VOLUME

32

NUMBER

19

JULY

2014

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Randomized, Phase III Trial of First-Line Figitumumab in

Combination With Paclitaxel and Carboplatin Versus
Paclitaxel and Carboplatin Alone in Patients With Advanced
NonSmall-Cell Lung Cancer
Corey 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
Corey J. Langer, University of Pennsylvania; Anthony J. Olszanski, Fox Chase
Cancer Center, Philadelphia, PA; Daniel
D. Karp, MD Anderson Center, Houston, TX; Rebecca J. Benner, Judith R.
Scranton, Pfizer Oncology, Groton, CT;
Silvia Novello, University of Turin,
Orbassano, Italy; Keunchil Park, Sungkyunkwan University School of Medicine, Seoul, Korea; Maciej Krzakowski,
The Maria Sklodowska-Curie Institute of
Oncology, Warsaw; Jacek Jassem,
Medical University of Gdansk, Gdansk,
Poland; Tony Mok, Chinese University,
Hong Kong, Special Administrative
Region, Peoples Republic of China.

Purpose
Figitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits the
insulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III study
compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in
patients with advanced nonsmall-cell lung cancer (NSCLC).
Patients and Methods
Patients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histology
received open-label figitumumab (20 mg/kg) plus paclitaxel (200 mg/m2) and carboplatin (area
under the concentration-time curve, 6 mg min/mL) or paclitaxel and carboplatin alone once every
3 weeks for up to six cycles. The primary end point was overall survival (OS).

Presented in part at the 46th Annual

Meeting of the American Society of
Clinical Oncology, Chicago, IL, June
4-8, 2010.

Results
Of 681 randomly assigned patients, 671 received treatment. The study was closed early by an
independent Data Safety Monitoring Committee because of futility and an increased incidence of
serious adverse events (SAEs) and treatment-related deaths with figitumumab. Median OS was
8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone (hazard
ratio [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); the
objective response rates were 33% and 35%, respectively. The respective rates of all-causality
SAEs were 66% and 51%; P .01). Treatment-related grade 5 adverse events were also more
common with figitumumab (5% v 1%; P .01).

Authors disclosures of potential conflicts of interest and author contributions are found at the end of this
article.

Conclusion
Adding figitumumab to standard chemotherapy failed to increase OS in patients with
advanced nonadenocarcinoma NSCLC. Further clinical development of figitumumab is not
being pursued.

Published online ahead of print at

www.jco.org on June 2, 2014.
Supported by Pfizer and by Grant No.
CA16672 from the National Cancer
Institute (Clinical and Translational
Research Center).

Clinical trial information: NCT00596830.

Corresponding author: Corey J. Langer,
MD, FACP, Professor of Medicine,
Hematology-Oncology Division, University of Pennsylvania, 3400 Civic Center
Blvd, 2 Perelman Center for Advanced
Medicine, Philadelphia, PA 19104;
e-mail: [email protected].
2014 by American Society of Clinical
Oncology
0732-183X/14/3219w-2059w/$20.00
DOI: 10.1200/JCO.2013.54.4932

J Clin Oncol 32:2059-2066. 2014 by American Society of Clinical Oncology

INTRODUCTION

Metastatic nonsmall-cell lung cancer (NSCLC) is

rarely curable and, despite significant treatment advances over the last decade, 5-year survival rates
remain below 5%.1 Current therapeutic options
include histology-based chemotherapy, antiangiogenic agents, and targeted agents inhibiting
epidermal growth factor receptor and anaplastic
lymphoma kinase. Insulin-like growth factor 1
(IGF-1) receptor (IGF-1R) is a central component
of cancer signal transduction pathways.2 Expression
of IGF-1R is detectable in 39% to 84% of advanced
NSCLCs and is more frequently found in squamous

cell lung cancer.3 The prognostic significance of

IGF-1R expression remains unclear. Several prospective studies suggest a relationship between circulating IGF-1 and cancer risk.4,5
Figitumumab (CP-751,871) is a fully human
immunoglobulin G2 monoclonal antibody that inhibits IGF-1R. In phase I trials, it was well tolerated
as a single agent and in combination with chemotherapy at 20 mg/kg every 3 weeks.6,7 In a randomized phase II study of patients with treatment-naive
advanced NSCLC, the originally reported objective
response rate (ORR) was 54% with figitumumab 10
or 20 mg/kg plus full-dose paclitaxel and carboplatin, and 42% with chemotherapy alone. Median
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2059

Langer et al

progression-free survival (PFS) was initially reported as 5.0 months

with figitumumab 20 mg/kg and 3.5 months with chemotherapy
alone. No unexpected toxicities were observed. These findings
prompted a prospective, randomized phase III trial of figitumumab
plus paclitaxel and carboplatin compared with chemotherapy alone as
first-line treatment for advanced NSCLC. However, the phase II data
were subsequently retracted after a reanalysis revealed a lower ORR in
both treatment arms (see Discussion).8
In this article, we report the results of the phase III trial, which was
restricted to patients with nonadenocarcinoma histology based on an
initial analysis of the phase II study that indicated potentially increased
figitumumab efficacy in this subset.8

