proclaim: randomized phase iii trial of pemetrexed ...€¦ · inefﬁcacious10; thus, there is a...

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Corresponding author: Suresh Senan,

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DOI: 10.1200/JCO.2015.64.8824

PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic RadiationTherapy Followed by Consolidation Chemotherapy in LocallyAdvanced Nonsquamous Non–Small-Cell Lung CancerSuresh Senan, Anthony Brade, Lu-hua Wang, Johan Vansteenkiste, Shaker Dakhil, Bonne Biesma,Maite Martinez Aguillo, Joachim Aerts, Ramaswamy Govindan, Belen Rubio-Viqueira, Conrad Lewanski,David Gandara, Hak Choy, Tony Mok, Anwar Hossain, Neill Iscoe, Joseph Treat, Andrew Koustenis,Belen San Antonio, Nadia Chouaki, and Everett Vokes

A B S T R A C T

PurposeThe phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatinand thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy.

Patients and MethodsPatients with stage IIIA/B unresectable nonsquamous non–small-cell lung cancer randomly received(1:1) pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously every 3 weeks for three cyclesplus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for fourcycles (arm A), or standard therapy with etoposide 50 mg/m2 and cisplatin 50 mg/m2 intravenously,every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of con-solidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The studywas designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1error of .05.

ResultsEnrollment was stopped early because of futility. Five hundred ninety-eight patients were randomlyassigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated.Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median,26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P, .001),during the overall treatment period.

ConclusionPemetrexed-cisplatin combinedwith TRT followed by consolidation pemetrexedwas not superior tostandard chemoradiotherapy for stage III unresectable nonsquamous non–small-cell lung cancer.

J Clin Oncol 34:953-962. © 2016 by American Society of Clinical Oncology

INTRODUCTION

Non–small-cell lung cancer (NSCLC) accountsfor approximately 85% of all lung cancers,1 andmore than 25% of NSCLC is locally advanceddisease.2 Standard care for patients with inoperablestage III NSCLC with a good performancestatus (PS) is concurrent platinum-based doubletchemoradiotherapy.3,4 The ideal concurrent che-motherapy regimen has not been determined.4 Thetwo most commonly used regimens are etoposide-cisplatin and carpoblatin-paclitaxel.5,6 The optimal

radiation dose and schedule for concurrenttreatment remains unclear, but standard dosesrange from 60 to 66 Gy.3,7,8

Despite improvements in locoregional controland survival, a meta-analysis revealed that con-current chemoradiation using older chemotherapyregimens in locally advanced NSCLC did notinfluence the rate of distant metastasis whencompared with sequential chemoradiotherapy.9

Indeed, more than 50% of patients develop dis-tant metastases,3 and up to almost 40% canexperience local recurrence.6,7 Consolidationchemotherapy with docetaxel has proven

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inefficacious10; thus, there is a demand for better management andmore effective, less toxic chemoradiotherapy regimens.

Pemetrexed, a multitargeted antifolate, has selective activity innonsquamous NSCLC11 and has been shown to enhance radiationsensitivity in vitro.12 Unlike other chemotherapy combinations,pemetrexed-cisplatin, a current standard of care for metastaticnonsquamous NSCLC, has a relatively well-tolerated safety profilewhen administered at full systemic dose with definitive thoracicradiation therapy (TRT).13-21 In the metastatic setting, main-tenance pemetrexed has shown a benefit in overall survival (OS) innonsquamous NSCLC after completion of four cycles of first-linetherapy.22,23 Pemetrexed has also been investigated in locallyadvanced NSCLC as consolidation therapy after pemetrexed-platinum–based chemoradiotherapy, with promising efficacy andsafety results,13,15,18,19 suggesting that this regimen may have asystemic effect and, at systemically active chemotherapy doses, mayreduce the risk of distant metastasis. Together, these factors formedthe basis of this study design, which used concurrent pemetrexed-cisplatin followed by consolidation pemetrexed.

The phase III PROCLAIM trial investigated whetherpemetrexed-cisplatin with concurrent TRT followed by pemetrexedconsolidation would produce superior survival compared withetoposide-cisplatin plus concurrent TRT followed by a non-pemetrexed consolidation treatment in stage IIIA/B NSCLC.

PATIENTS AND METHODS

PatientsEligible patients were $ 18 years old with a histologically/cytologically

confirmed diagnosis of nonsquamous NSCLC, stage IIIA/B disease withoutmalignant pleural/pericardial effusion (supraclavicular nodal involvementwas allowed), and an Eastern Cooperative Oncology Group PS of 0/1.Patients had a measurable lesion according to Response Evaluation Criteriain Solid Tumors v1.0,24 or evaluable disease on computed tomography imagingand adequate organ and pulmonary function.

Patients were excluded if the radiation plan encompassed a volume ofwhole lung receiving$ 20 Gy (V20) of more than 35% of lung volume or ifthey had had prior systemic chemotherapy for NSCLC. Study criteriadetails are available (Data Supplement).

This study protocol was approved by each institution’s ethics reviewboard and was conducted in accordance with the Declaration of Helsinkiand Good Clinical Practice guidelines. All patients provided written informedconsent before any study-related treatment or procedures commenced.

Study Design and TreatmentIn this open-label study, eligible patients were stratified by baseline PS

(0 v 1), sex (female vmale), disease stage (IIIA v IIIB), and positron emissiontomography (PET) scan (yes v no) and were randomly assigned (1:1) to oneof two arms. Arm A received pemetrexed 500 mg/m2 intravenously (IV) pluscisplatin 75 mg/m2 IV every 3 weeks for three cycles and concurrent TRTfollowed by four cycles of consolidation pemetrexed 500 mg/m2 IV every3 weeks. Patients received premedication, including folic acid and vitaminB12, according to the pemetrexed label.25 Arm B received etoposide 50 mg/m2

IVon days 1 to 5 every 4 weeks followed by cisplatin 50mg/m2 on days 1 and 8for two cycles plus concurrent TRT followed by two cycles of a platinum-baseddoublet regimen of choice as consolidation treatment: etoposide-cisplatin(same dose and schedule as during concurrent treatment) or vinorelbine30 mg/m2 IV on days 1 and 8 every 3 weeks and cisplatin on day 1 every3 weeks (vinorelbine-cisplatin) or paclitaxel 200 mg/m2 IV every 3 weeksfollowed by carboplatin IV (area under the concentration-time curve, 6)every 3 weeks (paclitaxel-carboplatin).

Concurrent TRT, 2 Gy/fraction daily/5 days per week to a target doseof 60 to 66 Gy in 30 to 33 fractions, started on day 1 of chemotherapy. Nofield reductions were permitted during radiotherapy, and the entireplanning treatment volume (PTV; $ 95% of PTV receiving $ 93% ofprescription dose) was treated daily. Radiation quality assurance isdescribed (Data Supplement).

