`Par v Novartis, IPR 2016-00084
`Page 1 of 11
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`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Renal-cell carcinoma accounts for
`
`2.6% of all cancers in the United States, and
`nearly 39,000 new cases of this disease and
`13,000 associated deaths were expected in 2006.1
`Surgical resection is the mainstay of treatment for
`tumors that are confined to the kidney. Distant
`metastases develop in about one third of patients,
`and most of these cases cannot be cured. Interleu-
`kin-2 and interferon alfa, alone or in combination,
`are the main treatments for metastatic renal-cell
`carcinoma. Treatment with these agents results in
`a median survival of 12.0 to 17.5 months.2-6 These
`cytokines, however, have limited efficacy and sub-
`stantial toxicity, and they rarely benefit patients
`with an extensive tumor burden and adverse prog-
`nostic factors. Such patients have a median survival
`of only 4 to 8 months.7-9
`Temsirolimus (CCI-779) is an inhibitor of mam-
`malian target of rapamycin (mTOR) kinase, a
`component of intracellular signaling pathways in-
`volved in the growth and proliferation of cells10,11
`and the response of such cells to hypoxic stress.12
`Temsirolimus binds to an abundant intracellular
`protein, FKBP-12, and in this way forms a complex
`that inhibits mTOR signaling.13,14 The disruption
`of mTOR signaling suppresses the production of
`proteins that regulate progression through the cell
`cycle15,16 and angiogenesis.17,18 The inhibition of
`angiogenesis by temsirolimus is clinically relevant
`because unregulated angiogenesis is prominent in
`renal-cell carcinoma.19
`Control of advanced renal-cell carcinoma was
`observed over a broad dose range in phase 1 trials
`of temsirolimus.20,21 A phase 2 study of temsiro-
`limus in cytokine-refractory metastatic renal-cell
`carcinoma showed evidence of improved survival,22
`and a study of temsirolimus plus interferon alfa
`identified tolerable doses and clinical indications
`of antitumor activity.23 Encouraged by these re-
`sults, we conducted a phase 3 trial in which we
`compared temsirolimus alone or temsirolimus
`plus interferon alfa with interferon alfa alone in
`metastatic renal-cell carcinoma.
`
`Methods
`
`Patients
`Eligibility criteria included histologically confirmed
`advanced renal-cell carcinoma (stage IV or recur-
`rent disease) and a Karnofsky performance score
`of 60 or more (on a scale of 0 to 100, with higher
`scores indicating better performance), with no pre-
`vious systemic therapy. Additional eligibility cri-
`
`teria were a tumor that was measurable according
`to the Response Evaluation Criteria in Solid Tumors
`(RECIST),24 and adequate bone marrow, renal, and
`hepatic functions, which were defined as a neutro-
`phil count of at least 1500 cells per cubic milli-
`meter, a platelet count of at least 100,000 cells per
`cubic millimeter, and a hemoglobin count of at
`least 8 g per deciliter; a serum creatinine level of
`no more than 1.5 times the upper limit of the nor-
`mal range; an aspartate aminotranferase level of
`no more than 3 times the upper limit of the nor-
`mal range (≤5 times if liver metastases were pres-
`ent); and a total bilirubin level of no more than
`1.5 times the upper limit of the normal range.
`A fasting level of total cholesterol of no more than
`350 mg per deciliter (9.1 mmol per liter) and a tri-
`glyceride level of no more than 400 mg per deci-
`liter (4.5 mmol per liter) were required. Patients
`with a history of brain metastases were eligible if
`their condition was neurologically stable and they
`did not require corticosteroids after surgical re-
`section or radiotherapy.
`At least three of the following six predictors
`of short survival were required: a serum lactate
`dehydrogenase level of more than 1.5 times the
`upper limit of the normal range, a hemoglobin
`level below the lower limit of the normal range;
`a corrected serum calcium level of more than
`10 mg per deciliter (2.5 mmol per liter), a time
`from initial diagnosis of renal-cell carcinoma to
`randomization of less than 1 year, a Karnofsky
`performance score of 60 or 70, or metastases in
`multiple organs.