PATIENTS AND METHODS

Patients
Eligible patients were at least 18 years old with histologically or cytologically confirmed advanced NSCLC; documented American Joint Committee
on Cancer9 stage IIIB or metastatic (stage IV or recurrent) disease not amenable to curative treatment; and a primary histology of predominantly squamous
cell, large cell, or adenosquamous carcinoma. Prior systemic treatment for
NSCLC and previous or concurrent therapy with IGF-1R inhibitors or growth
hormone agonists or antagonists were prohibited. Adjuvant chemotherapy
was permitted if completed at least 12 months before randomization. Prior
surgery or radiation therapy was permitted if completed at least 3 weeks before
randomization, with all acute toxicities resolved to National Cancer Institute
Common Terminology Criteria for Adverse Events version 3.0 grade 1. Patients had to have an Eastern Cooperative Oncology Group performance
status of 0 or 1 and adequate organ function. Exclusions included symptomatic CNS metastases, other active malignancies, uncontrolled hypertension, or
uncontrolled diabetes (baseline glycosylated hemoglobin [HbA1c] 8%).
The study was conducted in accordance with International Conference
on Harmonisation Good Clinical Practice guidelines, the declaration of Helsinki, and local regulatory requirements and laws. Institutional review board
or independent ethics committee approval was required for each investigator
and 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 figitumumab plus paclitaxel and carboplatin (investigational arm) or paclitaxel
and carboplatin alone (control arm), stratified by previous adjuvant chemotherapy, sex, and histology (squamous-cell v combined large-cell or adenosquamous cancer).
The primary end point was overall survival (OS), which was defined as
time from randomization to death as a result of any cause. Secondary end
points included PFS, ORR, and safety. The association between serum IGF-1
levels and OS was a preplanned exploratory objective.
All patients received carboplatin (area under the concentration-time
curve, 6 mg min/mL) and paclitaxel (200 mg/m2) intravenously on day 1 once
every 3 weeks for up to six cycles. In the investigational arm, patients also
received 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 discontinued early, patients could continue single-agent figitumumab (once every 3
weeks) until disease progression or intolerance. Additional cycles were permitted in patients exhibiting response, based on agreement between the study
sponsor and investigator. If figitumumab was discontinued, paclitaxel and
carboplatin were continued for a maximum of six cycles until disease progression or intolerance. Standard supportive therapies were instituted in both
arms. Guidelines for managing emergent hyperglycemia were provided,
including immediate treatment, protocol-defined figitumumab-dosage
modification, and continued oral glucose-lowering therapy if hyperglycemia
was expected to continue.
2060

2014 by American Society of Clinical Oncology

Study Procedures
Tumor assessment was performed at baseline and every 6 weeks until
radiologic disease progression or initiation of subsequent anticancer therapy
using Response Evaluation Criteria in Solid Tumors version 1.0.10 Adverse
events were graded using National Cancer Institute Common Terminology
Criteria for Adverse Events version 3.0. Clinical assessments, including hematology and serum chemistry, were performed at baseline, on day 1 of cycle 1 (all
measurements), days 8 and 15 of cycle 1 (hematology only), on day 1 of each
subsequent cycle, and at the end of treatment. Levels of HbA1c were measured
at baseline, before cycle 4, and at the end of treatment.
Serum samples were collected within 2 hours before chemotherapy
and/or figitumumab infusion at cycles 1 and 4 and at the end of treatment.
Total IGF-1 levels were determined by immunochemiluminometric assay at
MDS Pharma Services (now LabCorp; Mississauga, Ontario, Canada). An
independent Data Safety Monitoring Committee (DSMC) monitored safety
and efficacy.
Statistical Analysis
With one-sided .025 level testing and 90% power, 820 patients were
needed to detect a 30% improvement for figitumumab plus chemotherapy
over the median 10-month survival rate seen with paclitaxel plus carboplatin
therapy (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 randomization. The analysis set included all randomly assigned patients on an
intent-to-treat basis. Two-sided P values were determined.
Two interim analyses were planned after approximately one third and
two thirds of the anticipated number of events had occurred. A Lan-DeMets
spending function approach with OBrien-Fleming stopping bounds (Appendix Table A1 [online-only]) was used to reject the null hypothesis (efficacy
boundary) and the alternative hypothesis (futility boundary). Statistical analyses were conducted by Pfizer.