Standard chemotherapy dose adjustments applied. Treatment-relatedgrade 3 radiation pneumonitis and TRT interruptions greater than 7 daysbecause of intercurrent illness required discontinuation. To begin con-solidation chemotherapy, all previous nonhematologic toxicities, exceptneuropathy, had to be resolved to grade # 2. (Data Supplement).

Baseline and Treatment AssessmentsBaseline tumor assessments were performed within 28 days before

the start of treatment. Assessments were repeated at the end of concurrenttreatment, before consolidation, and during follow-up according to thestudy schedule (Data Supplement).

All patients who received at least one dose of chemotherapy wereevaluated for safety and assessed for toxicity before each cycle using theNational Cancer Institute Common Terminology Criteria for AdverseEvents v3.0.26 Analyses of OS (primary end point) and progression-freesurvival (PFS; secondary end point) were conducted on the intent-to-treat(ITT) population. OS was measured from the date of random assignmentto the date of death as a result of any cause. For each patient who was notknown to have died as of the data lock date, OSwas censored at the date thepatient was last known to be alive. PFS was defined as the time from thedate of random assignment to the first date of documented objectiveprogressive disease or death as a result of any cause. For each patient whowas not known to have died or to have had objective progressive disease asof the data lock date, PFS was censored at the date of the last objectiveprogression-free disease assessment. For patients who took subsequentsystemic anticancer therapy before disease progression or death, PFS wascensored at the date of the last objective progression-free disease assess-ment before the date of the subsequent systemic anticancer therapy.

Secondary end points included tumor response rates; 1-, 2-, and3-year survival rates; and assessment of the first disease failure sites. Diseasecontrol rate (DCR), defined per treatment arm as the proportion ofrandomly assigned patients having a confirmed best objective response ofstable disease, partial response, or complete response multiplied by 100,was also assessed.

Statistical AnalysesApproximately 600 patients were planned to be randomly assigned in

this superiority trial on a 1:1 basis, assuming a minimum of 355 deathswith 80% power to detect a hazard ratio (HR) of 0.74 (arm A v arm B) witha two-sided a level of .05 for the standard log-rank test.

OS and PFS were estimated using the Kaplan-Meier method.27 HRswere estimated using Cox proportional hazards models.28 A Cox regressionmodel was used to determine treatment effect on OS and PFS after adjustingfor potential prognostic variables. The percent of patients with first site ofdisease failure was compared between arms using Fisher’s exact test.Objective tumor response rates were compared between treatment armsusing an unadjusted, normal distribution approximation for the difference inrates. A 95% CI for response rate of each arm was calculated using an exactmethod. Adverse events (AEs) were compared using Fisher’s exact test.

An independent data monitoring committee evaluated unblindedsafety information 6 months after the first 100 patients and then after allpatients completed consolidation chemotherapy. Efficacy (futility) wasevaluated by the data monitoring committee after 165 deaths had occurredto assess the merits of continuing patient enrollment. The trial was to bestopped for futility if the one-sided log-rank P value was greater than .5,corresponding approximately to an observed HR of 1.00 under anexponential model.

All statistical analyses were performed using the software SAS version9.2 (SAS Institute, Cary, NC).

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RESULTS

An interim analysis, performed in July 2012, occurred after 173deaths and included data from 552 randomly assigned patients.Patient enrollment (n = 598) was terminated for futility beforereaching the accrual target of 600 patients. No new safety concernswere identified during the study; therefore, patients were permittedto continue their assigned study therapy.

Patient CharacteristicsBetween October 20, 2008, and August 31, 2012, 125 insti-

tutions in 21 countries screened 932 patients for entry; 334 patientswere not randomly assigned. The remaining 598 patients wererandomly assigned (301, arm A; 297, arm B) and comprised theITT population. Forty-three randomly assigned patients (18, armA; 25, arm B) were not treated (largely because of unmet protocolentry criteria and patient/physician decision), leaving 555 patients(283, arm A; 272, arm B) eligible for concurrent treatment (Fig 1).Baseline patient and disease characteristics were well balanced andreflected the target population (Table 1). Patients with supra-clavicular node involvement were included (arm A, 20 [6.6%]; arm

B, 19 [6.4%]). Median follow-up times for all patients were22.2 months (arm A) and 22.6 months (arm B) at final data lockand 32.9 and 35.7 months, respectively, for alive patients.

TreatmentOf 283 patients who began treatment with pemetrexed and

cisplatin (arm A) in the concurrent phase, 229 patients (80.9%)completed concurrent treatment as planned and received at leastone dose of pemetrexed in the consolidation phase. Of 272 patientswho began treatment with etoposide and cisplatin (arm B) in theconcurrent phase, 202 patients (74.3%) completed concurrenttreatment and received at least one dose of a platinum doubletregimen in the consolidation phase (Appendix Table A1,online only). The most frequent reason for discontinuationfrom concurrent treatment was AEs (arm A, 5.7%; arm B,8.1%; Fig 1).

Overall study compliance, measured by the percentage ofpatients who completed both treatment phases per protocol, was58.0% in arm A and 62.1% in arm B.

Delivered dose intensities were similar for both arms duringconcurrent treatment (arm A, 96.0% pemetrexed and 95.9%cisplatin; arm B, 97.0% etoposide and 94.9% cisplatin) and

Randomly assigned (ITT)(N = 598)

Arm A: Pem-Cis-TRT(n = 301)

Arm B: Eto-Cis-TRT(n = 297)

Concurrent phase: Eto-Cis(n = 272)

(safety population)

Concurrent phase: Pem-Cis(n = 283)*

(safety population)

Not treated (n = 18):Protocol criteria not met (n = 8)Patient decision (n = 3)Physician decision (n = 3)Sponsor decision (n = 1)Lost to follow-up (n = 1)Adverse event (n = 1)Progressive disease (n = 1)

Not treated (n = 25):Patient decision (n = 10)Protocol criteria not met (n = 9)Physician decision (n = 4)Progressive disease (n = 2)

Discontinued during concurrent phase (n = 53):Progressive disease (n = 13)Sponsor decision (n = 2)Physician decision (n = 8)Patient decision (n = 7)Adverse event (n = 16)Death (n = 6)Protocol violation (n = 1)

Discontinued during concurrent phase (n = 68)‡:Progressive disease (n = 18)Sponsor decision (n = 2)Physician decision (n = 14)Patient decision (n = 8)Adverse event (n = 22)Death (n = 3)Protocol entry criteria not met (n = 1)

Consolidation phase: Pem (n = 229)†

Consolidation treatmentcompleted Arm A

(n = 164)

Consolidation treatmentcompleted Arm B

(n = 169)

Consolidation phaseEto-CisVin-CisPac-Car

(n = 202): (n = 91) (n = 38) (n = 73)

Fig 1. Arm A represents concurrent pemetrexed-cisplatin (Pem-Cis) and thoracic radiation therapy (TRT) followed by consolidation pemetrexed. Arm B representsconcurrent etoposide-cisplatin (Eto-Cis) and TRT followed by one of three consolidation chemotherapy regimens of choice: Eto-Cis, vinorelbine-cisplatin (Vin-Cis), or paclitaxel-carboplatin (Pac-Car). The first patient was randomly assigned on October 20, 2008. ITT, intent to treat. (*) 281 patients who were assigned to concurrent treatment in Arm Areceived Pem-Cis. (†) 228patientswhowere assigned to consolidation treatment in armA receivedpemetrexed. (‡) Two patients discontinued during the recovery period afterreceiving concurrent treatment and are not included in the number of patients who discontinued concurrent treatment.

