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Randomized, Phase III Trial of First-Line Figitumumab inCombination With Paclitaxel and Carboplatin VersusPaclitaxel and Carboplatin Alone in Patients With AdvancedNon–Small-Cell Lung CancerCorey J. Langer, Silvia Novello, Keunchil Park, Maciej Krzakowski, Daniel D. Karp, Tony Mok,Rebecca J. Benner, Judith R. Scranton, Anthony J. Olszanski, and Jacek Jassem

See accompanying article doi: 10.1200/JCO.2013.54.4874

Corey J. Langer, University of Pennsyl-vania; Anthony J. Olszanski, Fox ChaseCancer Center, Philadelphia, PA; DanielD. Karp, MD Anderson Center, Hous-ton, TX; Rebecca J. Benner, Judith R.Scranton, Pfizer Oncology, Groton, CT;Silvia Novello, University of Turin,Orbassano, Italy; Keunchil Park, Sung-kyunkwan University School of Medi-cine, Seoul, Korea; Maciej Krzakowski,The Maria Sklodowska-Curie Institute ofOncology, Warsaw; Jacek Jassem,Medical University of Gdansk, Gdansk,Poland; Tony Mok, Chinese University,Hong Kong, Special AdministrativeRegion, People’s Republic of China.

Published online ahead of print atwww.jco.org on Month XX, 2014.

Supported by Pfizer and by Grant No.CA16672 from the National CancerInstitute (Clinical and TranslationalResearch Center).

Presented in part at the 46th AnnualMeeting of the American Society ofClinical Oncology, Chicago, IL, June4-8, 2010.

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Clinical trial information: NCT00596830.

Corresponding author: Corey J. Langer,MD, FACP, Professor of Medicine,Hematology-Oncology Division, Univer-sity of Pennsylvania, 3400 Civic CenterBlvd, 2 Perelman Center for AdvancedMedicine, Philadelphia, PA 19104;e-mail: corey.langer@uphs.upenn.edu.

© 2014 by American Society of ClinicalOncology

0732-183X/14/3299-1/$20.00

DOI: 10.1200/JCO.2013.54.4932

A B S T R A C T

PurposeFigitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits theinsulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III studycompared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment inpatients with advanced non–small-cell lung cancer (NSCLC).

Patients and MethodsPatients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histologyreceived open-label figitumumab (20 mg/kg) plus paclitaxel (200 mg/m2) and carboplatin (areaunder the concentration-time curve, 6 mg � min/mL) or paclitaxel and carboplatin alone once every3 weeks for up to six cycles. The primary end point was overall survival (OS).

ResultsOf 681 randomly assigned patients, 671 received treatment. The study was closed early by anindependent Data Safety Monitoring Committee because of futility and an increased incidence ofserious adverse events (SAEs) and treatment-related deaths with figitumumab. Median OS was8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone (hazardratio [HR], 1.18; 95% CI, 0.99 to 1.40; P � .06); median progression-free survival was 4.7 months(95% CI, 4.2 to 5.4) and 4.6 months (95% CI, 4.2 to 5.4), respectively (HR, 1.10; P � .27); theobjective response rates were 33% and 35%, respectively. The respective rates of all-causalitySAEs were 66% and 51%; P � .01). Treatment-related grade 5 adverse events were also morecommon with figitumumab (5% v 1%; P � .01).

ConclusionAdding figitumumab to standard chemotherapy failed to increase OS in patients with advancednonadenocarcinoma NSCLC. Further clinical development of figitumumab is not being pursued.

J Clin Oncol 32. © 2014 by American Society of Clinical Oncology

INTRODUCTION

Metastatic non–small-cell lung cancer (NSCLC) israrely curable and, despite significant treatment ad-vances over the last decade, 5-year survival ratesremain below 5%.1 Current therapeutic optionsinclude histology-based chemotherapy, antiangio-genic agents, and targeted agents inhibitingepidermal growth factor receptor and anaplasticlymphoma kinase. Insulin-like growth factor 1(IGF-1) receptor (IGF-1R) is a central componentof cancer signal transduction pathways.2 Expressionof IGF-1R is detectable in 39% to 84% of advancedNSCLCs and is more frequently found in squamous

cell lung cancer.3 The prognostic significance ofIGF-1R expression remains unclear. Several pro-spective studies suggest a relationship between cir-culating IGF-1 and cancer risk.4,5

Figitumumab (CP-751,871) is a fully humanimmunoglobulin G2 monoclonal antibody that in-hibits IGF-1R. In phase I trials, it was well toleratedas a single agent and in combination with chemo-therapy at 20 mg/kg every 3 weeks.6,7 In a random-ized phase II study of patients with treatment-naiveadvanced NSCLC, the originally reported objectiveresponse rate (ORR) was 54% with figitumumab 10or 20 mg/kg plus full-dose paclitaxel and carbopla-tin, and 42% with chemotherapy alone. Median

Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

© 2014 by American Society of Clinical Oncology 1

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progression-free survival (PFS) was initially reported as 5.0 monthswith figitumumab 20 mg/kg and 3.5 months with chemotherapyalone. No unexpected toxicities were observed. These findingsprompted a prospective, randomized phase III trial of figitumumabplus paclitaxel and carboplatin compared with chemotherapy alone asfirst-line treatment for advanced NSCLC. However, the phase II datawere subsequently retracted after a reanalysis revealed a lower ORR inboth treatment arms (see Discussion).8

In this article, we report the results of the phase III trial, which wasrestricted to patients with nonadenocarcinoma histology based on aninitial analysis of the phase II study that indicated potentially increasedfigitumumab efficacy in this subset.8