RESULTS

Patients and Treatment Exposure

Between April 2008 and September 2009, 681 patients from 163
sites in 25 countries were randomly assigned and 671 received treatment (figitumumab group, 338; control group, 333; Fig 1). Demographic and baseline characteristics were well balanced between
treatment arms (Table 1). Patients median age was 62 years. Most of
the patients were men and most had stage IV disease. Patients in the
figitumumab and control arms received a median of four and five
cycles of chemotherapy, respectively (Table 2); 33% and 44%, respectively, completed six cycles of paclitaxel, and 34% and 46% completed
six cycles of carboplatin. Figitumumab-treated patients received a
median of four figitumumab cycles; 109 (32%) of 338 figitumumabtreated patients received four to six cycles, seven (2%) of 338 patients
received 17 cycles, and four (1%) of 338 received more than 20 cycles.
A total of 124 (37%) of 338 patients received figitumumab after
completing or discontinuing chemotherapy (median of two maintenance cycles). Of these, 87 (26%) of 338 patients received figitumumab maintenance after six cycles (maintenance therapy could start
earlier than cycle 6).
On DSMC advice, enrollment was suspended in September 2009
because of a higher number of serious adverse events (SAEs) and
deaths in the figitumumab arm. The study was permanently closed to
new accrual in December 2009, after the first interim analysis indicated that the addition of figitumumab was highly unlikely to meet the
primary end point of improving OS over chemotherapy alone.
Follow-up for OS continued until March 2011. The overall median
follow-up time was 23.1 months (Table 3).
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Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

Randomly assigned, stratified by previous adjuvant chemotherapy,

sex, and histology (squamous cell v combined large cell or adenosquamous)
(N = 681)

Control arm
Allocated to chemotherapy
Received chemotherapy
Did not receive chemotherapy

Figitumumab arm
Allocated to figitumumab plus chemotherapy
Received figitumumab plus chemotherapy
Did not receive figitumumab plus chemotherapy
Received only chemotherapy

(n = 342)
(n = 338)
(n = 3)
(n = 1)*

Receiving figitumumab at time of data cutoff

Receiving chemotherapy at time of data cutoff
Discontinued figitumumab
Death
AE related to figitumumab
AE unrelated to figitumumab
Global health deterioration
Lost to follow-up
Objective progression or relapse
Other
Protocol violation
Patient refusal unrelated to AE
Discontinued chemotherapy
Death
AE related to chemotherapy
AE unrelated to chemotherapy
Global health deterioration
Lost to follow-up
Objective progression or relapse
Other
Protocol violation
Patient refusal unrelated to AE
Completed chemotherapy

(n = 2)
(n = 0)
(n = 336)
(n = 43)
(n = 2 2 )
(n = 3 2 )
(n = 1 0 )
(n = 2)
(n = 170)
(n = 22)
(n = 1)
(n = 34)
(n = 209)
(n = 40)
(n = 29)
(n = 27)
(n = 9 )
(n = 2)
(n = 78)
(n = 5)
(n = 1)
(n = 1 8 )
(n = 129)

Receiving chemotherapy at time of data cutoff

Discontinued figitumumab
AE unrelated to figitumumab (patient was randomly
assigned to figitumumab arm but received only
paclitaxel and carboplatin)
Discontinued chemotherapy
Death
AE related to chemotherapy
AE unrelated to chemotherapy
Global health deterioration
Lost to follow-up
Objective progression or relapse
Other
Protocol violation
Patient refusal unrelated to AE
Completed chemotherapy

Analyzed for efficacy

Analyzed for safety
Adverse events
Laboratory data

(n = 342)

Analyzed for efficacy

Analyzed for safety
Adverse events
Laboratory data

Follow-up after data cutoff

Discontinued figitumumab
Objective progression and death
Transition to off-study, single-patient IND

(n = 338)
(n = 334)

(n = 339)
(n = 332)
(n = 7)

(n = 0)
(n = 1)
(n = 1)

(n = 186)
(n = 32)
(n = 31)
(n = 13)
(n = 10)
(n = 1)
(n = 81)
(n = 8)
(n = 1)
(n = 9)
(n = 147)

(n = 339)
(n = 333)
(n = 324)

(n = 4 )
(n = 2 )
(n = 1 )
(n = 1)

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

Efficacy
At the final analysis, 259 patients in the figitumumab arm and
251 in the control arm had died (Table 3). The median OS was 8.6
months (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). Respective 1-year survival rates were 34% and 39%. The effect of figitumumab was similar across all subgroups based on demographic or
other 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 were
33% (95% CI, 28 to 38) and 35% (95% CI, 29 to 40; Table 3).
Safety
Alopecia and nausea were the most common treatmentemergent (all-causality) adverse events (AEs) of any grade and
occurred in a similar number of patients in each arm (Table 4).
www.jco.org

Any-grade AEs that occurred more frequently in the figitumumab

arm included hyperglycemia, diarrhea, decreased appetite, vomiting,
and decreased weight. Grade 3/4 AEs that occurred more frequently in
the figitumumab arm included hyperglycemia, decreased appetite,
dehydration, diarrhea, fatigue, and nausea.
Treatment-emergent (all-causality) SAEs occurred in 66% of the
figitumumab arm and 51% of the control arm (P .01 by Fishers
exact test). Excluding disease progression, the most common SAEs
were pneumonia (6% v 4%, respectively), dehydration (4% v 1%),
asthenia (3% v 1%), and hyperglycemia (3% v 1%). The SAEs were
judged to have a reasonable possibility of being treatment-related in
22% and 12% of patients, respectively.
Nonprogression grade 5 AEs occurred in 13% of the figitumumab arm and 10% of the control arm (P .22). The most common grade 5 AEs in the figitumumab arm were pulmonary
hemorrhage and pneumonia (2% each; Appendix Table A2). Grade 5
AEs were considered to be treatment-related in 5% of the
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Langer et al