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Pemetrexed-Cisplatin Versus Etoposide-Cisplatin in Stage III NSCLC


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numerically higher in arm A during consolidation treatment(95.4% pemetrexed) than in arm B (92.6% etoposide-cisplatin,87.5% vinorelbine-cisplatin, 90.7% paclitaxel-carboplatin;Appendix Tables A1 and A2, online only). A smaller percent-age of patients in arm A required dose adjustment, includingdose reductions and dose omissions during both treatmentphases (Appendix Table A3, online only).

Exposure to TRT was similar between arms (total mean[6SD] dose [Gy], 63.26 7.1, arm A; 61.96 10.5, arm B; AppendixTable A4, online only). Similar percentages of patients in each armreceived between 60 and 66 Gy (93.3%, arm A; 91.9%, arm B) orless than 60 Gy (6.0%, arm A; 8.1%, arm B) radiotherapy. A smallerpercentage of patients in arm A than in arm B (7.8% and 11.4%,respectively) had radiotherapy dose interruptions during theconcurrent phase.

EfficacyOS (Fig 2A) in arm Awas not significantly longer than in arm

B (HR, 0.98; 95% CI, 0.79 to 1.20; log-rank P = .831; median,26.8 v 25.0 months). One-, 2-, and 3-year OS rates were notsignificantly different for arm A versus arm B (76% v 77%, 52% v52%, and 40% v 37%, respectively). The censoring rates were41.2% (arm A) and 39.4% (arm B).

PFS (Fig 2B) was 1.6 months longer in arm A than in arm B,but this increase was not statistically significant (HR, 0.86; 95%CI, 0.71 to 1.04; log-rank P = .130; median, 11.4 v 9.8 months).

The objective response rate was not statistically differentbetween arms (35.9% in arm A v 33.0% in arm B). The DCR wassignificantly higher in armA compared with that in arm B (80.7% v70.7%), although it was not a protocol-specified end point(Table 2).

A smaller, but not statistically significant, percentage ofpatients had first relapse within the radiation treatment field(37.3%, arm A; 45.8%, arm B). A similar percentage of patientsin each arm had a distant relapse (50.0%, arm A; 45.8%, arm B)and/or brain metastasis (18.7%, arm A; 19.5%, arm B; Table 3).

Prespecified subgroup analyses (Fig 3) revealed a treatmenteffect across subgroups similar to that observed in the primaryanalysis of OS and PFS in the ITT population. In two subgroups,patients with the highest PTVs (. 700 mL) and stage IIIB disease,pemetrexed-cisplatin tended to provide a greater treatment benefitfor PFS (HR, 0.79; 95% CI, 0.55 to 1.13; HR, 0.76; 95% CI, 0.58 to0.98, respectively).

SafetyTreatment-emergent AEs possibly related to study treatment

during the overall study (protocol therapy and follow-up) and

Table 1. Baseline Patient and Disease Characteristics for Randomly Assigned Patients

Characteristic Arm A (n = 301) Arm B (n = 297)

Age, median (range), years 59.5 (28.0-83.7) 58.7 (34.6-80.4)SexFemale 124 (41.2) 119 (40.1)Male 177 (58.8) 178 (59.9)

ECOG PS0 148 (49.2) 145 (48.8)1 152 (50.5) 149 (50.2)

Disease stageIIIA 140 (46.5) 142 (47.8)IIIB 161 (53.5) 152 (51.2)

Smoking statusNever-smoker 50 (16.6) 58 (19.5)Smoker 232 (77.1) 221 (74.4)

HistologyAdenocarcinoma 226 (75.1) 226 (76.1)Large-cell carcinoma 16 (5.3) 21 (7.1)Other* 59 (19.6) 48 (16.2)

PTV, mean (SD), mL 607 (310)† 585 (413)‡PET scanYes 250 (83.1) 241 (81.1)No 51 (16.9) 56 (18.9)

OriginAfrican 15 (5.0) 12 (4.0)White 217 (72.1) 204 (68.7)East Asian 54 (17.9) 68 (22.9)Other (Hispanic/West Asian, Native American) 12 (4.0) 11 (3.6)Unknown 3 (1.0) 2 (0.7)

NOTE. Data are presented as No. (%) unless indicated otherwise. Data may not total 100% because of missing or unknown status.Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non–small-cell lung cancer; PET, positron emission tomography; PTV,planning treatment volume; SD, standard deviation.*Treatment by histology was not well established or adopted by the oncology community when the study started in 2008; for histology, “other” included poorlydifferentiated NSCLC, NSCLC, invasive non–small-cell carcinoma with glandular differentiation, and carcinoma bronchial. The high number of “other” should beconsidered in the context of when the study began (2008). Samples from 45 of 107 patients with histology of “other” according to investigators were tested during acentral pathologic review, and 19 of those were confirmed as adenocarcinoma, one as large-cell carcinoma, and 25 as “other.”†n = 280.‡n = 278.


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concurrent phase are listed in Table 4. During the overall study, theincidence of any grade 3 to 4 events was significantly lower in armA than in arm B (64.0% v 76.8%, P = .001). Thrombocytopenia(any grade) and neutropenia (any grade and grade 3 to 4) occurredsignificantly less frequently in arm A than in arm B (19.4% v31.3%, P= .002; 42.8% v 54.8%, P= .005; 24.4% v 44.5%, P,.001,respectively). Pneumonitis (any grade and grade 2) was sig-nificantly higher in arm A than in arm B (17.0% v 10.7%, P = .37;11.0% v 5.5%, P = .021, respectively). In the concurrent phase, theincidence of grade 3 to 4 neutropenia and febrile neutropeniawas significantly lower in arm A than in arm B (18.4% v 28.7%,

P = .005; 3.2% v 7.4%, P = .035, respectively), and pneumonitiswas low in both treatment arms.

