ORIGINAL ARTICLE
`
`Phase Ill Trial Comparing Paclitaxel Poliglumex CT2103
`PPX in Combination with Carboplatin Versus Standard
`Paclitaxel and Carboplatin in the Treatment of PS 2
`Patients with Chemotherapy Naive Advanced Non small
`Cell Lung Cancer
`
`Corey J Langer MD FACP Kenneth J OByrne MDt Mark A Socinski MDt
`Sergei M Mikhailov MD § Krzysztof LesniewskiKmak MD 11 Martin Smakal MD f1
`Tudor E Ciuleanu MD Sergey V Orlov MD Mircea Dediu MD PhD David Heigener MDff
`Amy J Eisenfeld PhDtt Larissa Sandalic MStt Fred B Oldham MDtt Jack W Singer MDtt
`and Helen J Ross MD§§
`
`status PS 2 patients with non small
`Introduction Performance
`cell lung cancer NSCLC experience more toxicity lower response
`rates and shorter survival
`times than healthier patients treated with
`standard chemotherapy Paclitaxel poliglumex PPX a macromol
`ecule drug conjugate of paclitaxel and polyglutamic acid reduces
`systemic exposure to peak concentrations of free paclitaxel and may
`in tumors due to enhanced vascular
`lead to increased concentrations
`
`permeability
`Methods
`PS 2 patients with advanced
`Chemotherapynaive
`NSCLC were randomized to receive
`carboplatin area under
`curve = 6 and either PPX 210 mgm210 min without routine
`steroid premedication or paclitaxel 225 mgm23 h with standard
`premedication every 3 weeks The primary end point was overall
`survival
`
`the
`
`Results A total of 400 patients were enrolled Alopecia arthralgias
`myalgias and cardiac events were significantly less frequent with
`and grade 3 neu
`PPXcarboplatin whereas grade
`neutropenia
`ropathy showed a trend of worsening There was no significant
`in the incidence of hypersensitivity reactions despite the
`difference
`
`Pneumalogie
`
`Fox Chase Cancer Center Philadelphia Pennsylvania tSt James Hospital
`Dublin Ireland lUniversity of North Carolina at Chapel Hill Chapel
`Hill North Carolina §Stavropol Regional Oncology Center Stavropol
`Russia MOddzial Chemioterapii Gdynia Poland ¶Ustav Onkologie a
`Na Plesi Nova Ves pod Plesi Czech Republic Institutul
`De Oncologie ClujNapoca Romania St Peters
`OncologicClinica
`burg Pavlov State University St Petersburg Russia tt Hospital Gross
`hansdorf Groshansdorf Germany Mel Therapeutics Inc Seattle
`Washington and §§Mayo Clinic Scottsdale Arizona
`from CTI
`Disclosure Dr Langer has received
`research support
`Corey J Langer MD FACP Fox Chase
`Address for correspondence
`Cancer Center 333 Cottman Avenue Philadelphia PA 19111 Email
`cjlangerfcccedu
`Presented at the 41st Annual Meeting of the American Society of Clinical
`Oncology Orlando Florida May 1317 2005
`Copyright 0 2008 by the International Association for the Study of Lung
`
`Cancer
`ISSN 155608640803060623
`
`absence of routine premedication in the PPX arm Overall survival
`was similar between treatment arms hazard ratio 097 log rankp =
`0769 Median and 1 year survival rates were 79 months and 31
`for PPX versus 8 months and 31 for paclitaxel Disease control
`rates were 64 and 69 for PPX and paclitaxel
`respectively Time
`to progression was similar 39 months for PPXcarboplatin versus
`46 months for paclitaxelcarboplatin p = 0210
`Conclusion
`PPXcarboplatin failed to provide superior survival
`compared with paclitaxelcarboplatin in the first line treatment of PS
`2 patients with NSCLC but
`the results with respect
`free survival and overall survival were comparable
`regimen was more convenient
`
`to progression
`and the PPX
`
`Key Words Non small cell
`PPX CT 2103 PS 2 Toxicity
`J Thorac Oncol 20083 623630
`
`lung cancer Paclitaxel poliglumex
`
`Pwith non small cell lung cancer NSCLC usually
`r present with inoperable advanced
`disease Untreated
`these patients have a 1 year survival
`rate of approximately
`101 Combination chemotherapy
`regimens provide a statis
`tically significant survival benefit with 1 year survival rates
`of 30 to 40 in performance
`status PS 0 to 1
`individuals
`rates exceeding 1028 Retrospective
`and 2 year survival
`reviews and meta analyses of phase III
`trials have shown that
`patients with compromised PS eg PS 2 have significantly