Table 1. Baseline Patient Characteristics

Figitumumab Arm
(n 342)
Characteristic
Sex
Male
Female
Age, years
Median
Range
Ethnicity
White
Asian
Black
Other
ECOG performance status
0
1
Not reported
Current disease stage
Stage IIIB
Stage IV
Not reported
Smoking status
Never smoked
Current smoker
Former smoker
Histology
Squamous cell
Large cell
Adenosquamous
Other
Prior treatments
Surgery
Radiation
Adjuvant chemotherapy

Control Arm
(n 339)

No. of
Patients

No. of
Patients

261
81

76
24

260
79

77
23

62
30-90

62
36-83

265
56
9
12

78
16
3
4

270
59
4
6

80
17
1
2

113
226
3

33
66
1

115
217
7

34
64
2

39
302
1

11
88
1

39
300
0

12
88

34
142
166

10
42
49

33
141
165

10
42
49

295
28
15
4

86
8
4
1

289
26
19
5

85
8
6
1

72
44
14

21
13
4

61
36
15

18
11
4

NOTE. Data are presented for all patients by randomized arm. The stratification
factors (histology, sex, and adjuvant chemotherapy) are presented as collected in the
case report forms rather than as collected by the randomization system.
Abbreviation: ECOG, Eastern Cooperative Oncology Group.

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

Systemic therapy included carboplatin/paclitaxel (n 3), cisplatin/vinorelbine (n 7), cisplatin/gemcitabine (n 4), carboplatin/gemcitabine (n 3),
cisplatin/etoposide (n 3), other regimens with carboplatin (n 3), other
regimens with cisplatin (n 4), and other nonplatinum regimens (n 2).

figitumumab arm and 1% of the control arm (P .01). With figitumumab, these grade 5 AEs included hemoptysis, pneumonia, unknown cause reported only as death, septic shock, cardiorespiratory
arrest, decrease of performance status, neutropenic sepsis, toxicity to
various agents, renal failure, hemorrhage, and hypovolemic shock
( 1% each). In the control arm, the grade 5 AEs included unknown
cause reported as death, pneumonia, septic shock, and dehydration
( 1% each).
Figitumumab was discontinued because of treatment-related
AEs in 7% of patients, and chemotherapy was discontinued for this
reason 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 total
IGF-1, a cutoff of 120 ng/mL was selected because it was associated
2062

2014 by American Society of Clinical Oncology

with the largest observed differences in treatment effect above and

below it. Baseline IGF-1 was not related to overall frequency or nature
of AEs. However, grade 5 AEs were more common among
figitumumab-treated patients with baseline IGF-1 levels less than 120
ng/mL (56%) than among those with baseline levels of 120 ng/mL or
higher (38%) and those in the control arm (37% and 36% in the low
and high IGF-1 groups, respectively). In the figitumumab arm, median OS for patients with low and high baseline IGF-1 was 7.0 months
and 10.4 months, respectively; in the control arm it was 10.1 and 9.4
months, respectively (Appendix Fig A1). For patients with high IGF-1,
there was no difference in OS between treatment groups (HR, 0.93;
P .67). For those patients with low IGF-1, OS was significantly
shorter in the figitumumab arm (HR, 1.37; P .01).
The rate of all-causality AEs did not vary markedly by baseline
HbA1c status, but the rate of grade 3/4 AEs for patients with no grade
5 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 baseline
HbA1c was 8.7 months in the figitumumab arm and 10.2 months in
the control arm (HR, 1.07; P .65). The respective values in patients
with 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 combining an IGF-1R inhibitor (figitumumab) with paclitaxel and carboplatin could improve OS versus chemotherapy alone as first-line
treatment for advanced nonadenocarcinoma NSCLC. When this trial
was initiated, IGF-1R was thought to play an important role in squamous cell histology NSCLC, an area of particular unmet need. Unexpectedly, adding figitumumab to chemotherapy proved deleterious.
The DSMC closed the study because of therapeutic futility and increased SAEs, including treatment-related deaths, in the figitumumab
arm. This outcome was disappointing given the originally reported
phase II ORR of 54% for combination therapy compared with 42% for
chemotherapy alone.8
The phase III study was designed and conducted in good faith
based on the aforementioned phase II trial findings in treatment-naive
advanced NSCLC. Following closure of the phase III trial, the phase II
data were retracted after a reanalysis revealed a lower ORR in both
treatment arms.8 In addition, median PFS no longer trended in favor
of figitumumab (4.5 months with figitumumab 20 mg/kg and 4.3
months with chemotherapy alone). The heightened toxicity of figitumumab in the phase III trial was not observed in the original phase I/II
trials in NSCLC, which enrolled more than 150 patients in total. In our
current study, the figitumumab combination failed to improve any
efficacy end points over chemotherapy alone. Overall survival, the
primary end point, was 8.6 months versus 9.8 months respectively.
The ORR with figitumumab (33%) was similar to that observed in the
phase II final analysis (37% in both the overall cohort [initially reported as 54%] and the nonadenocarcinoma cohort). Another advanced NSCLC trial, initiated after the phase III was underway, used
the same treatment in combination with figitumumab and the ORR
was 39%.12
Subgroup analysis suggests that figitumumab safety and tolerability were poorer in patients with low baseline IGF-1 ( 120 ng/mL)
compared with those with high IGF-1 ( 120 ng/mL), particularly
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Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