`Wyeth Research designed the trial and devel-
`oped the study protocol in collaboration with the
`principal academic investigators. Data were col-
`lected and analyzed by Wyeth Research and the
`academic investigators. Radiologic assessments
`were performed by the study investigators and
`Bio-Imaging Technologies. The academic investi-
`gators were responsible for the decision to publish
`the data. All the authors had access to the primary
`data and vouch for the integrity and completeness
`of the data reported in this article. Dr. Hudes
`drafted the manuscript and revised it on the basis
`of suggestions from the coauthors. The sponsor
`played no role in writing or revising the manu-
`script.
`The institutional review board at each partici-
`pating center approved the study protocol, and the
`study was conducted in accordance with interna-
`tional standards of good clinical practice. All pa-
`tients provided written informed consent.
`
`2272
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 11, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`NPC02237250
`
`NOVARTIS EXHIBIT 2179
`Par v Novartis, IPR 2016-00084
`Page 2 of 11
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`

`
`Temsirolimus for Advanced Renal-Cell Carcinoma
`
`Treatment
`Patients were stratified according to the geograph-
`ic location of the center (United States; Western
`Europe, Australia, and Canada; or Asia-Pacific,
`Eastern Europe, Africa, and South America) and
`whether they had undergone nephrectomy. Patients
`were randomly assigned in equal proportions, with
`the use of permuted blocks of three, to one of three
`treatment groups.
`The interferon group received interferon alfa-2a
`(Roferon-A, Roche) at a starting dose of 3 mil-
`lion U given subcutaneously three times per week
`for the first week. The dose was raised to 9 mil-
`lion U three times per week for the second week
`and to 18 million U three times per week for
`week 3, if this dose was tolerated. Patients who
`were unable to tolerate 9 million U or 18 million U
`received the highest tolerable dose, which could
`be 3 million U, 4.5 million U, or 6 million U.
`The temsirolimus group received 25 mg of tem-
`sirolimus (Wyeth Research) in a weekly 30-minute
`intravenous infusion. Premedication with 25 to
`50 mg of intravenous diphenhydramine or a simi-
`lar H1 blocker was given approximately 30 min-
`utes before each weekly temsirolimus infusion as
`prophylaxis against an allergic reaction. The com-
`bination-therapy group received 15 mg of temsi-
`rolimus in a 30-minute infusion weekly plus inter-
`feron at a starting dose of 3 million U three times
`per week for week 1 and 6 million U subcutane-
`ously three times per week thereafter.
`Treatment was continued as long as there was
`no disease progression, symptomatic deteriora-
`tion, or intolerable adverse events. It was withheld
`for grade 3 or 4 adverse events (defined according
`to the National Cancer Institute Common Toxicity
`Criteria, version 3.0) and restarted at a reduced
`dose after recovery to grade 2 or lower. For the
`combination-therapy group, one or both agents
`were withheld, depending on the adverse event.
`For grade 2 adverse events that were poorly toler-
`ated, dose reduction without treatment interrup-
`tion was permitted at the discretion of the treat-
`ing physician. Dose reduction was not required for
`adverse events that could be managed with sup-
`portive therapy.
`
`Evaluation
`At baseline, a complete blood count was performed,
`along with assessments of levels of serum choles-
`terol and triglycerides and renal and hepatic func-
`tion. Adverse events, serum chemical analyses, and
`blood counts were monitored weekly or biweekly.
`
`Required imaging studies before treatment includ-
`ed computed tomographic (CT) scans of the chest,
`abdomen, and pelvis; a radionuclide bone scan; and
`a magnetic resonance imaging or CT scan of the
`brain. Scanning was repeated at 8-week intervals
`to evaluate tumor size. Response to treatment was
`assessed with the use of RECIST.
`
`Statistical Analysis
`The primary end point was overall survival, calcu-
`lated on an intention-to-treat basis. We targeted a
`40% improvement in median overall survival, from
`4.9 months for interferon alone to 6.9 months for
`either of the temsirolimus-containing regimens.