`impaired survival compared with PS 0 to 1 patients68 This
`may be due to highly aggressive disease or comorbid condi
`tions and impaired organ function which can exacerbate
`chemotherapy toxicity Consequently PS 2 patients are often
`excluded from chemotherapy
`trials Toxicity may deter cli
`nicians from using standard platinum based combination reg
`imens for PS 2 patients who often receive palliative care or
`single agent non platinum therapy instead
`
`Journal of Thoracic Oncology
`
`Volume 3 Number 6 June 2008
`
`623
`
`Abraxis EX2008
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`Langer et al
`
`Journal of Thoracic Oncology
`
`Volume 3 Number 6 June 2008
`
`A recent prospectively planned subanalysis of Cancer
`and Leukemia Group B CALGB 9730 however demon
`strated that PS 2 patients benefited
`from platinum based
`therapy compared with a single agent9 Of the
`combination
`nearly 600 patients enrolled in CALGB 9730 99 were PS 2
`response rate median survival
`Within this cohort overall
`and 1 and 2 year survival rates were 24 47 months 18
`and 9 for the paclitaxelcarboplatin regimen versus 10
`24 months 10 and 0 for single agent paclitaxel
`Paclitaxel poliglumex PPX is an anionic polymeric
`macromolecule
`consisting of paclitaxel conjugated to glu
`tamic acid residues1° The large number of anionic charges
`renders this molecule water soluble The ester bond between
`
`is stable and resistant
`paclitaxel and the polyglutamate backbone
`to spontaneous hydrolysis therefore PPX is not broken down
`by plasma esterases Consequently the circulating polymer is
`relatively less toxic to normal tissue and theoretically better at
`to the target cells Aqueous solubility
`delivering paclitaxel
`also permits rapid intravenous administration and obviates
`the need for toxic solubilizing agents such as Cremophor
`Finally this molecule capitalizes on enhanced tumor perme
`to maximize tumor
`ability and retention of macromolecules
`paclitaxel exposure
`activity in NSCLC
`Preclinical models demonstrated
`lines and synergy with platinating agents including carbo
`trial of 28 patients with treatment naive
`platin1213 In a phase II
`advanced NSCLC PPX at a dose of 175 mgm2 every 3 weeks
`in a PS 0 to 1
`yielded a median survival of 81 months
`population and 54 months in a PS 2 cohort In phase I trials
`PPX has been combined at doses as high as 225 mgm2 every
`the curve AUC = 6
`3 weeks with carboplatin area under
`without untoward shortterm toxicity Based on cumulative
`neurotoxicity the recommended phase II dose in this setting
`was 210 mgm2
`from the phase II single agent
`The observations
`trial
`the ability to combine PPX at full dose with standard doses of
`carboplatin its convenient administration and the potential
`of decreased toxicity compared with standard paclitaxel
`laid
`trial PGT303 This trial also
`the groundwork for a phase III
`known as Selected Targeted Efficacy in Lung Cancer
`Lower Adverse Reactions 3 STELLAR 3 compared stan
`dard paclitaxelcarboplatin with PPXcarboplatin in PS 2
`patients
`
`to
`
`MATERIALS AND METHODS
`
`ver
`
`Study Design
`This open label phase III
`study compared paclitaxel
`225 mgm2 with PPX at 210 mgm2 each in combination with
`carboplatin AUC = 6 given every 3 weeks for up to 6
`from the study for disease
`cycles Patients were excluded
`progression PD intolerable toxicity withdrawal of consent
`or investigator discretion
`Randomization
`was stratified based on disease stage
`IV versus other gender history of brain metastases
`and
`geographic location US versus Western EuropeCanada
`sus Eastern Europe
`Antiemetic prophylaxis was permitted for carboplatin
`and
`including dexamethasone
`nausea
`
`to prevent
`
`delayed
`
`vomiting The paclitaxel arm required routine hypersensitiv
`ity prophylaxis however the use of routine antihistamines or
`hypersensitivity prophylaxis was prohibited on the PPX arm
`growth factor support was permitted accord
`Hematopoietic
`ing to American Society of Clinical Oncology guidelines15
`
`End Points
`The primary study end point was survival Secondary