Table 2. Study Drug Exposure

Control Arm (n 333)

Figitumumab Arm (n 338)

Figitumumab
Treatment Delivery
Cycles started
Median
Range
Duration of treatment, weeks
Median
Range
Patients with at least one dose reduction
Patients with at least one dose delay

No. of
Patients

Paclitaxel
No. of
Patients

4
1-52

Carboplatin
%

4
1-6

12.1
0.1-161.3
30
9
76
22

No. of
Patients

Paclitaxel
No. of
Patients

4
1-6

10.2
0.1-20.1
55
16
52
15

10.2
0.1-20.1
51
15
54
16

Carboplatin
No. of
Patients

5
1-6

5
1-6

12.3
0.1-23

12.6
0.1-23

52
42

16
13

44
42

13
13

Abbreviation: IND, investigational new drug.

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.

with respect to grade 5 AEs. Consequently, in the figitumumab arm,

median OS was shorter in patients with low IGF-1 compared with
those with high IGF-1 and was significantly shorter compared with
control patients who had low IGF-1 (HR, 1.37, P .01). Although
additional studies are required, these data suggest that low baseline
total IGF-1 may be a safety biomarker that identifies a subset of
patients for whom IGF-1R inhibition is particularly harmful. In a
phase I study of ganitumab, a human monoclonal antibody against
IGF-1R, treatment transiently increased IGF-1.13 Low baseline IGF-1
may indicate an inability to mount a compensatory increase in IGF-1
and greater likelihood of AEs.

Hyperglycemia of any grade occurred more frequently in the figitumumab arm than in the control arm (23% v 5%), as did grade 3/4
hyperglycemia(12%v1%).Hyperglycemiawasoneofthemostcommon
SAEs, with greater frequency in the figitumumab arm than in the control
arm. Hyperglycemia is likely a class effect stemming from impaired homeostatic control of glucose metabolism as a consequence of IGF-1R
inhibition.14 Hyperglycemia was rarely severe and was usually manageable with agents such as metformin, but could have contributed in subtle
ways to increased toxicity in the figitumumab arm.
Baseline HbA1c was not a strong biosafety marker, although
grade 3/4 AEs were slightly more common in patients with levels

Table 3. Efficacy Results

Figitumumab Arm (n 342)
End Point

No. of Patients

Median follow-up time, months

Overall survival (primary end point)
Patient deaths
Median, months
95% CI
One-year survival
Progression-free survival (investigator assessment)
Events
Objective progression
Death without objective progression
Median, months
95% CI
Best overall response (investigator assessment)
Complete response
Partial response
Stable disease
ORR
95% exact CI

Control Arm (n 339)

No. of Patients

23.3

Hazard Ratio

22.8
.06

259

76

251

8.6
7.4 to 9.3

74
9.8
8.6 to 10.9

34

1.18
0.99 to 1.40
39
.27

261
206
55

76
60
16

241
197
44

4.7
4.2 to 5.4

71
58
13
4.6
4.2 to 5.4

1.10
0.93 to 1.32
.68

2
111
126

0.6
32
37
33
28 to 38

3
114
120

0.9
34
35
35
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.

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Langer et al

Overall Survival (%)

Figitumumab
8.6 (7.4 to 9.3)

Median OS,
months (95% CI)
HR (95% CI)
P

100

80

Control
9.8 (8.6 to 10.9)

Progression-Free Survival (%)

1.18 (0.99 to 1.40)

.06

60

Figitumumab
Control

40

20

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

80

342 279 221 174 131 100 81

339 294 253 199 154 118 103

71
89

48
59

Control
4.6 (4.2 to 5.4)

1.10 (0.93 to 1.32)

.27

60

Figitumumab
Control

40

20

Time (months)
No. at risk
Figitumumab
Control

Figitumumab
4.7 (4.2 to 5.4)

Median PFS,
months (95% CI)
HR (95% CI)
P

100

10

12

14

16 18 20 22 24 26

Time (months)
35
39

15
15

4
3

1
0

No. at risk
Figitumumab
Control

342
339

231
236

127
114

38
47

17
21

8
12

6
8

2
4

2
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.