`The planned sample size of 200 patients per group
`was based on a power of 80% to detect a 40% im-
`provement for each comparison with the use of a
`two-sided stratified log-rank test at an overall 2.5%
`level of significance, with two planned interim
`analyses after approximately 164 and 430 deaths
`had occurred, and a final analysis, if necessary, af-
`ter a total of 504 deaths had occurred.
`Secondary efficacy end points were progres-
`sion-free survival as determined by the site inves-
`tigators’ assessment and a blinded assessment of
`imaging studies (performed by Bio-Imaging Tech-
`nologies), the objective response rate, and the
`clinical benefit rate, defined as the proportion of
`patients with stable disease for at least 24 weeks
`or an objective response. All patients who received
`any treatment were included in the analysis of
`safety. The characteristics of the patients in each
`group were compared with the use of the chi-
`square test for categorical variables and the Krus-
`kal–Wallis test for continuous variables. The pro-
`portion of patients with adverse events in each
`group was analyzed with the use of Fisher’s ex-
`act test.
`We explored the potential effect of the baseline
`characteristics of patients on progression-free and
`overall survival. The prespecified factors included
`age, sex, geographic region, nephrectomy status,
`tumor histologic type, time from metastasis to
`randomization, Karnofsky performance score, and
`levels of hemoglobin, serum lactate dehydroge-
`nase, and corrected serum calcium. These analyses
`were performed by testing for a nonzero interac-
`tion between the treatment group and the baseline
`variable in a stratified Cox proportional-hazards
`model that included the treatment group, baseline
`factors, and their interaction as explanatory vari-
`ables. We conducted separate analyses for the
`comparison of the temsirolimus group with the
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`2273
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`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 11, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`NPC02237251
`
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`Par v Novartis, IPR 2016-00084
`Page 3 of 11
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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 Characteristics of the Patients.*
`
`Characteristic
`
`Age
`
`Median — yr
`
`Range — yr
`
`<65 yr — no. (%)
`
`≥65 yr — no. (%)
`
`Sex — no. (%)
`
`Male
`
`Female
`
`Karnofsky performance score — no. (%)
`
`>70
`
`≤70
`
`Previous nephrectomy — no. (%)
`
`Tumor histologic type — no. (%)
`
`Clear-cell
`
`Interferon
`(N = 207)
`
`Temsirolimus
`(N = 209)
`
`Interferon plus
`Temsirolimus
`(N = 210)
`
`Total
`(N = 626)
`
`60
`
`23–86
`
`142 (69)
`
`65 (31)
`
`148 (71)
`
`59 (28)
`
`34 (16)
`
`171 (83)
`
`139 (67)
`
`58
`
`32–81
`
`145 (69)
`
`64 (31)
`
`139 (66)
`
`70 (33)
`
`41 (20)
`
`168 (80)
`
`139 (66)
`
`59
`
`32–82
`
`153 (73)
`
`57 (27)
`
`145 (69)
`
`65 (31)
`
`33 (16)
`
`177 (84)
`
`141 (67)
`
`170 (82)
`
`169 (81)
`
`163 (78)
`
`59
`
`23–86
`
`440 (70)
`
`186 (30)
`
`432 (69)
`
`194 (31)
`
`108 (17)
`
`516 (82)
`
`419 (67)
`
`502 (80)
`
`124 (20)
`
`Other
`
`37 (18)
`
`40 (19)
`
`47 (22)
`
`Protocol-defined poor prognostic features — no. (%)
`
`Lactate dehydrogenase level >1.5 times upper limit
`of normal
`
`48 (23)
`
`36 (17)
`
`33 (16)
`
`117 (19)
`
`Hemoglobin level <lower limit of normal
`
`Corrected serum calcium level >10 mg/dl
`(2.5 mmol/liter)
`
`168 (81)
`
`72 (35)
`
`Time from initial diagnosis to randomization <1 yr
`
`164 (79)
`
`Karnofsky performance score ≤70†
`
`≥2 sites of organ metastasis
`
`No. of poor prognostic features — no. (%)
`
`≥3 of 6
`
`<3 of 6
`
`MSKCC risk classification — no. (%)‡
`
`Poor risk (≥3 of 5 factors)
`
`Intermediate risk (1 or 2 of 5 factors)
`
`171 (83)
`
`165 (80)
`
`196 (95)
`
`11 (5)
`
`157 (76)
`
`50 (24)
`
`172 (82)
`
`54 (26)
`
`174 (83)
`
`168 (80)
`
`166 (79)
`
`195 (93)
`
`14 (7)
`
`145 (69)
`
`64 (31)
`
`178 (85)
`
`58 (28)
`
`179 (85)
`
`177 (84)
`
`168 (80)
`
`198 (94)
`
`12 (6)
`
`160 (76)
`
`50 (24)
`
`518 (83)
`
`184 (29)
`
`517 (83)
`
`516 (82)
`
`499 (80)
`
`589 (94)
`
`37 (6)
`
`462 (74)
`
`164 (26)
`
`* Percentages may not total 100 because of rounding.