`included response rate time to progression TTP
`objectives
`response was as
`safety and quality of life Radiographic
`sessed every 2 cycles For patients who completed therapy
`without evidence of PD indicator lesions were reevaluated
`every 8 weeks until documentation of PD or start of second
`line therapy
`on all patients Disease
`Safety data were collected
`related symptoms were measured by the Functional Assess
`ment of Cancer Therapy Lung Cancer Subscale FACTLCS
`at baseline and within 3 days of each treatment
`
`Eligibility Criteria
`All enrollees had histologically or cytologically con
`firmed NSCLC an Eastern Cooperative Oncology Group
`ECOG PS 2 and stage IV stage IIIb but not candidates for
`combined modality therapy with curative intent or locally
`advanced or recurrent disease previously treated with radia
`tion andor surgery Eligibility
`18 years
`stipulated age
`adequate organ function including baseline absolute neutro
`1500µL platelet
`100000µL creati
`count
`phil count
`15 times the upper limit of normal ULN bilirubin
`25 times ULN 5 times ULN in
`nine
`ULN transaminases
`patients with hepatic metastases and alkaline phosphatase
`25 times ULN unless bone metastases were present Pa
`tients with stable treated brain metastases were eligible
`Adequate contraception was required for female patients of
`reproductive potential
`Exclusion criteria included any small cell or carcinoid
`for NSCLC active un
`histology prior systemic therapy
`treated brain metastases other active primary invasive ma
`neuropathy clini
`lignancies
`requiring treatment grade
`cally significant infection exposure to other
`investigational
`agents within 4 weeks of study entry and unstable concom
`itant medical conditions The protocol was approved by the
`institutional review board at each participating institution All
`patients gave informed consent
`forms were carefully re
`case report
`Representative
`viewed to make certain that patient characteristics
`supported
`PS 2 designations
`
`Efficacy Parameters and Statistical
`Considerations
`Overall survival was defined as the interval between
`randomization and death from any cause Patients remaining
`alive including those lost to followup were censored at the
`date of last contact Nonstratified log rank testing was used
`for the formal primary comparison of survival This study
`targeted accrual of 370 evaluable patients with 80 power
`and 005 type I error to show a 15 month improvement in
`median survival from a projected baseline of 4 to 55 months
`In addition secondary analyses were conducted using Cox
`
`624
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`

`

`Journal of Thoracic Oncology
`
`Volume 3 Number 6 June 2008
`
`PPXCarboplatin Versus PaditaxelCarboplatin
`
`in NSCLC
`
`factors associated with sur
`
`regression models of prognostic
`in patients with NSCLC
`vival
`Response was assessed by response evaluation criteria
`in solid tumors16 Disease control was determined by the
`percentage of patients alive without PD for at least 12 weeks
`A twosided Fisher exact
`test with an a level of 005 for
`significance was used TTP was defined as the
`statistical
`interval between randomization and PD and was analyzed
`using an unstratified logrank test Toxicities were compared
`between the treatment arms using the Fishers exact test
`
`Quality of Life
`symptoms were measured
`by the
`Disease related
`FACTLCS a validated five point Likerttype scale ranging
`to 4 very much The total LCS score
`from 0 not at all
`ranged from 0 to 28 with higher scores indicative of fewer
`symptoms The percentage of patients with at least two point
`improvements in their LCS scores at the beginning of cycle 2
`was compared by treatment arm
`
`RESULTS
`
`Disposition of Patients
`Four hundred patients were enrolled between Decem
`ber 2002 and December 2003 199 patients were assigned to
`the PPX arm and 201 to the paclitaxel arm Three patients all
`treatment arm did not
`in the paclitaxel
`receive study treat
`ment one developed PD before starting therapy a second had