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 figitumumab
arm than in the control arm, regardless of baseline HbA1c (HR: patients
with low HbA1c, 1.07; patients with high levels, 1.26).
Beyond the failure to demonstrate efficacy, a worrisome finding
of this study was the relatively high frequency of treatment-related
deaths associated with figitumumab (5%), an effect that was not
detected in the phase II study. There are a number of potential reasons
that may provide insight for future clinical trial design, dosing levels,
and anticipation and management of toxicities, particularly where
combination regimens are involved. First, only about half of the 98
patients randomly assigned to figitumumab in the phase II trial received the 20 mg/kg dose, a sample that might have been too small to

Factor

HR

95% CI

Overall

681

1.18

0.99 to 1.40

Sex
Female
Male

159
522

1.09
1.20

0.75 to 1.60
0.99 to 1.46

ECOG PS
0
1

228
443

0.99
1.21

0.73 to 1.34
0.98 to 1.50

Nonsquamous
Yes
No

79
602

1.18
1.16

0.71 to 1.96
0.96 to 1.39

Smoker
Never
Current

67
283

1.46
1.11

0.83 to 2.57
0.85 to 1.45

Stage
IIIB
IV

78
602

1.28
1.16

0.75 to 2.19
0.97 to 1.40

HbA1c
< 5.7%
5.7%

267
371

1.07
1.26

0.81 to 1.41
1.00 to 1.60

Natural log HR (95% CI)

Fig 3. Forest plot of overall survival by

selected baseline characteristics. ECOG
PS, Eastern Cooperative Oncology Group
performance status; HbA1c, glycosylated
hemoglobin; HR, hazard ratio.

0.6 0.4 0.2

Favors figitumumab

2064

2014 by American Society of Clinical Oncology

detect safety signals. However, the incidence of grade 3/4 hyperglycemia was greater in the phase II study (20%) than in our current study
(12%).8 Second, there were inherent differences in the patient populations. For example, the phase III study enrolled patients with predominantly squamous cell histology and far more current smokers
(42% v 13%) than the phase II study. Hence, the phase III patient
population may have had more attendant comorbidities (latent or
overt), which might have rendered them more vulnerable to toxicity
or intercurrent grade 5 events. Third, the phase II trial was conducted
almost exclusively at tertiary referral centers, which may have led to
subtle differences in the types of patients enrolled and how they were
managed. As several study centers in the phase III trial enrolled only a
few patients each, the investigators may have initially lacked

0.2 0.4 0.6 0.8 1.0 1.2

Favors control

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135
5
12
23
19
13
15
9
35
20
23
5
11
13
17
3
8
2
9
17
1
0
3
1
2
1
0
8
3
2
1

1
1
1
1

40
1
4
7
6
4
4
3
10
6
7
1
3
4
5
1
2
1
3
5
1

Control Arm
(n 333)

106
5
2
7
11
3
20
3
2
31
15
4
1
14
15
2
15
0
6
1
0
0
1
2
2
1
0
14
12

No. of Patients

Grade 3

4
4

1
1
1
1

2
1

32
2
1
2
3
1
6
1
1
9
5
1
1
4
5
1
5

%
103
1
0
0
2
2
4
0
7
45
4
0
0
0
10
0
4
0
0
2
0
0
0
0
0
0
0
4
3

No. of Patients

1
1

2
13
1

1
1
1

30
1

Control Arm
(n 333)

91
2
0
0
2
0
0
0
0
33
1
0
0
2
5
0
3
0
0
0
0
0
0
0
1
0
0
4
6

No. of Patients

Grade 4

Figitumumab Arm
(n 338)

1
2

1
2

10
1

27
1

%
319
138
133
130
112
101
95
85
79
77
75
66
66
62
61
60
60
47
40
39
39
38
38
37
34
29
29
19
7

No. of Patients

%
94
41
39
38
33
30
28
25
23
23
22
20
20
18
18
18
18
14
12
12
12
11
11
11
10
9
9
6
2

Control Arm
(n 333)

306
146
103
75
86
45
88
47
17
78
61
60
29
57
52
61
68
57
50
12
44
32
26
22
24
35
35
34
18

No. of Patients

Any Grade
Figitumumab Arm
(n 338)

%
92
44
31
23
26
14
26
14
5
23
18
18
9
17
16
18
20
17
15
4
13
10
8
7
7
11
11
10
5

NOTE. A total of 10 randomly assigned patients did not receive any study treatment and were not included in the safety analyses. One patient randomly assigned to the figitumumab arm received only paclitaxel
and carboplatin and was included in the control arm in this analysis.

No. of Patients

Adverse Event

Any adverse event ( grade 5)

Alopecia
Nausea
Decreased appetite
Fatigue
Diarrhea
Anemia
Vomiting
Hyperglycemia
Neutropenia
Asthenia
Cough
Weight decreased
Peripheral neuropathy
Thrombocytopenia
Constipation
Dyspnea
Arthralgia
Peripheral sensory neuropathy
Dehydration
Myalgia
Dizziness
Hemoptysis
Headache
Pain in extremities
Paresthesia
Pyrexia
Leukopenia
Febrile neutropenia

Figitumumab Arm
(n 338)

Table 4. Most Common Treatment-Emergent (all-causality) Adverse Events for 10% of Patients (any grade) or 5% of Patients (grade 3 or 4)

Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

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2065

Langer et al

experience in managing figitumumab complications such as hyperglycemia and dehydration.