`† A Karnofsky performance score of 70 (scores range from 0 to 100, with higher scores indicating better performance)
`signifies that the patient is unable to work but is able to perform activities of daily living.
`‡ The Memorial Sloan-Kettering Cancer Center (MSKCC) model includes the first five poor-prognostic features listed in
`the table.
`
`interferon group and for the comparison of the
`combination-therapy group with the interferon
`group.
`Statistical analysis was performed by the study’s
`sponsor, Wyeth Research. An independent data
`and safety monitoring committee reviewed the
`
`study at 6-month intervals and at the predefined
`event milestones for the interim analyses. We re-
`port here on the results of the second interim
`analysis, conducted after 446 patients had died.
`On the basis of these data, the committee deter-
`mined that the O’Brien–Fleming condition25 for
`
`2274
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 11, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`NPC02237252
`
`NOVARTIS EXHIBIT 2179
`Par v Novartis, IPR 2016-00084
`Page 4 of 11
`
`

`
`Temsirolimus for Advanced Renal-Cell Carcinoma
`
`Temsirolimus
`
`Interferon
`
`Combination
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`ProbabilityofSurvival
`
`0.00
`
`0
`
`5
`
`10
`
`15
`Months
`
`20
`
`25
`
`30
`
`002
`
`337
`
`207
`209
`210
`
`126
`159
`135
`
`80
`110
`93
`
`42
`56
`50
`
`15
`19
`17
`
`No.atRisk
`Interferon
`Temsirolimus
`Combination
`
`A
`
`B
`
`Combination
`
`Temsirolimus
`
`Interferon
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`Survival
`
`ProbabilityofProgression-free
`
`0.00
`
`0
`
`5
`
`10
`
`15
`Months
`
`20
`
`25
`
`30
`
`001
`
`111
`
`574
`
`55
`91
`89
`
`24
`38
`32
`
`10
`14
`16
`
`No.atRisk
`Interferon
`Temsirolimus
`Combination
`
`207
`209
`210
`
`Figure 1. Kaplan–Meier Estimates of Overall Survival (Panel A) and Progres-
`sion-free Survival (Panel B).
`
`1st
`2nd
`3rd
`
`AUTHOR:
`Hudes
`RETAKE
`ICM
`interferon, temsirolimus, and combination-therapy
`FIGURE:
`1 of 2
`REG F
`groups were 1.9, 3.8, and 3.7 months, respectively
`CASE
`Revised
`(Fig. 1B). According to the independent radiologic
`Line
`4-C
`SIZE
`EMail
`ARTIST:
`ts
`H/T
`H/T
`assessments, the median progression-free survival
`22p3
`Enon
`Combo
`times for the interferon, temsirolimus, and com-
`AUTHOR,PLEASENOTE:
`bination-therapy groups were 3.1, 5.5, and 4.7
`Figurehasbeenredrawnandtypehasbeenreset.