PATIENTS AND METHODS

Patients

Eligible patients were at least 18 years old with histologically or cytolog-ically confirmed advanced NSCLC; documented American Joint Committeeon Cancer9 stage IIIB or metastatic (stage IV or recurrent) disease not amena-ble to curative treatment; and a primary histology of predominantly squamouscell, large cell, or adenosquamous carcinoma. Prior systemic treatment forNSCLC and previous or concurrent therapy with IGF-1R inhibitors or growthhormone agonists or antagonists were prohibited. Adjuvant chemotherapywas permitted if completed at least 12 months before randomization. Priorsurgery or radiation therapy was permitted if completed at least 3 weeks beforerandomization, with all acute toxicities resolved to National Cancer InstituteCommon Terminology Criteria for Adverse Events version 3.0 grade 1. Pa-tients had to have an Eastern Cooperative Oncology Group performancestatus of 0 or 1 and adequate organ function. Exclusions included symptom-atic CNS metastases, other active malignancies, uncontrolled hypertension, oruncontrolled diabetes (baseline glycosylated hemoglobin [HbA1c] � 8%).

The study was conducted in accordance with International Conferenceon Harmonisation Good Clinical Practice guidelines, the declaration of Hel-sinki, and local regulatory requirements and laws. Institutional review boardor independent ethics committee approval was required for each investigatorand center. Written informed consent was obtained from all patients.

Study Design and Treatment

Patients were randomly assigned in a 1:1 ratio to open-label figitu-mumab plus paclitaxel and carboplatin (investigational arm) or paclitaxeland carboplatin alone (control arm), stratified by previous adjuvant chem-otherapy, sex, and histology (squamous-cell v combined large-cell or ade-nosquamous cancer).

The primary end point was overall survival (OS), which was defined astime from randomization to death as a result of any cause. Secondary endpoints included PFS, ORR, and safety. The association between serum IGF-1levels and OS was a preplanned exploratory objective.

All patients received carboplatin (area under the concentration-timecurve, 6 mg �min/mL) and paclitaxel (200 mg/m2) intravenously on day 1 onceevery 3 weeks for up to six cycles. In the investigational arm, patients alsoreceived figitumumab 20 mg/kg intravenously on day 1 of each 3-week cycle,for up to 17 cycles (approximately 1 year of treatment).

On the investigational arm, if paclitaxel and/or carboplatin were discon-tinued early, patients could continue single-agent figitumumab (once every 3weeks) until disease progression or intolerance. Additional cycles were permit-ted in patients exhibiting response, based on agreement between the studysponsor and investigator. If figitumumab was discontinued, paclitaxel andcarboplatin were continued for a maximum of six cycles until disease progres-sion or intolerance. Standard supportive therapies were instituted in botharms. Guidelines for managing emergent hyperglycemia were provided, in-cluding immediate treatment, protocol-defined figitumumab-dosage modifi-cation, and continued oral glucose-lowering therapy if hyperglycemia wasexpected to continue.

Study Procedures

Tumor assessment was performed at baseline and every 6 weeks untilradiologic disease progression or initiation of subsequent anticancer therapyusing Response Evaluation Criteria in Solid Tumors version 1.0.10 Adverseevents were graded using National Cancer Institute Common TerminologyCriteria for Adverse Events version 3.0. Clinical assessments, including hema-tology and serum chemistry, were performed at baseline, on day 1 of cycle 1 (allmeasurements), days 8 and 15 of cycle 1 (hematology only), on day 1 of eachsubsequent cycle, and at the end of treatment. Levels of HbA1c were measuredat baseline, before cycle 4, and at the end of treatment.

Serum samples were collected within 2 hours before chemotherapyand/or figitumumab infusion at cycles 1 and 4 and at the end of treatment.Total IGF-1 levels were determined by immunochemiluminometric assay atMDS Pharma Services (now LabCorp; Mississauga, Ontario, Canada) usingthe ICMA method. An independent Data Safety Monitoring Committee(DSMC) monitored safety and efficacy.

Statistical Analysis

With one-sided .025 level testing and 90% power, 820 patients wereneeded to detect a 30% improvement for figitumumab plus chemotherapyover the median 10-month survival rate seen with paclitaxel plus carboplatintherapy (hazard ratio [HR], 0.77); 649 events were expected at full follow-up.The primary assessment was a log-rank test stratified by factors used in ran-domization. The analysis set included all randomly assigned patients on anintent-to-treat basis. Two-sided P values were determined.

Two interim analyses were planned after approximately one third andtwo thirds of the anticipated number of events had occurred. A Lan-DeMetsspending function approach with O’Brien-Fleming stopping bounds (Appen-dix Table A1 [online-only]) was used to reject the null hypothesis (efficacyboundary) and the alternative hypothesis (futility boundary). Statistical anal-yses were conducted by Pfizer.

RESULTS

Patients and Treatment Exposure

Between April 2008 and September 2009, 681 patients from 163sites in 25 countries were randomly assigned and 671 received treat-ment (figitumumab group, 338; control group, 333; Fig 1). Demo-graphic and baseline characteristics were well balanced betweentreatment arms (Table 1). Patients’ median age was 62 years. Most ofthe patients were men and most had stage IV disease. Patients in thefigitumumab and control arms received a median of four and fivecycles of chemotherapy, respectively (Table 2); 33% and 44%, respec-tively, completed six cycles of paclitaxel, and 34% and 46% completedsix cycles of carboplatin. Figitumumab-treated patients received amedian of four figitumumab cycles; 109 (32%) of 338 figitumumab-treated patients received four to six cycles, seven (2%) of 338 patientsreceived 17 cycles, and four (1%) of 338 received more than 20 cycles.A total of 124 (37%) of 338 patients received figitumumab aftercompleting or discontinuing chemotherapy (median of two mainte-nance cycles). Of these, 87 (26%) of 338 patients received figitu-mumab maintenance after six cycles (maintenance therapy could startearlier than cycle 6).