Furthermore, although patient and disease characteristics were
well balanced between arms, we cannot exclude the possibility that
minor baseline demographic imbalances in this study might have
produced inconsistent results. Although figitumumab was combined
with the same full-dose chemotherapy doublet as in the phase II study,
lower doses of the doublet might have improved the tolerability of the
combination. Finally, the difference in the incidence of treatmentrelated grade 5 AEs between the figitumumab and control arms (5% v
1%), may indicate that signaling through IGF-1R and its attendant
pathways is critical in maintaining homeostasis, such that inhibition
significantly disrupts the insulin receptor/IGF-1R/growth-hormone
signaling axis. This concern may be heightened in patients with advanced squamous cell NSCLC, who often have multiple comorbidities
and who constituted the vast majority of participants in this trial. Our
experience highlights the potential discrepancies between phase II and
phase III trials in both safety and efficacy, and underscores the importance of identifying a priori the patient population(s) most likely to
benefit from therapy. However, as seen in our current study, inclusion
of such a selected patient group (predominantly squamous cell
NSCLC) does not guarantee improved safety or efficacy.
In conclusion, though the phase II trial suggested an ORR advantage for adding figitumumab to standard chemotherapy in advanced
NSCLC, our current phase III study involving nonadenocarcinoma
patients failed to show any benefit and unexpectedly suggested a
possible detrimental effect. This may be a class effect and should be
assessed in current and future trials examining IGF-1R inhibitors.
Further clinical development of figitumumab is not being pursued.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an authors immediate family member(s) indicated a

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financial or other interest that is relevant to the subject matter under

consideration in this article. Certain relationships marked with a U
are those for which no compensation was received; those relationships
marked with a C were compensated. For a detailed description of the
disclosure categories, or for more information about ASCOs conflict of
interest policy, please refer to the Author Disclosure Declaration and the
Disclosures of Potential Conflicts of Interest section in Information
for 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), Eisai (C), Bristol-Myers
Squibb (C), BeiGene (C), AVEO Pharmaceuticals (C), Pfizer (C), Taiho
Pharmaceutical (C), Boehringer Ingleheim (C), GlaxoSmithKline (C)
Stock Ownership: Rebecca J. Benner, Pfizer; Judith R. Scranton, Pfizer
Honoraria: Silvia Novello, Eli Lilly, Boehringer, Roche; Keunchil Park,
Eli Lilly, Roche, AstraZeneca; Tony Mok, AstraZeneca, Roche, Eli Lilly,
Merck Serono, Eisai, Bristol-Myers Squibb, BeiGene, AVEO
Pharmaceuticals, 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 Jassem
Provision of study materials or patients: Corey J. Langer, Silvia Novello,
Keunchil Park, Daniel D. Karp
Collection and assembly of data: Keunchil Park, Maciej Krzakowski,
Tony Mok, Rebecca J. Benner, Judith R. Scranton, Anthony J. Olszanski
Data 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 Jassem
Manuscript writing: All authors
Final approval of manuscript: All authors

6. Haluska P, Shaw HM, Batzel GN, et al: Phase

I dose escalation study of the anti insulin-like growth
factor-I receptor monoclonal antibody CP-751,871 in
patients with refractory solid tumors. Clin Cancer
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7. Lacy MQ, Alsina M, Fonseca R, et al: Phase
I, pharmacokinetic and pharmacodynamic study of
the anti-insulinlike growth factor type 1 receptor
monoclonal antibody CP-751,871 in patients with
multiple myeloma. J Clin Oncol 26:3196-3203,
2008
8. Karp DD, Paz-Ares LG, Novello S, et al: Retraction: Phase II study of the antiinsulin-like
growth factor type 1 receptor antibody CP-751,871
in combination with paclitaxel and carboplatin in
previously untreated, locally advanced, or metastatic
non-small-cell lung cancer. J Clin Oncol 30:4179,
2012
9. American Joint Committee on Cancer: AJCC
Cancer Staging Manual (ed 6). New York, NY,
Springer, 2002, pp 167-181
10. Therasse P, Arbuck SG, Eisenhauer EA, et
al: New guidelines to evaluate the response to
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for Research and Treatment of Cancer, National

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11. Sobin LH, Wittekind C (eds): International
Union Against Cancer (UICC), TNM Classification of
Malignant Tumours (ed 6). New York, NY, WileyLiss, 2002
12. Goto Y, Sekine I, Tanioka M, et al: Figitumumab combined with carboplatin and paclitaxel in
treatment-nave Japanese patients with advanced
non-small cell lung cancer. Invest New Drugs 30:
1548-1556, 2012
13. Murakami H, Doi T, Yamamoto N, et al: Phase
1 study of ganitumab (AMG 479), a fully human
monoclonal antibody against the insulin-like growth
factor receptor type I (IGF1R), in Japanese patients
with advanced solid tumors. Cancer Chemother
Pharmacol 70:407-414, 2012
14. Gualberto A, Pollak M: Emerging role of
insulin-like growth factor receptor inhibitors in oncology: Early clinical trial results and future directions.
Oncogene 28:3009-3021, 2009

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Figitumumab Alone or With Paclitaxel and Carboplatin in NSCLC