`an elevated baseline bilirubin and did not meet eligibility
`criteria and a third was withdrawn from the study due to
`rapid PD and intercurrent pneumonitis
`The arms were well balanced with regard to baseline
`characteristics Table 1 Seventyseven
`percent of patients
`were male 94 white and 63 from Eastern Europe Me
`dian age was 61 years on the PPX arm and 63 years on the
`paclitaxel arm Seventythree
`percent of patients had stage IV
`disease and 7 had brain metastases at baseline Russia
`contributed the largest proportion of patients 35 followed
`by the United States 23 The differences between Eastern
`European enrollees and their Western European US and
`Canadian counterparts are delineated in Table 2
`
`Treatment Completion Rates
`The median number of cycles was four in each arm In
`the PPX arm 27 of patients completed six cycles of therapy
`compared with 36 in the paclitaxel arm p = 00411
`Fishers exact test The most frequent
`treatment were PD 36 versus 34 respectively
`adverse effects 27 versus 20 respectively Nine percent
`in the PPX arm compared with
`of patients withdrew consent
`6 in the paclitaxel arm
`
`reasons for stopping
`and
`
`Efficacy
`Median overall survival was 78 months in the PPX aim
`and 79 months in the paclitaxel aim Fig 1A Oneyear sur
`vival was identical at 31 The 18 and 24 month survival rates
`in the PPX arm 20 and 13 respec
`were numerically higher
`tively compared with the paclitaxel arm 11 and 11 respec
`tively but these differences were not statistically significant
`
`TABLE 1 Demographic
`
`and Baseline Characteristics
`
`PPXCarboplatin
`n = 199
`
`PaclitaxelCarboplatin
`
`n = 201
`
`Gender
`
`Male
`
`Female
`
`Race
`
`White
`
`Black
`
`Asian
`
`Hispanic
`
`Other
`Age at randomization yr
`Mean SD
`Median range
`
`Geographic
`
`site
`
`United States
`
`Western Europe and
`Canada
`
`Eastern Europe
`
`Stage at randomization
`
`ITIa
`
`TIM
`
`IV
`
`History of brain metastases
`
`Yes
`No
`
`Smoking history
`
`Yes
`No
`
`151 76
`48 24
`
`18995
`84
`21
`00
`00
`
`611 106
`610 3586
`46 23
`3015
`123 62
`21
`5126
`146 73
`
`147
`185 93
`170 85
`2915
`
`PPX paclitaxel poliglumex SD standarddeviation
`
`156 78
`45 22
`188 94
`95
`1 <1
`21
`1 <1
`
`615 101
`630 3689
`45 22
`27 13
`129 64
`00
`55 27
`146 73
`15 7
`186 93
`171 85
`30 15
`
`TABLE 2 Demographic
`Entry Based on Region
`
`and Baseline Characteristics at
`
`Region5 weight
`
`loss within 6 mo of
`randomization
`
`Histologic diagnosis
`Squamous cell carcinoma
`Adenocarcinoma
`
`Other
`
`Stage at enrollment
`
`Stage IVrecurrent
`
`Stage TIM
`
`History of brain metastases
`
`Prior radiation
`Median FACTLCS score
`
`Current use of tobacco
`
`Baseline opioid use
`Baseline hemoglobin 11 gdL
`
`USWestern
`
`EuropeCanada
`n = 148
`58 39
`
`43 29
`78 53
`27 18
`122 82
`26 18
`2114
`47 32
`
`187
`4631
`19 13
`110 74
`
`Eastern
`
`Europe
`n = 252
`104 41
`
`13453
`72 29
`46 18
`170 67
`80 32
`83
`40 16
`113 45
`12 5
`220 87
`
`170
`
`FACTLCS functional assessment of cancer
`
`therapy lung cancer subscale
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`625
`
`

`

`Langer et al
`
`Journal of Thoracic Oncology
`
`Volume 3 Number 6 June 2008
`
`PPXICarbo
`
`PaclitaxelCarbo
`
`PPX
`
`Control
`
`N Median
`
`199
`
`201
`
`78 mo
`79 mo
`
`Log rank P = 769
`
`were better on PPX compared with paclitaxel 37 versus
`
`25 26 versus 5 and 13 versus 5 respectively Survival
`for men was similar in both arms with virtually identical
`median survival 79 versus 79 months and 1 29 versus
`33 and 2 year 13 versus 13 survival rates
`Cox multivariate stepwise modeling with all other factors
`constant demonstrated that weight
`loss before study entry
`tobacco use elevated lactate dehydrogenase levels and elevated
`calcium levels significantly
`increased the probability of death
`
`100
`
`200
`
`300
`
`400
`
`500
`
`600
`
`700
`
`800
`
`Time from randomization days
`
`these results significantly fa
`
`EEU
`
`US W EU Can
`
`N Median
`
`EEU
`US W EU Can
`
`129
`
`72
`
`94 mo
`63 mo
`
`Log rank P = 003
`
`A
`
`1°
`
`09
`
`08
`
`07
`
`06
`
`05
`
`04
`
`03
`
`02
`
`01
`
`10
`
`09