In addition to esophagitis, febrile neutropenia was the onlyother treatment-related serious AE that occurred in $ 5% of treatedpatients (4.2% in arm A v 8.5% in arm B, P = .054). There were nosignificant differences between arms in discontinuations because ofpossibly drug-relatedAEs (11.0% in armAv 8.8% in armB) or possiblydrug-related deaths (five [1.8%] in arm A v three [1.1%] in arm B).

The eight treatment-related AEs that led to death are as follows:for arm A, acute respiratory failure, pulmonary hemorrhage, car-diorespiratory arrest, pneumonia, and neutropenic sepsis, and arm

A

B

1.0

0.8

0.6

0.4

0.2

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72

Time From Random Assignment (months)

Time From Random Assignment (months)

Surv

ival

Pro

babi

lity

(%)

1.0

0.8

0.6

0.4

0.2

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 720

Surv

ival

Pro

babi

lity

(%)

Median overall survival, mo (95% CI)

HR (95% CI), 0.98 (0.79 to 1.20)

Log-rank P = .831

Pem-Cis: 26.8 (20.4 to 30.9)

Eto-Cis: 25.0 (22.2 to 29.8)

Pem-cis censored

Eto-Cis censored

Pem-cis censored

Eto-Cis censored

Pem-Cis: 301 282 268 239 221 194 178 157 145 126 98 75 67 56 46 42 33 25 19 14 10 3 1 0 0

Eto-Cis: 297 278 262 232 216 201 179 164 140 113 97 82 69 56 49 46 31 26 22 16 10 6 3 1 0

No. at risk

No. at risk

Median progression-free survival, mo (95% CI)

Eto-Cis: 9.8 (8.4 to 11.7)

HR (95% CI), 0.86 (0.71 to 1.04)

Log-rank P = .130

Pem-Cis: 11.4 (10.3 to 13.2)

Pem-Cis: 301 237 197 155 114 98 81 68 58 45 33 31 27 21 19 16 13 10 6 4 2 1 0 0

Eto-Cis: 297 234 184 125 100 89 66 56 47 37 30 25 19 17 15 13 10 7 5 5 2 1 1 0

Fig 2. Kaplan-Meier estimates of (A) overallsurvival (OS; primary end point) in the intent-to-treat (ITT) population and (B) progression-freesurvival (PFS) in the ITT population. OS wasmeasured from the date of random assign-ment to the date of death as a result of anycause. At the cutoff date for data inclusion inthe analysis, if a patient had not died, OS wascensored at the last date they were known tostill be alive. PFS was measured from the dateof random assignment to the first date ofdocumented objective progression of diseaseor of death as a result of any cause. PFS wascensored at the date of the last objectiveprogression-free disease assessment beforethe date of any subsequent systemic anti-cancer therapy or death, whichever appliedfirst. Eto-Cis, etoposide-cisplatin; HR, hazardratio; Pem-Cis, pemetrexed-cisplatin.




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B, respiratory failure, aspiration, and hypovolemic shock. Twodeaths, possibly related to treatment, occurred in arm A within30 days of study discontinuation because of respiratory failure andpneumonitis.

Postdiscontinuation TherapySimilar percentages of patients received postdiscontinuation

anticancer therapy (42.5%, arm A; 49.2%, arm B), includingsystemic therapy (33.2%, arm A; 36.0%, arm B), palliative radi-otherapy (20.3%, arm A; 27.9%, arm B), or surgery (7.0%, arm A;8.4%, arm B). Systemic therapy use was similar between arms,except for pemetrexed, which was higher in arm B (21.5%) than inarm A (8.6%), and the selection of platinum (cisplatin: 9.3%, armA; 7.4%, arm B; carboplatin: 7.0%, arm A; 9.8%, arm B).

DISCUSSION

In this trial, pemetrexed-cisplatin plus concurrent TRT followed byconsolidation pemetrexed did not improve OS compared withetoposide-cisplatin plus concurrent TRT followed by consolidationtherapy with a non–pemetrexed-platinum doublet. The mediansurvival times were not significantly different between arms A andB; both arms achieved higher median survival times (. 5 months)than anticipated on the basis of historical data,10,29-31 including a

systematic review of 32 published trials of etoposide-cisplatinadministered concurrently with TRT.6 However, the observedOS in PROCLAIM was in the same range as that reported in theRTOG 0617 trial,7 possibly reflecting higher use of staging PETscans in both trials (. 81% of patients). The evidence of thesignificant impact of PET staging on survival outcomes because ofstage migration is well documented.32,33 Future analyses willexplore the stage migration effect on survival outcomes, including3-year survival, in the subgroup of patients who underwent a stagingPET scan (n = 491), compared with those who did not (n = 107).

Investigator-assessed PFS trended in favor of the pemetrexed-cisplatin arm, and the relative treatment effect was consistentacross subgroups and similar to that observed in the unadjustedanalysis of PFS. In addition, patients with stage IIIB disease andhigher PTV (. 700 mL), two characteristics generally associatedwith poorer survival outcomes,31 trended to a higher OS benefitfrom the pemetrexed regimen, indicating the need for furtherinvestigation of pemetrexed-cisplatin in patients with larger tumors.

Although the objective response rate was comparable betweentreatment arms, DCR was high in both arms and it improvedsignificantly in arm A compared with arm B on the basis of a higherpercentage of stabilizations and fewer progressions as bestresponse during treatment. The higher number of stabilizationsthan responses in this study may be related to the fact thatapproximately 50% of randomly assigned patients had stage IIIB

Table 2. Summary of Objective Tumor Responses

Response

Arm A (n = 301) Arm B (n = 297)

No. % 95% CI No. % 95% CI P

CR 4 1.3 0.36 to 3.37 0 0 —

PR 104 34.6 29.2 to 40.2 98 33.0 27.7 to 38.7SD 135 44.9 39.1 to 50.7 112 37.7 32.2 to 43.5PD 11 3.7 1.8 to 6.4 19 6.4 3.9 to 9.8Unknown* 19 6.3 — 39 13.1 —

Not performed† 28 9.3 — 29 9.8 —

ORR‡ (CR + PR) 108 35.9 30.5 to 41.6 98 33.0 27.7 to 38.7 .458DCR§ (CR + PR + SD) 243 80.7 75.8 to 85.0 210 70.7 65.2 to 75.8 .004

NOTE. Tumor response was assessed using RECIST v1.0.24 The P value is based on unadjusted, normal distribution approximation for the difference in rates. The 95%CIs for ORR and DCR are based on an exact methodAbbreviations: CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.*Unknown response on the basis of RECIST, could not be determined because of incomplete postbaseline lesion data.†Not performed because no baselinemeasurementswere provided (patients randomly assigned but not treated) or because no postbaseline assessmentwas available.‡Defined as the proportion of PR or CR multiplied by 100.§Defined as the proportion of SD, PR, or CR multiplied by 100.