`Pleasecheckcarefully.
`months, respectively. The shorter estimate of pro-
`gression-free survival by the site investigators re-
`JOB:
`35622
`ISSUE:
`flected the inclusion of patients with symptom-
`atic deterioration that had begun before scheduled
`radiologic measurements of the tumor.
`The objective response rates of 4.8%, 8.6%, and
`8.1% among patients receiving interferon, temsiro-
`limus, and combination therapy, respectively, did
`
`05-31-07
`
`early acceptance of the alternative hypothesis was
`reached, and the data were released to the spon-
`sor. The significance level for stopping the study
`at the second interim analysis was P<0.0135. All
`reported P values are two-sided and have not been
`adjusted for multiple testing.
`
`R esults
`
`From July 2003 to April 2005, a total of 626 patients
`were enrolled in the study. We randomly assigned
`207 of these patients to receive interferon, 209 to
`receive temsirolimus, and 210 to receive a combi-
`nation of interferon and temsirolimus. A total of
`45 patients were ineligible (15 in the interferon
`group, 17 in the temsirolimus group, and 13 in the
`combination-therapy group), and 10 patients did
`not receive any treatment (7 in the interferon group,
`1 in the temsirolimus group, and 2 in the combi-
`nation-therapy group).
`
`Characteristics of the Patients
`Table 1 shows that the three treatment groups
`were well balanced on the basis of age, sex, and
`performance-status score. Approximately 80% of
`patients in each group had a Karnofsky perfor-
`mance score of 60 or 70. Clear-cell carcinoma was
`the histology of the tumor in approximately 80%
`of patients. Two thirds of the patients had under-
`gone nephrectomy, and approximately 80% had
`received a diagnosis of metastatic disease within
`12 months before enrollment. Three or more poor
`prognostic factors were present in 94% of the pa-
`tients. A total of 19 patients were lost to follow-up
`(10 in the interferon group, 4 in the temsirolimus
`group, and 5 in the combination-therapy group).
`
`Efficacy
`As compared with interferon alone, treatment with
`temsirolimus alone was associated with a hazard
`ratio for death of 0.73 (95% confidence interval
`[CI], 0.58 to 0.92; P = 0.008). As compared with in-
`terferon, the combination of interferon plus tem-
`sirolimus resulted in a hazard ratio for death of
`0.96 (95% CI, 0.76 to 1.20; P = 0.70). Figure 1A
`shows the overall survival times in the three groups.
`Median survival was 7.3 months in the interferon
`group, 10.9 months in the temsirolimus group, and
`8.4 months in the combination-therapy group
`(Table 2). As determined by the site investigators,
`the median progression-free survival times in the
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`2275
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`The New England Journal of Medicine
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`Downloaded from nejm.org on March 11, 2016. For personal use only. No other uses without permission.
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` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
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`NPC02237253
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`NOVARTIS EXHIBIT 2179
`Par v Novartis, IPR 2016-00084
`Page 5 of 11
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`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 2. Summary of Efficacy Measures.
`
`End Point
`
`Interferon
`(N = 207)
`
`Temsirolimus
`(N = 209)
`
`Interferon plus
`Temsirolimus
`(N = 210)
`
`Median overall survival — mo (95% CI)
`
`7.3 (6.1–8.8)
`
`10.9 (8.6–12.7)
`
`8.4 (6.6–10.3)
`
`Median progression-free survival — mo (95% CI)
`
`Site investigators’ assessment
`
`Independent assessment*
`
`1.9 (1.9–2.2)
`
`3.1 (2.2–3.8)
`
`Median time to treatment failure — mo (95% CI)†
`
`1.9 (1.7–1.9)
`
`3.8 (3.6–5.2)
`
`5.5 (3.9–7.0)
`
`3.8 (3.5–3.9)
`
`3.7 (2.9–4.4)
`
`4.7 (3.9–5.8)
`
`2.5 (1.9–3.6)
`
`Objective response rate — % (95% CI)*
`
`4.8 (1.9–7.8)
`
`8.6 (4.8–12.4)
`
`8.1 (4.4–11.8)
`
`Clinical benefit (objective response or stable dis-
`ease for ≥24 wk) — % (95% CI)*
`
`15.5 (10.5–20.4)
`
`32.1 (25.7–38.4)
`
`28.1 (22.0–34.2)
`
`* This category includes only patients who underwent tumor assessment after the baseline assessment: 153 patients in
`the interferon group (74%), 192 patients in the temsirolimus group (92%), and 168 patients in the combination-thera-
`py group (80%).