`
`08
`
`07
`
`n
`
`05
`
`04
`
`03
`
`6k
`
`2
`
`11
`
`Response and TTP
`response rate was 20 for the PPX arm
`The overall
`with 1 complete responses and 37 for the paclitaxel arm
`with 2 complete responses
`vored the paclitaxel arm Table 4 Blended response rates
`differed by geographic region 35 for Eastern Europe 23
`and 14 for the United
`for Western Europe and Canada
`rate was 64 in the PPX arm com
`States Disease control
`pared with 69 in the paclitaxel arm
`Median TTP was 39 months in the PPX arm and 46
`months on the paclitaxel arm p = 0210 The proportion of
`therapy and the type of therapy
`patients receiving subsequent
`administered were not different
`in the 2 arms Eighteen
`percent of those enrolled in the PPX arm went on to radiation
`therapy compared with 13 in the paclitaxel arm Nearly
`50 in each arm received additional chemotherapy no spe
`cific agents predominated Roughly 7 of patients received
`
`epidermal growth factor receptor
`second line or subsequent
`
`therapy
`
`tyrosinekinase inhibitors as
`
`Quality of Life
`FACTLCS evaluations were completed by 180 pa
`tients on the PPXcarboplatin arm and 172 patients on the
`paclitaxelcarboplatin arm No significant difference
`in the
`FACTLCS scores was seen
`
`Toxicity
`
`Drug Delivery
`Patients received nearly 90 of planned doses during the
`cycles The mean delivered dose inten
`second and subsequent
`sity per cycle was comparable in both arms In Eastern Europe
`75 of patients received 4 to 6 cycles compared with 44 and
`49 in the United States and Western EuropeCanada
`respec
`tively The mean normalized carboplatin dose per cycle per
`patient was the same for both arms AUC = 56
`
`Relative Toxicities
`Patients enrolled in the paclitaxel arm were signifi
`cantly more likely to experience cardiac toxicity alopecia
`toxicity Table 5 However those in the
`and musculoskeletal
`PPX arm experienced
`significantly more nausea and vomit
`ing More grade 34 neuropathy was seen on the PPX arm 17
`versus 10 but this difference was not statistically signifi
`later in the PPX arma median of 89 days compared with 54
`days for the paclitaxel arm log rank p < 0001 By day 100
`the incidence was equal Fatigue was higher in the PPX arm
`than the paclitaxel arm 15 versus 8 p = 005 however
`
`cant Time to first manifestation of neuropathy was generally
`
`100
`
`200
`
`300
`
`400
`
`500
`
`600
`
`700
`
`800
`
`Time from randomization days
`
`EEU
`
`US W EU Can
`
`N Median
`
`EEU
`US W EU Can
`
`82 mo
`123
`76 67 mo
`
`Log rank P = 029
`
`100
`
`200
`
`300
`
`400
`
`500
`
`600
`
`700
`
`800
`
`Time from randomization days
`
`02
`
`01
`
`10
`
`09
`
`08
`
`07
`
`06
`
`05
`
`04
`
`03
`
`02
`
`01
`
`fsurvival
`
`Probabilityo
`
`FIGURE 1 Overall survival using Kaplan Meier estimation
`A Paclitaxel poliglumexcarboplatin versus paclitaxelcarbo
`platin 8 PaclitaxelcarboplatinUnited
`versus Eastern Europe C PPXcarboplatin
`
`StatesWestern
`
`EuropeCanada
`United StatesWestern EuropeCanada
`
`versus Eastern Europe
`
`Prespecified analyses by stratification factors Table 3
`demonstrated that median survival
`in the paclitaxel arm was
`in Eastern Europe and Russia than in the
`significantly better
`United States and Western Europe 94 versus 63 months
`p = 0003 Fig 1B There was less difference
`in median
`survival on the PPX arm 82 versus 67 months p = 0029
`Fig 1C Women on the paclitaxel arm had a median survival
`similar to those in the experimental arm 83 versus 79
`months However at 12 18 and 24 months survival rates
`
`626
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`

`

`Journal of Thoracic Oncology
`
`Volume 3 Number 6 June 2008
`
`PPXCarboplatin Versus PaditaxelCarboplatin
`
`in NSCLC
`
`TABLE 3 Subgroup Analysis of Overall Survival
`
`PPXCarboplatin
`
`PaclitaxelCarboplatin
`
`Subgroup
`
`Overall
`
`Gender
`
`Male
`
`Female
`
`Geographic
`
`location
`
`United States
`
`Western EuropeCanada
`
`Eastern Europe
`
`Disease stage at randomization
`
`IV
`
`Other
`
`199
`
`151
`
`48
`
`46
`
`30
`
`123
`
`146
`
`53
`
`Median Survival
`d 95 CI
`237205271
`
`237199275
`236 174380