Table 3. Summary of First Sites of Disease Failure

Arm A (n = 166) Arm B (n =190)

PRelapse location No. % 95% CI No. % 95% CI

Local relapse*Within the radiation treatment field 62 37.3 30.0 to 45.2 87 45.8 38.6 to 53.2 .132Inside thorax, outside of radiation field 34 20.5 14.6 to 27.4 31 16.3 11.4 to 22.4 .337

Distant relapse* 83 50.0 42.2 to 57.8 87 45.8 38.6 to 53.2 .457Brain metastasis 31 18.7 13.1 to 25.4 37 19.5 14.1 to 24.7 .893

NOTE. P values are based on Fisher’s exact test; 95%CI was based on an exact method. Study arms included all randomly assigned patients with objective progressivedisease. All responses were physician scored and not centrally reviewed. Pathologic confirmation of recurrence was not mandatory.*Some patients (approximately 8%) relapsed in more than one site.


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disease and nearly 30% for whom data were available had highPTVs (. 700 mL).

The incidence of possible treatment-related grade 3 to 4 eventsduring the study was significantly lower in arm A. Concurrenttreatment toxicities were generally consistent with overall studytoxicities. In arm A, the incidence of grade 3 to 4 neutropenia

across all treatment phases and febrile neutropenia during con-current treatment were significantly lower than in arm B. Thetolerability of concurrent chemoradiotherapy with pemetrexed-cisplatin was supported by the lower incidence of dose adjustmentsin arm A than in arm B, and a higher percentage of patients in armA who completed concurrent treatment as planned and received

White (n = 421)Nonwhite (n = 177)

Male (n = 355)Female (n = 243)

IIIA (n = 282)IIIB (n = 313)

Never-smoker (n = 108)Smoker (n = 453)

1 (n = 301)0 (n = 293)

Adenocarcinoma (n = 452)Large-cell carcinoma (n = 37)Other (n = 107)

East Asia (n = 97)

Non–East Asia (n = 501)

< 65 (n = 426)≥ 65 (n = 172)

No (n = 107) Yes (n = 491)

< 350 mL (n = 104)350−700 mL (n = 283)> 700 mL (n = 159)

Stage of disease

Race

Sex

Smoking status

ECOG PS

Histology

Region

Age, years

PET scan staging

Planned PTV

1.00

0.87

0.90

1.10

1.08

1.03

1.23

0.96

1.18

0.951.04

0.95

1.35

1.00

1.07

0.90

0.76 0.88

0.94

0.99

0.99 0.81

HRPem-Cis arm (n = 301); Eto-Cis arm (n = 297)

A

0.3 1.0 2.5Favors Pem-Cis Favors Eto-Cis

Treatment HR (95% CI)

White (n = 421)Nonwhite (n = 177)

Male (n = 355)Female (n = 243)

IIIA (n = 282)IIIB (n = 313)

Never-smoker (n = 108)Smoker (n = 453)

1 (n = 301)0 (n = 293)

Adenocarcinoma (n = 452)Large-cell carcinoma (n = 37)Other (n = 107)

East Asia (n = 97)

Non–East Asia (n = 501)

< 65 (n = 426)≥ 65 (n = 172)

No (n = 107) Yes (n = 491)

< 350 mL (n = 104)350−700 mL (n = 283)> 700 mL (n = 159)

Stage of disease

Race

Sex

Smoking status

ECOG PS

Histology

Region

Age, years

PET scan staging

Planned PTV

HRPem-Cis arm (n = 301); Eto-Cis arm (n = 297)

B

0.3 1.0 2.5Favors Pem-Cis Favors Eto-Cis

Treatment HR (95% CI)

0.95

0.81

0.84

0.75

0.97

0.92

0.97

0.80

0.94

0.801.04

0.76

1.02

0.95

0.90

0.76

0.700.68

0.85

0.87

0.830.79

Fig 3. (A) Overall survival and (B) progression-free survival hazard ratios (HRs; armA over arm B) in subgroups accordingto baseline characteristics. ECOG PS,Eastern Cooperative Oncology Group per-formance status; Eto-Cis, etoposide-cisplatin;Pem-Cis, pemetrexed-cisplatin; PET,positron emission tomography; PTV, planningtreatment volume.




http://www.jco.org

consolidation treatment. This is in contrast to the East AsianKCSG-LU05-04 trial, in which approximately one-third of thepatients who received concurrent chemoradiotherapy withdocetaxel-cisplatin did not receive consolidation chemotherapywith the same chemotherapy regimen.34 The incidence of anygrade pneumonitis in PROCLAIM was significantly higher in armA because of grade 2 events, whereas grade 3 to 4 events wereobserved in less than 3% of patients in both arms. Similar lowincidences of grades 3 to 4 radiation pneumonitis were reported inthe RTOG 0617 and KCSG-LU05-04 trials.7,34

Local relapse occurred in 37.3% and 20.5% of patients withinand outside (but still within the thorax) of the radiation field inarm A of PROCLAIM, respectively. There was a similar pattern of

local and distant relapse in PROCLAIM and the standard arm ofthe RTOG 0617.7 The PROCLAIM study did not generate mature5-year survival data because the protocol-specified follow-upperiod was 3 years.

In conclusion, the PROCLAIM trial did not demonstratesuperior OS for pemetrexed-cisplatin with pemetrexed con-solidation compared with etoposide-cisplatin plus consolidationtherapy, in keeping with early stopping of enrollment for futility. Asignificantly lower incidence of drug-related grade 3 to 4 AEs,including neutropenia, was observed during the overall studyperiod for pemetrexed-cisplatin. Grade 3 to 4 neutropenia andfebrile neutropenia were also lower for pemetrexed-cisplatinduring concurrent therapy. The PROCLAIM trial showed that

Table 4. Possible Treatment-Related Treatment-Emergent Adverse Events During the Overall Study and Concurrent Phases (any grade) That Occurred in $ 10% ofPatients in Either Arm

CTCAE Term

Overall Study Concurrent Phase

Arm A (n = 283) Arm B (n = 272) Arm A (n = 283) Arm B (n = 272)