On DSMC advice, enrollment was suspended in September 2009because of a higher number of serious adverse events (SAEs) anddeaths in the figitumumab arm. The study was permanently closed tonew accrual in December 2009, after the first interim analysis indi-cated that the addition of figitumumab was highly unlikely to meet theprimary end point of improving OS over chemotherapy alone.Follow-up for OS continued until March 2011. The overall medianfollow-up time was 23.1 months (Table 3).

Langer et al

2 © 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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Efficacy

At the final analysis, 259 patients in the figitumumab arm and251 in the control arm had died (Table 3). The median OS rate was 8.6months (95% CI, 7.4 to 9.3) and 9.8 months (95% CI, 8.6 to 10.9),respectively (HR, 1.18; 95% CI, 0.99 to 1.40; P � .06; Fig 2A). Respec-tive 1-year survival rates were 34% and 39%. The effect of figitu-mumab was similar across all subgroups based on demographic orother baseline characteristics (Fig 3).

Median PFS was 4.7 months for the figitumumab arm (95% CI,4.2 to 5.4) and 4.6 months for the control arm (95% CI, 4.2 to 5.4; HR,1.10; 95% CI, 0.93 to 1.32; P � .27; Fig 2B). Respective ORRs were33% (95% CI, 28 to 38) and 35% (95% CI, 29 to 40; Table 3).

Safety

Alopecia and nausea were the most common treatment-emergent (all-causality) adverse events (AEs) of any grade andoccurred in a similar number of patients in each arm (Table 4).

Any-grade AEs that occurred more frequently in the figitumumabarm included hyperglycemia, diarrhea, decreased appetite, vomiting,and decreased weight. Grade 3/4 AEs that occurred more frequently inthe figitumumab arm included hyperglycemia, decreased appetite,dehydration, diarrhea, fatigue, and nausea.

Treatment-emergent (all-causality) SAEs occurred in 66% of thefigitumumab arm and 51% of the control arm (P � .01 by Fisher’sexact test). Excluding disease progression, the most common SAEswere pneumonia (6% v 4%, respectively), dehydration (4% v 1%),asthenia (3% v 1%), and hyperglycemia (3% v � 1%). The SAEs werejudged to have a reasonable possibility of being treatment-related in22% and 12% of patients, respectively.

Nonprogression grade 5 AEs occurred in 13% of the figitu-mumab arm and 10% of the control arm (P � .22). The most com-mon grade 5 AEs in the figitumumab arm were pulmonaryhemorrhage and pneumonia (2% each; Appendix Table A2). Grade 5AEs were considered to be treatment-related in 5% of the

Randomly assigned, stratified by previous adjuvant chemotherapy,sex, and histology (squamous cell v combined large cell or adenosquamous)

(N = 681)

Figitumumab arm Allocated to figitumumab plus chemotherapy (n = 342) Received figitumumab plus chemotherapy (n = 338) Did not receive figitumumab plus chemotherapy (n = 3)

*)1 = n( yparehtomehc ylno devieceR

Control arm)933 = n( yparehtomehc ot detacollA )233 = n( yparehtomehc devieceR )7 = n( yparehtomehc eviecer ton diD

)243 = n( ycaciffe rof dezylanAAnalyzed for safety

)833 = n( stneve esrevdA )433 = n( atad yrotarobaL

)4 = n( ffotuc atad retfa pu-wolloF)2 = n( bamumutigif deunitnocsiD)1 = n( htaed dna noissergorp evitcejbO

Transition to off-study, single-patient IND (n = 1)

)933 = n( ycaciffe rof dezylanAAnalyzed for safety

)333 = n( stneve esrevdA )423 = n( atad yrotarobaL

Receiving figitumumab at time of data cutoff (n = 2)Receiving chemotherapy at time of data cutoff (n = 0)

)633 = n( bamumutigif deunitnocsiD)34 = n( htaeD)22 = n( bamumutigif ot detaler EA)23 = n( bamumutigif ot detalernu EA)01 = n( noitaroireted htlaeh labolG)2 = n( pu-wollof ot tsoL)071 = n( espaler ro noissergorp evitcejbO)22 = n( rehtO)1 = n( noitaloiv locotorP)43 = n( EA ot detalernu lasufer tneitaP)902 = n( yparehtomehc deunitnocsiD)04 = n( htaeD)92 = n( yparehtomehc ot detaler EA)72 = n( yparehtomehc ot detalernu EA)9 = n( noitaroireted htlaeh labolG)2 = n( pu-wollof ot tsoL)87 = n( espaler ro noissergorp evitcejbO)5 = n( rehtO)1 = n( noitaloiv locotorP)81 = n( EA ot detalernu lasufer tneitaP)921 = n( yparehtomehc detelpmoC

Receiving chemotherapy at time of data cutoff (n = 0))1 = n( bamumutigif deunitnocsiD

AE unrelated to figitumumab (patient was randomly (n = 1)assigned to figitumumab arm but received only paclitaxel and carboplatin)

)681 = n( yparehtomehc deunitnocsiD)23 = n( htaeD)13 = n( yparehtomehc ot detaler EA)31 = n( yparehtomehc ot detalernu EA)01 = n( noitaroireted htlaeh labolG)1 = n( pu-wollof ot tsoL)18 = n( espaler ro noissergorp evitcejbO)8 = n( rehtO)1 = n( noitaloiv locotorP)9 = n( EA ot detalernu lasufer tneitaP)741 = n( yparehtomehc detelpmoC

Fig 1. CONSORT diagram. (*) Patient analyzed in control arm for safety. AE, adverse events; IND, XXXX.

Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

www.jco.org © 2014 by American Society of Clinical Oncology 3

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figitumumab arm and 1% of the control arm (P � .01). With figitu-mumab, these grade 5 AEs included hemoptysis, pneumonia, un-known cause reported only as death, septic shock, cardiorespiratoryarrest, decrease of performance status, neutropenic sepsis, toxicity tovarious agents, renal failure, hemorrhage, and hypovolemic shock(� 1% each). In the control arm, the grade 5 AEs included unknowncause reported as death, pneumonia, septic shock, and dehydration(� 1% each).

Figitumumab was discontinued because of treatment-relatedAEs in 7% of patients, and chemotherapy was discontinued for thisreason in 9% of patients in each arm.

Relationship of Total IGF-1 and HbA1c to Outcomes

For the exploratory analysis of outcomes based on baseline totalIGF-1, a cutoff of 120 ng/mL was selected because it was associated

with the largest observed differences in treatment effect above andbelow it. Baseline IGF-1 was not related to overall frequency or natureof AEs. However, grade 5 AEs were more common amongfigitumumab-treated patients with baseline IGF-1 levels less than 120ng/mL (56%) than among those with baseline levels of 120 ng/mL orhigher (38%) and than those in the control arm (37% and 36% in thelow and high IGF-1 groups, respectively). In the figitumumab arm,median OS for patients with low and high baseline IGF-1 was 7.0months and 10.4 months, respectively; in the control arm it was 10.1and 9.4 months, respectively (Appendix Fig A1). For patients withhigh IGF-1, there was no difference in OS between treatment groups(HR, 0.93; P � .67). For those patients with low IGF-1, OS wassignificantly shorter in the figitumumab arm (HR, 1.37; P � .01).

The rate of all-causality AEs did not vary markedly by baselineHbA1c status, but the rate of grade 3/4 AEs for patients with no grade5 events was slightly lower in those with baseline levels less than 5.7%than in those with levels � 5.7% (figitumumab arm, 30% v 36%;control arm, 33% v 35%). Median OS in patients with low baselineHbA1c was 8.7 months in the figitumumab arm and 10.2 months inthe control arm (HR, 1.07; P � .65). The respective values in patientswith high HbA1c were 8.2 and 9.7 months (HR, 1.26; P � .05).

DISCUSSION

This was the first randomized phase III study to test whether combin-ing an IGF-1R inhibitor (figitumumab) with paclitaxel and carbopla-tin could improve OS versus chemotherapy alone as first-linetreatment for advanced nonadenocarcinoma NSCLC. When this trialwas initiated, IGF-1R was thought to play an important role in squa-mous cell histology NSCLC, an area of particular unmet need. Unex-pectedly, adding figitumumab to chemotherapy proved deleterious.The DSMC closed the study because of therapeutic futility and in-creased SAEs, including treatment-related deaths, in the figitumumabarm. This outcome was disappointing given the originally reportedphase II ORR of 54% for combination therapy compared with 42% forchemotherapy alone.8

The phase III study was designed and conducted in good faithbased on the aforementioned phase II trial findings in treatment-naiveadvanced NSCLC. Following closure of the phase III trial, the phase IIdata were retracted after a reanalysis revealed a lower ORR in bothtreatment arms.8 In addition, median PFS no longer trended in favorof figitumumab (4.5 months with figitumumab 20 mg/kg and 4.3months with chemotherapy alone). The heightened toxicity of figitu-mumab in the phase III trial was not observed in the original phase I/IItrials in NSCLC, which enrolled more than 150 patients in total. In ourcurrent study, the figitumumab combination failed to improve anyefficacy end points over chemotherapy alone. Overall survival, theprimary end point, was 8.6 months versus 9.8 months respectively.The ORR with figitumumab (33%) was similar to that observed in thephase II final analysis (37% in both the overall cohort [initially re-ported as 54%] and the nonadenocarcinoma cohort). Another ad-vanced NSCLC trial, initiated after the phase III was underway, usedthe same treatment in combination with figitumumab and the ORRwas 39%.12

Subgroup analysis suggests that figitumumab safety and tolera-bility were poorer in patients with low baseline IGF-1 (� 120 ng/mL)compared with those with high IGF-1 (� 120 ng/mL), particularly

Table 1. Baseline Patient Characteristics

Characteristic

Figitumumab Arm(n � 342)

Control Arm(n � 339)

No. ofPatients %

No. ofPatients %

SexMale 261 76 260 77Female 81 24 79 23

Age, yearsMedian 62 62Range 30-90 36-83

EthnicityWhite 265 78 270 80Asian 56 16 59 17Black 9 3 4 1Other 12 4 6 2

ECOG performance status0 113 33 115 341 226 66 217 64Not reported 3 1 7 2

Current disease stage�

Stage IIIB 39 11 39 12Stage IV 302 88 300 88Not reported 1 � 1 0

Smoking statusNever smoked 34 10 33 10Current smoker 142 42 141 42Former smoker 166 49 165 49

HistologySquamous cell 295 86 289 85Large cell 28 8 26 8Adenosquamous 15 4 19 6Other 4 1 5 1

Prior treatmentsSurgery 72 21 61 18Radiation 44 13 36 11Adjuvant chemotherapy† 14 4 15 4

NOTE. Data are presented for all patients by randomized arm. The stratificationfactors (histology, sex, and adjuvant chemotherapy) are presented as collected in thecase report forms rather than as collected by the randomization system.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; TNM, tumor-node-metastases.

�TNM Classification of Malignant Tumours (6th ed).11

†Systemic therapy included carboplatin/paclitaxel (n � 3), cisplatin/vinorel-bine (n � 7), cisplatin/gemcitabine (n � 4), carboplatin/gemcitabine (n � 3),cisplatin/etoposide (n � 3), other regimens with carboplatin (n � 3), otherregimens with cisplatin (n � 4), and other nonplatinum regimens (n � 2).