`
`217 164291
`188 118275
`249 219326
`
`201
`
`156
`
`45
`
`45
`
`27
`
`129
`
`146
`
`55
`
`Median Survival
`d 95 CI
`239 206287
`
`239 204288
`248 167323
`
`173 100248
`206 103322
`287 233347
`
`Hazard Ratio
`
`097 078121
`
`104 080134
`076 048120
`
`079 050123
`108 063186
`100 075133
`
`Log Rank
`Test p
`
`0769
`
`0780
`
`0239
`
`0298
`
`0773
`
`0992
`
`0528
`
`237 189283
`246182311
`
`History of brain metastases
`
`Yes
`No
`
`14
`
`185
`
`207 145320
`237 206275
`
`15
`
`186
`
`236 205277
`274181404
`
`229 87328
`239 206292
`
`092 071119
`109 070170
`
`113 051250
`097 077122
`
`0715
`
`0770
`
`0778
`
`Hazard ratio CT2103 to paclitaxel was estimated by Cox regression with treatment arm as a single covariate
`PPX paclitaxel poliglumex CI confidence
`
`intervals
`
`TABLE 4 Efficacy Results in the Intent to Treat Population
`
`PPXCarboplatin
`
`PaclitaxeUCarboplatin
`
`No patients
`
`Survival
`
`rate
`
`rate
`
`Median d
`95 CI
`Hazard ratio 95 CI
`logrank p value
`1yr survival
`95 CI
`2yr survival
`95 CI
`Time to progression
`Median d
`95 CI
`Hazard ratio 95 CI
`logrank p value
`Disease control
`95 CI
`
`Response rate patients
`
`with measurable
`
`199
`
`237
`
`201
`
`239
`
`205271
`206287
`097 078121 0769
`
`
`3131
`
`24372437
`
`
`1313
`
`522522
`
`118
`
`31
`2538
`
`11
`418
`
`139
`
`100129
`118156
`114 093140 0210
`
`64 570
`
`69 6275
`
`disease only
`No patients
`PR + CR 95 CI
`Confirmed PR + CR
`95 CI
`PPX paclitaxel poliglumex CI confidence
`complete response
`
`191
`20 1527
`13 919
`
`192
`37 3044
`28 2235
`
`intervals PR partial
`
`response CR
`
`grade 34 fatigue was similar between arms 2 versus 3
`p = 066
`The incidence of grade 34 thrombocytopenia
`was sig
`nificantly higher in the PPX arm p < 0001 but was not
`associated with more thrombocytopenic
`bleeding or higher
`transfusion requirements Five percent of patients on the PPX
`
`growth factor support
`
`in the United StatesWestern Europe
`
`arm required platelet transfusions compared with 3 on the
`paclitaxel arm p = 042 The incidence of febrile neutro
`penia was 6 in the PPX arm versus 3 in the paclitaxel arm
`p = 032 The reported incidence of neutropenia in Eastern
`Europe was 24 compared with 47 in the United States
`and 42 in Western EuropeCanada The use of supportive
`care including transfusions erythropoietin and granulocyte
`colony stimulating factor was similar between treatment
`regions The use of
`arms but different based on geographic
`red blood cell growth factor support
`in the United States
`Western EuropeCanada was 38 compared with less than
`1 in Eastern Europe p < 0001 the use of white blood cell
`Canada was 31 compared with 7 in Eastern Europe p <
`0001 Seven percent of those in Eastern Europe required red
`compared with 16 in the United
`blood cell
`transfusions
`StatesWestern EuropeCanada p = 0006
`Twelve percent of patients in each arm died within 30
`days of treatment but only 1 of all deaths were attributable
`to study drugs There were 75 disease related deaths and
`35 were due to comorbidities
`infusion time for the PPX combination was 48
`Total
`minutes compared with 224 minutes for the paclitaxel com
`bination The incidence of hypersensitivity reactions was 2
`tions of steroids and H1 and H2 blockers compared with 1
`for the PPXcarboplatin arm without routine hypersensitivity
`reaction prophylaxis However 28 of PPX patients mostly
`in the United States and Canada received steroid prophylaxis
`andor antihistamines beginning
`in cycle 1 as antiemetic
`prophylaxis for carboplatin
`
`for the paclitaxelcarboplatin arm with standard premedica
`
`DISCUSSION
`STELLAR 3 is the first dedicated phase III
`trial ever
`conducted and reported in treatment naive PS 2 patients with
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`627
`
`

`

`Langer et al
`
`Journal of Thoracic Oncology
`
`Volume 3 Number 6 June 2008
`
`TABLE 5 No
`
`Patients with Treatment Related Adverse Effects by Maximum NCI Common Toxicity Grade
`PaclitaxeUCarboplatin n = 198
`PPXCarboplatin n = 199
`
`Adverse Effects
`
`All Grades
`
`Grade 3
`
`Grade 4