Any Gr* Gr 3–4 Any Gr* Gr 3–4 Any Gr† Gr 3–4 Any Gr† Gr 3–4

$ 1 CTCAE 281 (99.3) 181 (64.0) 269 (98.9) 209 (76.8) 278 (98.2) 160 (56.5) 265 (97.4) 173 (63.6)LaboratoryNeutrophils/granulocytes (ANC/AGC) 121 (42.8) 69 (24.4) 149 (54.8) 121 (44.5) 102 (36.0) 52 (18.4) 112 (41.2) 78 (28.7)Hemoglobin 114 (40.3) 25 (8.8) 124 (45.6) 37 (13.6) 78 (27.6) 16 (5.7) 83 (30.5) 22 (8.1)Leukocytes (total WBC) 104 (36.7) 64 (22.6) 111 (40.8) 82 (30.1) 96 (33.9) 53 (18.7) 99 (36.4) 69 (25.4)Lymphopenia 61 (21.6) 51 (18.0) 52 (19.1) 40 (14.7) 57 (20.1) 48 (17.0) 47 (17.3) 37 (13.6)Platelets 55 (19.4) 19 (6.7) 85 (31.3) 29 (10.7) 50 (17.7) 15 (5.3) 60 (22.1) 19 (7.0)Potassium, serum low 18 (6.4) 8 (2.8) 29 (10.7) 9 (3.3) 13 (4.6) 7 (2.5) 21 (7.7) 8 (2.9)

NonlaboratoryNausea 170 (60.1) 10 (3.5) 137 (50.4) 11 (4.0) 158 (55.8) 10 (3.5) 122 (44.9) 10 (3.7)Fatigue 154 (54.4) 17 (6.0) 146 (53.7) 13 (4.8) 121 (42.8) 12 (4.2) 115 (42.3) 7 (2.6)Dysphagia 143 (50.5) 23 (8.1) 115 (42.3) 18 (6.6) 135 (47.7) 19 (6.7) 110 (40.4) 16 (5.9)Esophagitis 136 (48.1) 44 (15.5) 138 (50.7) 56 (20.6) 134 (47.3) 44 (15.5) 129 (47.4) 51 (18.8)Vomiting 110 (38.9) 11 (3.9) 90 (33.1) 17 (6.3) 105 (37.1) 10 (3.5) 78 (28.7) 14 (5.1)Anorexia 91 (32.2) 11 (3.9) 79 (29.0) 10 (3.7) 81 (28.6) 10 (3.5) 63 (23.2) 8 (2.9)Rash: dermatitis associated with radiation‡ 77 (27.2) 0 (0.0) 64 (23.5) 4 (1.5) 74 (26.1) 0 (0.0) 62 (22.8) 4 (1.5)Constipation 71 (25.1) 1 (0.4) 72 (26.5) 4 (1.5) 65 (23.0) 0 (0.0) 59 (21.7) 1 (0.4)Mucositis/stomatitis‡ 62 (21.9) 3 (1.1) 40 (14.7) 5 (1.8) 47 (16.6) 3 (1.1) 36 (13.2) 5 (1.8)Pneumonitis 48 (17.0) 5 (1.8) 29 (10.7) 7 (2.6) 4 (1.4) 0 (0.0) 4 (1.5) 2 (0.7)GI pain‡ 46 (16.3) 5 (1.8) 23 (8.5) 2 (0.7) 38 (13.4) 4 (1.4) 18 (6.6) 2 (0.7)Weight loss 46 (16.3) 3 (1.1) 45 (16.5) 1 (0.4) 42 (14.8) 3 (1.1) 34 (12.5) 1 (0.4)Cough 46 (16.3) 1 (0.4) 33 (12.1) 1 (0.4) 23 (8.1) 0 (0.0) 18 (6.6) 1 (0.4)Infection‡ 42 (14.8) 8 (2.8) 33 (12.1) 7 (2.6) 25 (8.8) 6 (2.1) 17 (6.3) 5 (1.8)Dyspnea 42 (14.8) 6 (2.1) 23 (8.5) 4 (1.5) 16 (5.7) 4 (1.4) 12 (4.4) 2 (0.7)Diarrhea 38 (13.4) 3 (1.1) 40 (14.7) 5 (1.8) 31(11.0) 3 (1.1) 30 (11.0) 4 (1.5)Heartburn/dyspepsia 38 (13.4) 4 (1.4) 30 (11.0) 1 (0.4) 27 (9.5) 1 (0.4) 26 (9.6) 1 (0.4)Neuropathy, sensory 37 (13.1) 0 (0.0) 56 (20.6) 0 (0.0) 15 (5.3) 0 (0.0) 17 (6.3) 0 (0.0)Pulmonary/upper respiratory pain‡ 35 (12.4) 6 (2.1) 34 (12.5) 5 (1.8) 22 (7.8) 3 (1.1) 28 (10.3) 2 (0.7)Pain other than pulmonary or GI‡ 33 (11.7) 1 (0.4) 53 (19.5) 4 (1.5) 20 (7.1) 1 (0.4) 26 (9.6) 1 (0.4)Rash‡ 33 (11.7) 0 (0.0) 27 (9.9) 1 (0.4) 27 (9.5) 0 (0.0) 19 (7.0) 1 (0.4)Renal event‡ 30 (10.6) 5 (1.8) 16 (5.9) 4 (1.5) 23 (8.1) 3 (1.1) 14 (5.1) 4 (1.5)Fever (in the absence of neutropenia) 29 (10.2) 0 (0.0) 24 (8.8) 1 (0.4) 12 (4.2) 0 (0.0) 17 (6.3) 1 (0.4)Dizziness 29 (10.2) 2 (0.7) 21 (7.7) 1 (0.4) 25 (8.8) 1 (0.4) 17 (6.3) 1 (0.4)Dysgeusia 29 (10.2) 0 (0.0) 21 (7.7) 0 (0.0) 23 (8.1) 0 (0.0) 16 (5.9) 0 (0.0)Alopecia 23 (8.1) 0 (0.0) 98 (36.0) 1 (0.4) 17 (6.0) 0 (0.0) 90 (33.1) 1 (0.4)Febrile neutropenia 16 (5.7) 15 (5.3) 28 (10.3) 26 (9.6) 10 (3.5) 9 (3.2) 22 (8.1) 20 (7.4)

NOTE. Treatment-emergent adverse events refers to any untoward medical occurrence that occurs or worsens at any time after treatment baseline and that does notnecessarily have to have a causal relationship with this treatment. Treatment-related events include those with a causal relationship to either chemotherapy, radio-therapy, or both. Adverse events were graded in accordance with CTCAE v3.0 and Medical Dictionary for Regulatory Activities v17.1. Bold data indicate a significantP value (, .05) on the basis of Fisher’s exact test.Abbreviations: AGC, absolute granulocyte count; ANC, absolute neutrophil count; CTCAE, Common Terminology Criteria for Adverse Events; Gr, grade; WBC, whiteblood cells.*Possible study treatment–related grade 5 events in arm A for the overall study included three events (one febrile neutropenia and two pneumonitis), whereas in arm B,one patient experienced two grade 5 events (one febrile neutropenia and one renal failure).†Possible study treatment–related grade 5 events in arm A during the concurrent phase included one patient with one event (febrile neutropenia), and in arm B, onepatient experienced two grade 5 events (febrile neutropenia and renal failure).‡Combined term.