`† The time to treatment failure was determined by the site investigators.
`
`not differ significantly (Table 2). By contrast, the
`proportion of patients with stable disease for at
`least 6 months or an objective response was greater
`in the temsirolimus group (32.1%) and the com-
`bination-therapy group (28.1%) than in the in-
`terferon group (15.5%) (P<0.001 and P = 0.002,
`respectively, by the Cochran–Mantel–Haenszel
`test, stratified according to whether the patient
`had undergone nephrectomy and according to geo-
`graphic region).
`In exploratory subgroup analyses using a Cox
`proportional-hazards model, the salutary effects
`of temsirolimus alone on overall survival were
`consistent across the prespecified factors tested,
`with two exceptions. For the analysis comparing
`temsirolimus with interferon, we found an inter-
`action of treatment with age (P = 0.02) and the
`baseline serum lactate dehydrogenase level (P =
`0.008) (Fig. 2). The effect of temsirolimus on over-
`all survival was greater among patients under 65
`years of age than among older patients and among
`patients with a serum lactate dehydrogenase level
`of more than 1.5 times the upper limit of the nor-
`mal range than among those with lower levels.
`
`Adverse Events
`Table 3 lists adverse events. Asthenia was most
`common in the two groups receiving interferon
`alone or in combination. Grade 3 or 4 asthenia was
`reported in 11% of patients in the temsirolimus
`group, in 26% of those in the interferon group
`(P<0.001), and in 28% of those in the combination-
`therapy group (P<0.001). The proportions of pa-
`
`tients who reported dyspnea, diarrhea, nausea, or
`vomiting were similar in the three groups. As com-
`pared with patients in the interferon group, mild
`to moderate rash, peripheral edema, and stoma-
`titis affected more patients who received temsi-
`rolimus, either alone or in combination with inter-
`feron.
`Anemia, neutropenia, and thrombocytopenia
`were more common in the combination-therapy
`group than in the interferon group (P<0.001 for
`anemia, neutropenia, and thrombocytopenia) or in
`the temsirolimus group (P<0.001 for neutropenia
`and thrombocytopenia, and P = 0.002 for anemia).
`Hyperglycemia, hypercholesterolemia, and hyper-
`lipidemia were more common in the temsirolimus
`group and the combination-therapy group, reflect-
`ing inhibition of mTOR-regulated glucose and lipid
`metabolism. Grade 3 or 4 adverse events occurred
`in 67% of patients in the temsirolimus group, as
`compared with 78% of patients in the interferon
`group (P = 0.02) and 87% of patients in the combi-
`nation-therapy group (P = 0.02).
`Dose reductions and dose delays were less com-
`mon in the temsirolimus group (Table 4). The dif-
`ferent frequencies of adverse events that resulted
`in dose delays or dose reductions led to different
`mean relative dose intensities in the three groups.
`In the interferon group, the mean dose of inter-
`feron received over the first 8 weeks of treatment
`was 30.2 million U per week, or approximately
`56% of the maximum planned dose. For the tem-
`sirolimus group, the mean weekly dose of temsi-
`rolimus was 23.1 mg, or 92% of the planned dose.
`
`2276
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 11, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`NPC02237254
`
`NOVARTIS EXHIBIT 2179
`Par v Novartis, IPR 2016-00084
`Page 6 of 11
`
`

`
`Temsirolimus for Advanced Renal-Cell Carcinoma
`
`The combination-therapy group received a mean
`interferon dose of 13.1 million U per week and a
`mean temsirolimus dose of 10.9 mg per week, or
`72% and 73%, respectively, of the planned weekly
`doses.