`
`All Grades
`
`Grade 3
`
`Grade 4
`
`Nonhematologic
`
`Infection and infestation
`
`Neuropathy
`
`Cardiac
`
`Alopecia
`
`Arthralgia
`
`Myalgia
`
`Fatigue
`
`Nausea
`Vomiting NOS
`
`Hematologic
`
`Neutropcnia
`
`Febrile neutropenia
`
`Thrombocytopenia
`
`5 3
`
`0
`
`9950
`27 14
`13 7
`17 9
`29 15
`97 49
`59 30
`72 36
`116
`72 36
`
`0
`
`0
`
`1 <1
`30 15
`2 1
`2 1
`4 2
`9 5
`8 4
`18 9
`42
`38 19
`
`1 <1
`3 2
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`35 18
`5 3
`5 3
`
`42
`117 59
`6 3
`83 42
`33 17
`29 15
`16 8
`70 35
`39 20
`53 27
`5 3
`25 13
`
`0
`
`1 <1
`189
`1 <1
`2 1
`5 3
`5 3
`10 5
`3 2
`147
`21
`147
`
`0
`
`1 <1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 <1
`17 9
`21
`
`0
`
`NCI National Cancer Institute PPX paclitaxel poliglumex NOS not otherwise specified
`
`NSCLC Based on the preplanned
`statistical analysis PPX
`failed to yield superior survival compared with paclitaxel
`in
`this setting the primary end point but disease control
`rates
`TTP and overall survival rates were comparable as was dose
`for PPX in the PS 2 popu
`delivery Hence potential utility
`lation still exists
`An unplanned subanalysis of women enrolled in this study
`levels reported at the American Society of
`by baseline estradiol
`Clinical Oncology
`annual meeting in 2006 demonstrated a
`for PPX in women with premeno
`significant survival advantage
`levels >30 pgmL17 This observation will be
`pausal estradiol
`prospectively evaluated in a phase III study
`The overall survival
`for PS 2 patients enrolled in this
`trial was substantially longer than expected based on previ
`ously reported data In the Lilenbaum et al study CALGB
`97309 the median survival
`for PS 2 patients
`receiving
`paclitaxel and carboplatin was 47 months compared with
`nearly 8 months for both arms in this trial A previous phase
`II study of PPX alone at a lower dose of 175 mgm2 showed
`survival of 54 months in the PS 2 cohort Whereas survival
`in North America and Western Europe mirrored recent expe
`rience with carboplatin and paclitaxel in PS 2 patients Table
`6 Eastern Europe differed substantially with far better sur
`
`support
`
`vival observed in both aims This may be due to a younger
`population with fewer comorbidities less prior radiation less
`advanced disease less baseline anemia and possibly lower
`nervous
`incidence of readily recognizable
`system
`central
`metastases It may also be due to contamination by PS 0 to
`forms does not
`1 patients although auditing of case report
`this theory and there are no known
`geographic
`in the nature of PS evaluation Still PS designa
`differences
`tion remains highly subjective and open to debate
`PPXcarboplatin produced fewer myalgias and arthral
`gias less alopecia and delayed time to neuropathy but more
`nausea vomiting and fatigue and overall worse neuropathy
`The increased incidence of nau
`than paclitaxelcarboplatin
`sea and vomiting in the PPX arm may have been due to lack
`of routine premedication for hypersensitivity reaction Febrile
`neutropenia rates were comparable in each arm Although the
`thrombocytopenia was significantly
`incidence of grade
`higher for the PPX arm it was readily manageable and did
`transfusions PPX administration
`not result in more platelet
`was also more convenient
`than paclitaxel with a significantly
`shorter administration time 48 versus 224 minutes and no
`significant increase in hypersensitivity reactions despite the
`absence of routine premedication
`
`TABLE 6 Comparative Analysis of TaxaneBased Regimens in Treatment naive PS 2
`NSCLC in North America
`
`Study
`
`CALGB 97308
`CALGB 97308
`ECOG 15944
`ECOG 15996
`
`PGT303
`
`PGT303
`
`Regimen
`
`Paclitaxel
`
`Paclitaxelcarboplatin
`
`Paclitaxelcarboplatin
`
`Paclitaxelcarboplatin
`
`Paclitaxelcarboplatin
`
`PPXcarboplatin
`
`No Patients
`
`50
`
`49
`
`15
`
`38
`
`201
`
`199
`
`Median Survival mo
`24
`47
`46
`
`61
`
`80
`79
`
`1yr Survival CYO
`
`10
`
`19
`
`13
`
`19
`
`31
`
`31
`
`lung cancer CALGB Cancer and Leukemia Group B ECOG Eastern
`PS perfoimance status NSCLC non small cell