Senan et al


pemetrexed-cisplatin has an acceptable safety profile, in a scenarioin which concurrent chemoradiation remains the standard of care.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Disclosures provided by the authors are available with this article atwww.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Anthony Brade, Lu-hua Wang, JohanVansteenkiste, Ramaswamy Govindan, David Gandara, Hak Choy,

Tony Mok, Anwar Hossain, Neill Iscoe, Joseph Treat, Andrew Koustenis,Nadia Chouaki, Everett VokesProvision of study materials or patients: Suresh Senan, Anthony Brade,Lu-hua Wang, Johan Vansteenkiste, Shaker Dakhil, Bonne Biesma,Maite Martinez Aguillo, Joachim Aerts, Ramaswamy Govindan, BelenRubio-Viqueira, Conrad Lewanski, David Gandara, Everett VokesCollection and assembly of data: Suresh Senan, Lu-hua Wang, JohanVansteenkiste, Shaker Dakhil, Bonne Biesma, Maite Martinez Aguillo,Joachim Aerts, Belen Rubio-Viqueira, Conrad Lewanski, Belen SanAntonio, Nadia ChouakiData analysis and interpretation: Suresh Senan, Anthony Brade, JohanVansteenkiste, Bonne Biesma, Joachim Aerts, Ramaswamy Govindan,Conrad Lewanski, Tony Mok, Anwar Hossain, Neill Iscoe, Joseph Treat,Andrew Koustenis, Belen San Antonio, Nadia ChouakiManuscript writing: All authorsFinal approval of manuscript: All authors

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34. Ahn JS, Ahn YC, Kim JH, et al: Multinationalrandomized phase III trial with or without con-solidation chemotherapy using docetaxel and cis-platin after concurrent chemoradiation in inoperablestage III non–small-cell lung cancer: KCSG-LU05-04.J Clin Oncol 33:2660-2666, 2015

AffiliationsSuresh Senan, VUMedical Center, Amsterdam; Bonne Biesma, Jeroen Bosch Hospital, ’s-Hertogenbosch; and Joachim Aerts, Erasmus

MC Rotterdam/Amphia Hospital Breda, Breda, the Netherlands; Anthony Brade, Princess Margaret Hospital, University of Toronto; NeillIscoe, Eli Lilly Canada, Toronto, Ontario, Canada; Lu-huaWang, Chinese Academy ofMedical Sciences and Peking UnionMedical College,Beijing; Tony Mok, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, People’s Republic of China;Johan Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Shaker Dakhil, Cancer Center of Kansas, Wichita, KS; RamaswamyGovindan, Washington University School of Medicine, Saint Louis, MO; David Gandara, University of California, Davis Health System,Sacramento, CA; Hak Choy, UT Southwestern Medical Center, Dallas, TX; Anwar Hossain, Joseph Treat, and Andrew Koustenis, Eli Lillyand Company, Indianapolis, IN; Everett Vokes, University of Chicago, Chicago, IL; MaiteMartinez Aguillo, Hospital of Navarre, Irunlarrea,Pamplona; Belen Rubio-Viqueira, Hospital Universitario Quiron Madrid; and Belen San Antonio, Eli Lilly and Company, Madrid, Spain;Conrad Lewanski, Charing Cross Hospital, London, United Kingdom; and Nadia Chouaki, Eli Lilly and Company, Neuilly-sur-Seine,France.

n n n

GLOSSARY TERMS

cisplatin: an inorganic platinum agent (cis-diamminedichloroplatinum) with antineoplastic activity. Cisplatinforms highly reactive, charged, platinum complexes that bind tonucleophilic groups such as GC-rich sites in DNA, inducing intrastrandand interstrand DNA cross-links, as well as DNA-protein cross-links.These cross-links result in apoptosis and cell growth inhibition. Car-boplatin and oxaliplatin are other members of this class.

non–small-cell lung cancer (NSCLC): a type of lung cancerthat includes squamous cell carcinoma, adenocarcinoma, and large-cellcarcinoma.

overall survival: the duration between random assignment anddeath.

progression-free survival: time from random assignment untildeath or first documented relapse, categorized as either locoregional(primary site or regional nodes) failure or distant metastasis or death.


Senan et al


AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

PROCLAIM: Randomized, Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed byConsolidation Chemotherapy in Locally Advanced Nonsquamous Non–Small-Cell Lung Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Suresh SenanHonoraria: Varian Medical SystemsConsulting or Advisory Role: Varian Medical SystemsResearch Funding: Company: Varian Medical SystemsOther Relationship: Member of the Trial Management Group(noncompensated) for the PROCLAIM study sponsored by LillyOncology; it is evaluating concurrent chemoradiotherapy schemes forstage III lung cancer.

Anthony BradeResearch Funding: Abbvie/Bayer

Lu-hua WangNo relationship to disclose

Johan VansteenkisteHonoraria: Eli LillySpeakers’ Bureau: Eli Lilly

Shaker DakhilNo relationship to disclose

Bonne BiesmaConsulting or Advisory Role: Eli Lilly

Maite Martinez AguilloNo relationship to disclose

Joachim AertsStock or Other Ownership: Amphera B.V.Consulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, AstraZeneca,Roche, MSD, VerastemResearch Funding: Eli Lilly, GenentechPatents, Royalties, Other Intellectual Property: Erasmus MC

Ramaswamy GovindanHonoraria: Boehringer IngelheimConsulting or Advisory Role: GlaxoSmithKline, Boehringer Ingelheim,Clovis Oncology, Helsinn Therapeutics (US), Genentech, Abbvie, Celgene,Bayer AG, Novartis,Research Funding: Bayer, GlaxoSmithKline, MethylGene, AbbvieTravel, Accommodations, Expenses: Boehringer Ingelheim, Celgene,Merck, Amgen, Genentech, GlaxoSmithKline

Belen Rubio-ViqueiraConsulting or Advisory Role: Eli Lilly, Boehringer Ingelheim

Conrad LewanskiHonoraria: Eli Lilly, AstraZeneca, RocheConsulting or Advisory Role: Eli Lilly, AstraZeneca, Roche

David GandaraHonoraria: Eli LillyConsulting or Advisory Role: Eli LillyResearch Funding: Eli LillyTravel, Accommodations, Expenses: Eli Lilly

Hak ChoyHonoraria: Boehringer IngelheimConsulting or Advisory Role: Vertex, Boehringer Ingelheim, Bayer AGResearch Funding: Celgene