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with respect to grade 5 AEs. Consequently, in the figitumumab arm,median OS was shorter in patients with low IGF-1 compared withthose with high IGF-1 and was significantly shorter compared withcontrol patients who had low IGF-1 (HR, 1.37, P � .01). Althoughadditional studies are required, these data suggest that low baselinetotal IGF-1 may be a safety biomarker that identifies a subset ofpatients for whom IGF-1R inhibition is particularly harmful. In aphase I study of ganitumab, a human monoclonal antibody againstIGF-1R, treatment transiently increased IGF-1.13 Low baseline IGF-1may indicate an inability to mount a compensatory increase in IGF-1and greater likelihood of AEs.

Hyperglycemia of any grade occurred more frequently in the figitu-mumab arm than in the control arm (23% v 5%), as did grade 3/4hyperglycemia(12%v1%).HyperglycemiawasoneofthemostcommonSAEs, with greater frequency in the figitumumab arm than in the controlarm. Hyperglycemia is likely a class effect stemming from impaired ho-meostatic control of glucose metabolism as a consequence of IGF-1Rinhibition.14 Hyperglycemia was rarely severe and was usually manage-able with agents such as metformin, but could have contributed in subtleways to increased toxicity in the figitumumab arm.

Baseline HbA1c was not a strong biosafety marker, althoughgrade 3/4 AEs were slightly more common in patients with levels

Table 2. Study Drug Exposure

XXXX

Figitumumab Arm (n � 338) Control Arm (n � 333)�

Figitumumab Paclitaxel Carboplatin Paclitaxel Carboplatin

No. ofPatients %

No. ofPatients %

No. ofPatients %

No. ofPatients %

No. ofPatients %

Cycles startedMedian 4 4 4 5 5Range 1-52† 1-6 1-6 1-6 1-6

Duration of treatment, weeksMedian 12.1 10.2 10.2 12.3 12.6Range 0.1-161.3† 0.1-20.1 0.1-20.1 0.1-23 0.1-23

Patients with at least one dose reduction 30 9 55 16 51 15 52 16 44 13Patients with at least one dose delay 76 22 52 15 54 16 42 13 42 13

Abbreviation: IND, XXXX.�Patients in the chemotherapy arm who received carboplatin, n � 332.†Includes experience after data cutoff from the last ongoing patient, who transitioned to single patient IND in September 2012.

Table 3. Efficacy Results

End Point

Figitumumab Arm (n � 342) Control Arm (n � 339)

Hazard Ratio PNo. of Patients % No. of Patients %

Median follow-up time, months 23.3 22.8Overall survival (primary end point) .06�

Patient deaths 259 76 251 74Median, months† 8.6 9.8 1.18‡95% CI 7.4 to 9.3 8.6 to 10.9 0.99 to 1.40One-year survival§ 34 39

Progression-free survival (investigator assessment) .27�

Events 261 76 241 71Objective progression 206 60 197 58Death without objective progression 55 16 44 13

Median, months† 4.7 4.6 1.1095% CI 4.2 to 5.4 4.2 to 5.4 0.93 to 1.32

Best overall response (investigator assessment)¶ .68�Complete response 2 0.6 3 0.9Partial response 111 32 114 34Stable disease 126 37 120 35ORR 33 3595% exact CI 28 to 38 29 to 40

Abbreviation: ORR, objective response rate.�Two-sided stratified log-rank test.†Brookmeyer and Crowley method.‡Stratified Cox proportional hazards model v Arm B.§Kaplan-Meier method.¶Confirmed no sooner than 4 weeks after initial observation.�Pearson �2 test.

Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

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� 5.7% than in those with levels less than 5.7% in both treatment arms.Median OS was approximately 1.5 months shorter in the figitumumabarm than in the control arm, regardless of baseline HbA1c (HR: patientswith low HbA1c, 1.07; patients with high levels, 1.26).

Beyond the failure to demonstrate efficacy, a worrisome findingof this study was the relatively high frequency of treatment-relateddeaths associated with figitumumab (5%), an effect that was notdetected in the phase II study. There are a number of potential reasonsthat may provide insight for future clinical trial design, dosing levels,and anticipation and management of toxicities, particularly wherecombination regimens are involved. First, only about half of the 98patients randomly assigned to figitumumab in the phase II trial re-ceived the 20 mg/kg dose, a sample that might have been too small to

detect safety signals. However, the incidence of grade 3/4 hyperglyce-mia was greater in the phase II study (20%) than in our current study(12%).8 Second, there were inherent differences in the patient popu-lations. For example, the phase III study enrolled patients with pre-dominantly squamous cell histology and far more current-smokers(42% v 13%) than the phase II study. Hence, the phase III patientpopulation may have had more attendant comorbidities (latent orovert), which might have rendered them more vulnerable to toxicityor intercurrent grade 5 events. Third, the phase II trial was conductedalmost exclusively at tertiary referral centers, which may have led tosubtle differences in the types of patients enrolled and how they weremanaged. As several study centers in the phase III trial enrolled only afew patients each, the investigators may have initially lacked

BA

0

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all S

urvi

val (

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Time (months)

100

80

60

40

20

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

lortnoC bamumutigiF Median OS, 8.6 (7.4 to 9.3) 9.8 (8.6 to 10.9) months (95% CI)HR (95% CI) 1.18 (0.99 to 1.40)P 60.

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0

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lortnoC bamumutigiF Median PFS, 4.7 (4.2 to 5.4) 4.6 (4.2 to 5.4) months (95% CI)HR (95% CI) 1.10 (0.93 to 1.32)P 72.