`
`Discussion
`
`This randomized trial compared interferon alone,
`temsirolimus alone, and a combination of the two
`drugs for the treatment of newly diagnosed met-
`astatic renal-cell carcinoma. The principal finding
`was that, as compared with interferon alone, treat-
`ment with temsirolimus was associated with a
`moderate prolongation of overall survival in pa-
`tients with advanced renal-cell carcinoma and a
`poor prognosis. The median overall survival in the
`group given temsirolimus alone was 10.9 months,
`as compared with 7.3 and 8.4 months in the groups
`given interferon alfa or combination therapy, re-
`spectively. Median progression-free survival times
`in these three groups were 3.8, 1.9, and 3.7 months,
`respectively, as determined by the site investigators’
`assessment, and 5.5, 3.1, and 4.7 months, as deter-
`mined by independent radiologists. Temsirolimus
`alone was associated with grade 3 or grade 4 ad-
`verse events in fewer patients than was interferon
`alfa alone. The most common adverse effects of
`temsirolimus were asthenia, rash, anemia, nausea,
`dyspnea, diarrhea, peripheral edema, hyperlipid-
`emia, and hyperglycemia. These symptoms were
`usually manageable with supportive care or a re-
`duction in the drug dose.
`Unlike temsirolimus alone, the combination of
`temsirolimus plus interferon did not improve over-
`all survival. The group that received this combina-
`tion had the greatest number of patients with
`grade 3 or 4 adverse events and consequently had
`more delays and reductions in treatment. The mean
`dose intensity of temsirolimus was also lower in
`the combination-therapy group than in the tem-
`sirolimus group (10.9 mg vs. 23.1 mg per week).
`These delays and reductions could explain the fail-
`ure of the combination therapy to improve overall
`survival more than interferon alone. It is also pos-
`sible that the high rate of serious adverse events
`reduced overall survival in the combination group.
`This study involved patients with extensive
`metastatic disease and multiple adverse prognos-
`tic factors. Such patients would be expected to
`have a shorter survival than patients enrolled in
`studies of cytokine therapy2-6,26 or in trials of suni-
`
`Subgroup
`
`Age
`<65 yr
`≥65 yr
`Sex
`Male
`Female
`Initial diagnosis to randomization
`<1 yr
`≥1 yr
`Karnofsky performance score
`≤70
`>70
`Prior nephrectomy
`Yes
`No
`Tumor histologic type
`Clear-cell
`Other
`Hemoglobin level
`<1× lower limit of normal
`≥1× lower limit of normal
`Lactate dehydrogenase level
`≤1.5× upper limit of normal
`>1.5× upper limit of normal
`Corrected serum calcium level
`≤10 mg/dl
`>10 mg/dl
`Geographic area
`United States
`Western Europe, Canada,
` or Australia
`Asia–Pacific, Eastern Europe,
`Africa, or South America
`
`No. of
`Patients
`
`Hazard Ratio (95% CI)
`
`287
`129
`
`287
`129
`
`338
`78
`
`340
`75
`
`278
`138
`
`339
`73
`
`340
`76
`
`315
`84
`
`276
`126
`
`122
`87
`
`207
`
`0.0
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`Temsirolimus
`Better
`
`Interferon
`Better
`
`Figure 2. Hazard Ratios for Overall Survival among Subgroups of Patients.
`Hudes
`AUTHOR:
`1st
`RETAKE
`Hazard ratios (indicated by circles) with 95% confidence intervals (indicat-
`ICM
`2nd
`2 of 2
`FIGURE:
`ed by horizontal lines) are shown for subgroups of patients receiving inter-
`REG F
`3rd
`feron alfa or temsirolimus. Data are missing for the serum lactate dehydro-
`CASE
`Revised
`Line
`4-C
`genase level in 17 patients, the serum calcium level in 14 patients, the
`SIZE
`EMail
`ARTIST:
`ts
`H/T
`H/T
`tumor histologic type in 4 patients, and the Karnofsky performance score
`22p3
`Enon
`Combo
`in 1 patient.