Tony MokHonoraria: AstraZeneca, Genentech, Eli Lilly, Pfizer, BoehringerIngelheim, Merck Sharp & Dohme, Amgen, Janssen Pharmaceuticals(a Johnson & Johnson), Clovis Oncology, GlaxoSmithKline, Novartis, SFJPharmaceuticals Group, ACEA Biosciences, Merck Serono, BioMarinPharmaceutical, Vertex Pharmaceuticals, Bristol-Myers Squibb, AVEO &Biodesix, prIME OncologyConsulting or Advisory Role: AstraZeneca, Genentech, Eli Lilly, Pfizer,Boehringer Ingelheim, Merck Sharp & Dohme, Janssen Pharmaceuticals(a Johnson & Johnson), Amgen, Clovis Oncology, GlaxoSmithKline,Novartis, SFJ Pharmaceuticals Group, ACEA Biosciences, Merck Serono,BioMarin Pharmaceutical, Vertex, AVEO& Biodesix, Bristol-Myers SquibbSpeakers’ Bureau: AstraZeneca, Genentech, Eli Lilly, Pfizer, BoehringerIngelheim, Merck Sharp & Dohme, Amgen, Janssen Pharmaceuticals(a Johnson & Johnson), Clovis Oncology, GlaxoSmithKline, Novartis,Bristol-Myers Squibb, prIME Oncology

Anwar HossainEmployment: Eli Lilly

Neill IscoeEmployment: Eli LillyStock or Other Ownership: Eli Lilly

Joseph TreatEmployment: Eli LillyStock or Other Ownership: Eli LillyTravel, Accommodations, Expenses: Eli Lilly

Andrew KoustenisEmployment: Eli LillyStock or Other Ownership: Eli Lilly

Belen San AntonioEmployment: Eli LillyStock or Other Ownership: Eli LillyHonoraria: Eli Lilly

Nadia ChouakiEmployment: Eli LillyStock or Other Ownership: Eli Lilly

Everett VokesStock or Other Ownership: McKessonConsulting or Advisory Role: Abbvie, AstraZeneca, BoehringerIngelheim, Celgene, Clovis Oncology, GeneCentric, Genentech, Merck,Synta, VentiRx, Eisai Medical Research, Eli Lilly, Transgene, Amgen

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Acknowledgment

We thank the patients, their families, the study sites, and the study personnel who participated in this clinical trial. Medical writing supportwas provided by Susan Reinwald, Marissa Philpott, and Lucy Rutherford, and editorial support was provided by Jeanne Claypoole ofinVentiv Health Clinical.

Appendix

Table A1. Treatment Delivery/Compliance: Concurrent Phase

Characteristic

Arm A (n = 283)* Arm B (n = 272)

Pem Cis Eto Cis

Received planned number of cycles† No. (%) 231 (81.6) 231 (81.6) 253 (93.0) 253 (93.0)Percentage mean dose-intensity‡ (SD) 96.0 (7.6) 95.9 (7.7) 97.0 (9.5) 94.9 (12.1)

NOTE. Arm A: three cycles of Pem-Cis planned in the concurrent phase followed by four cycles of Pem in the consolidation phase. Arm B: two cycles of Eto-Cis plannedin the concurrent phase followed by two cycles of Eto-Cis, Vin-Cis, or Pac-Car in the consolidation phase.Abbreviations: Car, carboplatin; Cis, cisplatin; Eto, etoposide; Pac, paclitaxel; Pem, pemetrexed; SD, standard deviation; Vin, vinorelbine.*ArmA: two patients switched to ArmB resulting in a total of 281 patients receiving treatment with both pemetrexed and cisplatin. One of the two patients discontinuedtreatment during the concurrent phase and one received consolidation treatment. Both patients are counted as Arm A patients in the safety analyses.†Patient is counted if he/she received at least one dose of chemotherapy in a given cycle.‡Dose-intensity is calculated as (actual mean dose/planned mean dose) 3 100%.

Table A2. Treatment Delivery/Compliance: Consolidation Phase

Arm A (n = 229)*Arm B (n = 202)

Characteristic Pem Eto-Cis (n = 91) Vin-Cis (n = 38)† Pac-Car (n = 73)

Received planned number of cycles‡ No. (%) 168 (73.4) 81 (89.0) 33 (86.8) 68 (93.2)Percentage mean dose-intensity§(SD) 95.4 (9.7) 92.6 (11.6) 87.5 (13.6) 90.7 (17.3)

NOTE. Arm A: three cycles of Pem-Cis planned in the concurrent phase followed by four cycles of Pem in the consolidation phase. Arm B: two cycles of Eto-Cis plannedin the concurrent phase followed by two cycles of Eto-Cis, Vin-Cis, or Pac-Car in the consolidation phase.Abbreviations: Car, carboplatin; Cis, cisplatin; Eto, etoposide; Pac, paclitaxel; Pem, pemetrexed; SD, standard deviation; Vin, vinorelbine.*228 patients received pemetrexed consolidation treatment and one patient was treated with arm B consolidation, for a total of 229 patients.†38 patients were treated with Vin-Cis, but the dose-intensity could not be calculated for one patient (data missing).‡Patient is counted if he/she received at least one dose of chemotherapy in a given cycle.§Dose-intensity is calculated as (actual mean dose/planned mean dose) 3 100%.

Table A3. Dose Adjustments

Dose Adjustments

Dose Reductions Dose Omissions

Arm A (n = 283) Arm B (n = 272) Arm A (n = 283) Arm B (n = 272)

Overall phaseNo. dose adjustments 63 125 2 72Patients with a dose adjustment, No. (%) 35 (12.4) 64 (23.5) 2 (0.7) 49 (18.0)

Concurrent phaseNo. dose adjustments 39 52 2 53Patients with a dose adjustment, No. (%) 21 (7.4) 29 (10.7) 2 (0.7) 39 (14.3)

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Senan et al


Table A4. Summary of Radiotherapy Delivered

Characteristic Arm A (n = 283) Arm B (n = 272)

Total dose, Gy, mean (SD) 63.2 (7.1) 61.9 (10.5)Patients receiving 66 Gy, No. (%) 191 (67.5) 180 (66.4)No. fractions, mean (SD) 31.6 (3.5) 31.0 (5.3)No. days on TRT, mean (SD) 45.3 (7.1) 45.2 (8.5)Delivered PTV dose maximum, Gy, mean (SD) 64.6 (7.8) 63.8 (9.5)V20, %, mean (SD) 27.0 (6.9) 26.1 (7.9)V5, %, mean (SD) 54.9 (15.2) 53.7 (17.3)Method of radiotherapy delivery, No. (%)Three-dimensional conformal radiotherapy 200 (70.7) 189 (69.5)IMRT 69 (24.4) 72 (26.5)Combination IMRT and three-dimensional conformal 14 (4.9) 10 (3.7)

Abbreviations: IMRT, intensity-modulated radiotherapy; PTV, planned treatment volume; SD, standard deviation; TRT, thoracic radiation therapy; V5, volume of wholelung minus PTV receiving $ 5 Gy of radiation expressed as a percent; V20, volume of whole lung minus PTV receiving $ 20 Gy of radiation expressed as a percent.

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