FigitumumabControl

No. at riskFigitumumab 342 279 221 174 131 100 81 71 48 35 15 4 1 0Control 339 294 253 199 154 118 103 89 59 39 15 3 0

No. at riskFigitumumab 342 231 127 38 17 8 6 2 2 1 0Control 339 236 114 47 21 12 8 4 0

Fig 2. Kaplan-Meier estimates of (A) overall survival (OS) and (B) progression-free survival (PFS) in the randomly assigned population. HR, hazard ratio.

Favors figitumumab Favors control

Factor n HR 95% CI Natural log HR (95% CI)

Overall 681 1.18 0.99 to 1.40

Sex Female 159 1.09 0.75 to 1.60 Male 522 1.20 0.99 to 1.46

ECOG PS 0 228 0.99 0.73 to 1.34 1 443 1.21 0.98 to 1.50

Nonsquamous Yes 79 1.18 0.71 to 1.96 No 602 1.16 0.96 to 1.39

Smoker Never 67 1.46 0.83 to 2.57 Current 283 1.11 0.85 to 1.45

Stage IIIB 78 1.28 0.75 to 2.19 IV 602 1.16 0.97 to 1.40

HbA1c < 5.7% 267 1.07 0.81 to 1.41 ≥ 5.7% 371 1.26 1.00 to 1.60

–0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8 1.0 1.2

Fig 3. Forest plot of overall survival byselected baseline characteristics. ECOGPS, Eastern Cooperative Oncology Groupperformance status; HbA1c, glycosylatedhemoglobin; HR, hazard ratio.

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experience in managing figitumumab complications such as hyper-glycemia and dehydration.

Furthermore, although patient and disease characteristics werewell balanced between arms, we cannot exclude the possibility thatminor baseline demographic imbalances in this study might haveproduced inconsistent results. Although figitumumab was combinedwith the same full-dose chemotherapy doublet as in the phase II study,lower doses of the doublet might have improved the tolerability of thecombination. Finally, the difference in the incidence of treatment-related grade 5 AEs between the figitumumab and control arms (5% v1%), may indicate that signaling through IGF-1R and its attendantpathways is critical in maintaining homeostasis, such that inhibitionsignificantly disrupts the insulin receptor/IGF-1R/growth-hormonesignaling axis. This concern may be heightened in patients with ad-vanced squamous cell NSCLC, who often have multiple comorbiditiesand who constituted the vast majority of participants in this trial. Ourexperience highlights the potential discrepancies between phase II andphase III trials in both safety and efficacy, and underscores the impor-tance of identifying a priori the patient population(s) most likely tobenefit from therapy. However, as seen in our current study, inclusionof such a selected patient group (predominantly squamous cellNSCLC) does not guarantee improved safety or efficacy.

In conclusion, though the phase II trial suggested an ORR advan-tage for adding figitumumab to standard chemotherapy in advancedNSCLC, our current phase III study involving nonadenocarcinomapatients failed to show any benefit and unexpectedly suggested apossible detrimental effect. This may be a class effect and should beassessed in current and future trials examining IGF-1R inhibitors.Further clinical development of figitumumab is not being pursued.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Although all authors completed the disclosure declaration, the followingauthor(s) and/or an author’s immediate family member(s) indicated a

financial or other interest that is relevant to the subject matter underconsideration in this article. Certain relationships marked with a “U”are those for which no compensation was received; those relationshipsmarked with a “C” were compensated. For a detailed description of thedisclosure categories, or for more information about ASCO’s conflict ofinterest policy, please refer to the Author Disclosure Declaration and theDisclosures of Potential Conflicts of Interest section in Informationfor Contributors.Employment or Leadership Position: Rebecca J. Benner, Pfizer (C);Judith R. Scranton, Pfizer (C) Consultant or Advisory Role: Corey J.Langer, Pfizer (C); Keunchil Park, Boheringer Ingelheim (U), Eli Lilly(U), Roche (U); Daniel D. Karp, Pfizer (U); Tony Mok, AstraZeneca (C),Roche (C), Eli Lilly (C), Merck Serono (C), Gisai (C), Bristol-MyersSquibb (C), BeiGene (C), AVEO Pharmaceuticals (C), Pfizer (C), TaihoPharmaceutical (C), Boehringer Ingleheim (C), GlaxoSmithKline (C)Stock Ownership: Rebecca J. Benner, Pfizer; Judith R. Scranton, PfizerHonoraria: Silvia Novello, Eli Lilly, Boehringer, Roche; Keunchil Park,Eli Lilly, Roche, AstraZeneca; Tony Mok, AstraZeneca, Roche, Eli Lilly,Merck Serono, Gisai, Bristol-Myers Squibb, BeiGene, AVEOPharmaceuticals, Pfizer, Taiho Pharmaceutical, Boehringer Ingleheim,GlaxoSmithKline Research Funding: Corey J. Langer, Pfizer; Daniel D.Karp, Pfizer; Tony Mok, AstraZeneca Expert Testimony: None Patents,Royalties, and Licenses: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Corey J. Langer, Tony Mok, Rebecca J. Benner,Judith R. Scranton, Anthony J. Olszanski, Jacek JassemProvision of study materials or patients: Corey J. Langer, Silvia Novello,Keunchil Park, Daniel D. KarpCollection and assembly of data: Keunchil Park, Maciej Krzakowski,Tony Mok, Rebecca J. Benner, Judith R. Scranton, Anthony J. OlszanskiData analysis and interpretation: Corey J. Langer, Silvia Novello,Keunchil Park, Daniel D. Karp, Tony Mok, Rebecca J. Benner, Judith R.Scranton, Anthony J. Olszanski, Jacek JassemManuscript writing: All authorsFinal approval of manuscript: All authors