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 support
was 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, Mansoor
Noorali Saleh, Lee C. Drinkard, MD, Haralambos E. Raftopoulos, MD, Isidoro Barneto Aranda, Luis Alfonso Gurpide Ayarra, Pilar Lopez
Criado, Felipe Cardenal Alemany, Marta Lopez-Brea Piqueras, Amelia Insa Molla, Roy Timothy Webb, MD, Maciej Krzakowski, PhD, Kazimierz
Roszkowski-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 Yousif
Gabrail, 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, Everett
Emmett 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, Peter
Berzinec, 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, Michael
Vaslamatzis, MD, Stephen Lloyd Graziano, MD, Ping Fai So, MD, Frank Griesinger, MD, PhD, Martin Reck, MD, Martin Sebastian, MD, Sylvia
Guetz, 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, Janak
K. Choksi, MD, Troy Hancil Guthrie Jr, MD, Sing Hung Lo, MD, Stephen Begbie, MD, Haluk Tezcan, MD, Susan Amy Sajer, MD, David William
Zenk, MD, Samuel Spence McCachren Jr, MD, Stephen Daniel Myers, MD, Mark Ramsey Hutchins, MD, Richard Scott Siegel, Eric Powell
Lester, 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, Lee
M. Zehngebot, MD, Hector A. Velez Cortes, Stacey Kay Knox, MD, Sergey V. Orlov, MD, Mikhail V. Kopp, MD, Bruno Coudert, MD, Radj
Gervais, MD, Robert Harold Gersh, MD, Michael Alan Savin, MD, Rama Koteswararoa Koya, MD, Marcus Alan Neubauer, MD, Alexander Illya
Spira, MD, Jacek Jassem, PhD, Edward Thomas OBrien, MD, Linda L. Ferris, MD, Richard C. Frank, MD, Beth Ann Hellerstedt, MD, Donald
Anthony Richards, MD, Takeshi Horai, MD, Noboru Yamamoto, MD, Hiroshi Isobe, MD, Miyako Satouchi, MD, Shinji Atagi, MD, Isamu
Okamoto, MD, Toshiyuki Sawa, MD, Hiroaki Okamoto, MD, Koji Takeda, MD, Tetsu Shinkai, MD, Richard Wilhelm Eek, MD, Valentina Ilieva
Tzekova, PhD, Susan Fox, MD, Jan Novotny, MD, Maurice Perol, MD, Masaaki Kawahara, MD, Pilar Lopez Criado, Raul Manuel Marquez
Vazquez, Susanna Stoll, MD, Alessandra Curioni, MD, Ismail Oguz Kara, PhD, Sinan Yavuz, MD, PhD, Tarek Mouris Mekhail, MD, Athanassios
Argiris, 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

Analysis

No. of
Events

Plan for first interim analysis

Plan for second interim analysis
Plan for final analysis
Computed boundaries for actual first interim analysis
Observed results for first interim analysis

216
433
649
225
225

Efficacy Boundaries for

Rejecting the Null Hypothesis

Futility Boundaries for Rejecting

the Alternative Hypothesis

Z Score

Hazard Ratio

Z Score

Hazard Ratio

3.710
2.511
1.993
3.632

0.603
0.785
0.855
0.616

0.695
1.003

1.10
0.908

0.595
1.407

1.083
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 on
the z score boundaries.
Based on interim data.

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Langer et al

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

Figitumumab Arm (n 338)

Control Arm (n 333)

Adverse Event

No. of Patients

No. of Patients

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

43
7
7
5
4
3
1
2
2
0
0
2
2
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0

13
2
2
1
1
1
1
1
1

32
4
3
2
1
3
3
1
1
3
2
0
0
1
1
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1

10
1
1
1
1
1
1
1
1
1
1

1
1
1
1
1
1
1
1
1
1
1
1
1
1

1
1

1
1
1
1
1
1
1

P .22 by two-sided Fishers exact test. Some patients had more than one grade 5 adverse event.

Overall Survival (%)

100

Median OS,
months (95% CI)
HR (95% CI)
P

80

Figitumumab
(n = 192)
7.0 (5.8 to 8.2)

Control
(n = 182)
10.1 (8.0 to 11.4)

1.37 (1.09 to 1.73)

.01

60

Figitumumab
Control

40

20

B
100

Overall Survival (%)

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

Median OS,
months (95% CI)
HR (95% CI)
P

80

193 153 116 86

182 157 138 108

65
88

52
67

41
60

36
51

19
30

Control
(n = 96)
9.4 (8.6 to 11.1)

0.93 (0.67 to 1.29)

.67

60

Figitumumab
Control

40

20

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

Time (months)
No. at risk
Figitumumab
Control

Figitumumab
(n = 120)
10.4 (9.0 to 12.0)

Time (months)
13
21

6
6

0
2

No. at risk
Figitumumab
Control

120 100
96 85

82
72

73
57

56
40

42
33

36
27

31
23

26
16

19
10

8
5

4
1

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 baseline
IGF-1 120 ng/mL. HR, hazard ratio.

2014 by American Society of Clinical Oncology

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