`
`AUTHOR, PLEASE NOTE:
`Figure has been redrawn and type has been reset.
`Please check carefully.
`tinib malate or sorafenib.27,28 Although the defi-
`35622
`ISSUE:
`05-31-07
`JOB:
`nition of poor prognosis varies in published re-
`ports, certain features are common to all variants
`of this category: an interval of less than 1 year
`from the original diagnosis to the development of
`metastatic disease, metastases in multiple organs,
`a low Karnofsky score, anemia, and elevated se-
`rum levels of lactate dehydrogenase and calcium.29
`In previous studies, patients with none or only
`one of these features had a median survival of
`
`n engl j med 356;22 www.nejm.org may 31, 2007
`
`2277
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 11, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2007 Massachusetts Medical Society. All rights reserved.
`
`NPC02237255
`
`NOVARTIS EXHIBIT 2179
`Par v Novartis, IPR 2016-00084
`Page 7 of 11
`
`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 3. Adverse Events Occurring in at Least 20% of Patients in Any Group.*
`
`Adverse Event
`
`Interferon
`(N = 200)
`
`Temsirolimus
`(N = 208)
`
`Asthenia
`
`Rash
`
`Anemia
`
`Nausea
`
`Anorexia
`
`All
`Grades
`
`Grade
`3 or 4
`
`All
`Grades
`
`Grade
`3 or 4
`
`percentage of patients
`
`64
`
`6
`
`42
`
`41
`
`44
`
`16
`
`26
`
`0
`
`22
`
`4
`
`4
`
`2
`
`51
`
`47
`
`45
`
`37
`
`32
`
`28
`
`11
`
`4
`
`20
`
`2
`
`3
`
`5
`
`Interferon plus
`Temsirolimus
`(N = 208)
`
`All
`Grades
`
`Grades
`3 or 4
`
`62
`
`21
`
`61
`
`40
`
`38
`
`20
`
`28
`
`1
`
`38
`
`3
`
`8
`
`6
`
`Pain
`
`Dyspnea
`
`Hyperlipidemia
`
`Infection
`
`Diarrhea
`
`Peripheral edema
`
`Hyperglycemia
`
`Cough
`
`24
`
`14
`
`14
`
`20
`
`8
`
`11
`
`14
`
`6
`
`1
`
`4
`
`2
`
`0
`
`2
`
`0
`
`28
`
`27
`
`27
`
`27
`
`27
`
`26
`
`26
`
`9
`
`3
`
`5
`
`1
`
`2
`
`11
`
`1
`
`1
`
`26
`
`38
`
`34
`
`27
`
`16
`
`17
`
`23
`
`26
`
`10
`
`8
`
`11
`
`5
`
`0
`
`6
`
`2
`
`2
`
`Hypercholesterolemia
`
`Fever
`
`Abdominal pain
`
`Stomatitis
`
`Constipation
`
`Back pain
`
`Vomiting
`
`Weight loss
`
`4
`
`50
`
`17
`
`4
`
`18
`
`14
`
`28
`
`25
`
`0
`
`4
`
`2
`
`0
`
`1
`
`4
`
`2
`
`2
`
`24
`
`24
`
`21
`
`20
`
`20
`
`20
`
`19
`
`19
`
`1
`
`4
`
`1
`
`0
`
`3
`
`2
`
`1
`
`60
`
`17
`
`21
`
`19
`
`15
`
`30
`
`32
`
`3
`
`3
`
`5
`
`0
`
`2
`
`2
`
`6
`
`0
`
`Headache
`
`Increased creatinine level
`
`Thrombocytopenia
`
`Chills
`
`Increased aspartate amino-
`transferase level
`
`Neutropenia
`
`Leukopenia
`
`15
`
`10
`
`8
`
`30
`
`14
`
`12
`
`17
`
`0