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13. Murakami H, Doi T, Yamamoto N, et al: Phase1 study of ganitumab (AMG 479), a fully humanmonoclonal antibody against the insulin-like growthfactor receptor type I (IGF1R), in Japanese patientswith advanced solid tumors. Cancer ChemotherPharmacol 70:407-414, 2012

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Acknowledgment

We thank the participating patients and their families, as well as the network of investigators (Appendix), research nurses, study coordinators,and operations staff. We also posthumously acknowledge the contribution of Valentina Tzekova, MD, University Hospital Queen Joanna,

Sofia, Bulgaria, to the study. We also thank Janos Strausz and Igor Bondarenko for their contributions to the study. Medical writing supportwas provided by Nicola Crofts at ACUMED (Tytherington, United Kingdom) and was funded by Pfizer.

Appendix

Investigators. Charles A. Butts, MD, Daniele Marceau, MD, Christopher Charles Croot, MD, Shirish Madhav Gadgeel, MD, MansoorNoorali Saleh, Lee C. Drinkard, MD, Haralambos E. Raftopoulos, MD, Isidoro Barneto Aranda, Luis Alfonso Gurpide Ayarra, Pilar LopezCriado, Felipe Cardenal Alemany, Marta Lopez-Brea Piqueras, Amelia Insa Molla, Roy Timothy Webb, MD, Maciej Krzakowski, PhD, KazimierzRoszkowski-Sliz, PhD, Janusz Rolski, MD, Tadeusz Tobiasz, MD, Petr Zatloukal, MD, Jitka Jakesova, MD, Martin Smakal, MD, Saime Ayse Kars,MD, PhD, Ismail Oguz Kara, MD, PhD, John Allan Ellerton, MD, Kurt Aigner, MD, Sabine Zoechbauer-Mueller, MD, PhD, Nashat YousifGabrail, MD, Hari Menon, MD, Anand Pathak, MD, Digambar Behera, MD, Charles Arthur Henderson, MD, Anthony Mark Landis, MD,Carlos Gil Moreira Ferreira, MD, Ulf Petrausch, MD, Daniel C. Betticher, PhD, Barna Szima, MD, Zsuzsanna Mark, MD, Zsolt Szekely Papai,MD, Attila Somfai, MD, Janos Strausz, MD, PhD, Adam Richard Broad, MD, Bogdan N. Kotiv, MD, Dmitriy P. Udovitsa, MD, Henrik Riska,MD, Matti Pietilainen, MD, Nathan Adam Pennell, William Graydon Harker, MD, Daniel David Karp, MD, Donald St Paul Gravenor, MD,Giorgio Vittorio Scagliotti, PhD, Francesco Grossi, MD, Davide Pastorelli, MD, Filippo De Marinis, PhD, Alain Catalin Mita, MD, EverettEmmett Vokes, MD, Jose Rodrigues Pereira, MD, Violina Taskova, MD, Constanta Velinova Timcheva, PhD, Krassimir Dimitrov Koynov, MD,Tatyana Vasileva Koynova, MD, Wieslaw Wiktor Jedrzejczak, PhD, Dae-Seog Heo, MD, Keunchil Park, MD, Heung Tae Kim, MD, PeterBerzinec, Pavol Demo, MD, Ewa Jankowska, MD, Michael T. Slaughter, MD, Tony S.K. Mok, PhD, Tsai Chun-Ming, Su Wu-Chou, MD,Meng-Chih Lin, MD, Chih-Hsin Yang, MD, Joseph Thomas Meschi, MD, Konstantinos Syrigos, PhD, George Fountzilas, PhD, MichaelVaslamatzis, MD, Stephen Lloyd Graziano, MD, Ping Fai So, MD, Frank Griesinger, MD, PhD, Martin Reck, MD, Martin Sebastian, MD, SylviaGuetz, MD, Dennis Eli Slater, MD, Jean-Claude Guerin, Jean Yves Douillard, PhD, Claude El Kouri, MD, Herve Lena, MD, Patrick Merle, MD,Gerard Zalcman, PhD, Joerg Mezger, MD, PhD, Fabrice Paganin, MD, Christos Emmanouilides, MD, Sandip Abhay Shah, MD, Ganesha D.Vashishta, MD, Yaroslav Shparyk, MD, Nataliya L. Voytko, MD, Igor Mykolayovych Bondarenko, PhD, Vera Andreevna Gorbunova, PhD,Vasily I. Borisov, PhD, Oleksandr Yu. Popovych, PhD, Igor O. Vynnichenko, MD, Goetz H. Kloecker, MD, James Patrick Daugherty, MD, JanakK. Choksi, MD, Troy Hancil Guthrie Jr, MD, Sing Hung Lo, MD, Stephen Begbie, MD, Haluk Tezcan, MD, Susan Amy Sajer, MD, David WilliamZenk, MD, Samuel Spence McCachren Jr, MD, Stephen Daniel Myers, MD, Mark Ramsey Hutchins, MD, Richard Scott Siegel, Eric PowellLester, MD, Tarek Eldawy Mohamed, MD, Erwin Lee Robin, MD, Nicholas Oswald Iannotti, MD, Ahmad Ali Tarhini, MD, Corey Jay Langer,MD, Steven Charles Buck, MD, CheolWon Suh, MD, Brian Nicholson Mathews, MD, David Holden Henry, MD, Manuel Francisco Gonzalez,MD, Juraj Beniak, MD, Robert Matthew Jotte, MD, Michaela Long Tsai, MD, William Connelly Waterfield, MD, David A. Van Echo, MD,Waseemullah Khan, MD, Gary E. Goodman, MD, John Ward McClean, MD, Ronald George Steis, MD, Konstantin Hristov Dragnev, MD, LeeM. Zehngebot, MD, Hector A. Velez Cortes, Stacey Kay Knox, MD, Sergey V. Orlov, MD, Mikhail V. Kopp, MD, Bruno Coudert, MD, RadjGervais, MD, Robert Harold Gersh, MD, Michael Alan Savin, MD, Rama Koteswararoa Koya, MD, Marcus Alan Neubauer, MD, Alexander IllyaSpira, MD, Jacek Jassem, PhD, Edward Thomas O’Brien, MD, Linda L. Ferris, MD, Richard C. Frank, MD, Beth Ann Hellerstedt, MD, DonaldAnthony Richards, MD, Takeshi Horai, MD, Noboru Yamamoto, MD, Hiroshi Isobe, MD, Miyako Satouchi, MD, Shinji Atagi, MD, IsamuOkamoto, MD, Toshiyuki Sawa, MD, Hiroaki Okamoto, MD, Koji Takeda, MD, Tetsu Shinkai, MD, Richard Wilhelm Eek, MD, Valentina IlievaTzekova, PhD, Susan Fox, MD, Jan Novotny, MD, Maurice Perol, MD, Masaaki Kawahara, MD, Pilar Lopez Criado, Raul Manuel MarquezVazquez, Susanna Stoll, MD, Alessandra Curioni, MD, Ismail Oguz Kara, PhD, Sinan Yavuz, MD, PhD, Tarek Mouris Mekhail, MD, AthanassiosArgiris, MD, Brian Vincent Geister, MD, Samir Ezzeldin Witta, MD, Joseph Ward Leach, MD, and Nicholas James Robert, MD.