`Cooperative Oncology Group PPX paclitaxel poliglumex
`
`628
`
`Copyright © 2008 by the International Association for the Study of Lung Cancer
`
`

`

`Journal of Thoracic Oncology
`
`Volume 3 Number 6 June 2008
`
`PPXCarboplatin Versus PaditaxelCarboplatin
`
`in NSCLC
`
`The toxic death rates in this study were comparable
`trials including ECOG 1594
`with those observed in recent
`ECOG 1599 and CALGB 97304918 The reduction in toxic
`in the 1990s and
`deaths compared with trials
`completed
`earlier is likely due to better ancillary and supportive
`care
`management The optimal approach to patients with NSCLC
`remains unknown particularly in patients with compromised
`PS STELLAR 3 showed that
`two platinum based doublets
`than expected sur
`are relatively well tolerated with better
`vival rates in PS 2 patients The results of STELLAR 4 in
`which PPX at a dose of 175 mgm2 was compared with
`investigators choice of single agent gemcitabine or vinorel
`bine as frontline therapy for PS 2 patients and overall median
`survival exceeded 7 months suggested that
`the addition of a
`confer a survival ben
`platinating agent may not necessarily
`efit Safety analysis of STELLAR 4 suggested a similar
`outcome and less neuropathy
`and neutropenia
`for the 175
`mgm2 PPX dose compared with the 210 mgm2 dose used in
`STELLAR 3 No published PS 2 specific phase III
`to
`date has compared a platinum combination with a nonplati
`num single agent
`In the absence of a proven dose response
`for taxanes in NSCLC and given the similar survival rates in
`STELLAR 3 and 4 future studies of PPX in NSCLC will be
`175 mgm2
`conducted at a dose of
`In a Cox multivariate analysis of prognostic
`factors the
`included ex
`most significant negative prognostic
`trathoracic metastasis p = 0006 antecedent weight
`5 p = 0006 and LCS score <18 p = 0019 Geo
`graphic site Eastern Europe versus Western EuropeUnited
`StatesCanada had a clearcut bearing on outcome p
`0001 These factors should be considered as stratifications
`
`factors
`
`loss
`
`trial
`
`in future trials
`
`investigation in the
`Several other strategies are under
`PS 2 population The Southwest Oncology Group recently
`the role of
`reported the results of a phase II
`trial
`investigating
`erlotinib in PS 2 patients20 and the CALGB has completed a
`PS 2 specific randomized phase II
`trial evaluating docetaxel
`in combination with either bortezomib or cetuximab21
`Other chemotherapy only studies are also in progress
`Gridelli et al22 are completing a randomized phase II
`trial of
`followed after two cycles by
`pemetrexed either alone or
`in advanced NSCLC patients
`unsuitable
`for
`gemcitabine
`platinum based treatment To date the sequential arm has not
`shown superiority to the single agent arm22 US Oncology in
`gemcitabine alone to combi
`is comparing
`a phase III
`trial
`nation gemcitabinecarboplatin Single agent versus doublet
`has been tested in several European trials in
`chemotherapy
`elderly NSCLC patients with somewhat conflicting results
`but has never been tested exclusively in PS 2 patients
`
`CONCLUSIONS
`PS 2 patients constitute a sizable percentage of new
`NSCLC patients yet they have been largely excluded from or
`trials in the last 10 to 15 years
`underrepresented in clinical
`based on a general perception of overall poor outcome
`Single agent therapy is considered by many to be the standard
`approach despite data showing
`a benefit of combination
`therapy The results of STELLAR 3 confirmed the tolerability
`
`and efficacy of doublet
`treatment with carboplatin plus either
`PPX or paclitaxel Future studies in PS 2 patients should focus
`on the nature of comorbidities pretreatment disease character
`istics treatment related quality of life and toxicity management
`Patients with poor PS require special attention to ensure clini
`therapeutic benefits In this vein newer che
`cally meaningful
`motherapeutics such as PPX have a potential
`role
`
`ACKNOWLEDGMENTS
`Inc
`Supported by Cell Therapeutics
`
`randomised trial
`
`non small cell
`
`trial
`
`lung
`
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