Table A1. Boundaries for the Planned Interim Analyses and First Interim Analysis Results

AnalysisNo. ofEvents

Efficacy Boundaries forRejecting the Null Hypothesis

Futility Boundaries for Rejectingthe Alternative Hypothesis

Z Score Hazard Ratio� Z Score Hazard Ratio�

Plan for first interim analysis 216 3.710 0.603 �0.695 1.10Plan for second interim analysis 433 2.511 0.785 1.003 0.908Plan for final analysis 649 1.993 0.855Computed boundaries for actual first interim analysis 225 3.632 0.616 �0.595 1.083Observed results for first interim analysis 225 �1.407† 1.209†

�Hazard ratio was computed from z score boundary assuming proportional hazards and approximating the SE using the No. of events. Decisions were based onthe z score boundaries.

†Based on interim data.

Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

www.jco.org © 2014 by American Society of Clinical Oncology 9

TA1-TA2,FA1,AQ:M

rich4/zlj-jco/zlj-jco/zlj99910/zlj4422-14z xppws S�1 4/14/14 7:13 4/Color Figure(s): F1-F3, FA1 Art: 44932 Input-FA

Table A2. Grade 5 All-Causality Adverse Events, Excluding Disease Progression

Adverse Event

Figitumumab Arm (n � 338) Control Arm (n � 333)

No. of Patients % No. of Patients %

Total� 43 13 32 10Pulmonary hemorrhage 7 2 4 1Pneumonia 7 2 3 1Cardiopulmonary failure 5 1 2 1Sepsis 4 1 1 � 1Death 3 1 3 1Pulmonary embolism 1 � 1 3 1Respiratory failure 2 1 1 � 1Renal failure 2 1 1 � 1Cerebrovascular accident 0 3 1Gastrointestinal hemorrhage 0 2 1Cardiovascular disorder 2 1 0Hemorrhage 2 1 0Sudden death 1 � 1 1 � 1Performance status decreased 1 � 1 1 � 1Arrhythmia 1 � 1 0Emphysema 1 � 1 0Hypovolemic shock 1 � 1 0Hypoxia 1 � 1 0Myocardial infarction 1 � 1 0Multiorgan failure 1 � 1 0Neutropenia 1 � 1 0Neutropenic sepsis 1 � 1 0Staphylococcal infection 1 � 1 0Toxicity to various agents 1 � 1 0Asphyxia 0 1 � 1Cardiac failure 0 1 � 1Dehydration 0 1 � 1Dyspnea 0 1 � 1Pulmonary edema 0 1 � 1Suicide 0 1 � 1Superior vena cava syndrome 0 1 � 1

�P � .22 by two-sided Fisher’s exact test. Some patients had more than one Grade 5 adverse event.

BA

0

Over

all S

urvi

val (

%)

Time (months)

100

80

60

40

20

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

lortnoC bamumutigiF )281 = n( )291 = n(

Median OS, 7.0 (5.8 to 8.2) 10.1 (8.0 to 11.4) months (95% CI)HR (95% CI) 1.37 (1.09 to 1.73)P 10.

FigitumumabControl

Over

all S

urvi

val (

%)

Time (months)

100

80

60

40

20

lortnoC bamumutigiF )69 = n( )021 = n(

Median OS, 10.4 (9.0 to 12.0) 9.4 (8.6 to 11.1) months (95% CI)HR (95% CI) 0.93 (0.67 to 1.29)P 76.

FigitumumabControl

No. at riskFigitumumab 193 153 116 86 65 52 41 36 19 13 6 0Control 182 157 138 108 88 67 60 51 30 21 6 2 0

No. at riskFigitumumab 120 100 82 73 56 42 36 31 26 19 8 4 1 0Control 96 85 72 57 40 33 27 23 16 10 5 1 0

Fig A1. Kaplan-Meier estimates of overall survival (OS) in patients with (A) total baseline insulin-like growth factor 1 (IGF-1) less than 120 ng/mL or (B) total baselineIGF-1 � 120 ng/mL. HR, hazard ratio.

Langer et al

10 © 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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