Randomized, phase III trial of figitumumab
in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer
G. V. Scagliotti1*, I. Bondarenko2, F. Blackhall3, F. Barlesi4, T.-C. Hsia5, J. Jassem6, J. Milanowski7,
S. Popat8, J. M. Sanchez-Torres9, S. Novello1, R. J. Benner10, S. Green10, K. Molpus10,
J.-C. Soria11 & F. A. Shepherd12
1Department of Oncology, University of Turin, Orbassano, Turin, Italy; 2Department of Oncology, Dnepropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital #4, Dnepropetrovsk, Ukraine; 3Manchester Cancer Research Centre Lung Group, Manchester University and Christie Hospital NHS Foundation Trust,
Manchester,
UK; 4Department of Multidisciplinary Oncology and Therapeutic Innovations, Aix Marseille University—Assistance Publique Hôpitaux de Marseille, Marseille, France; 5Department of Internal Medicine, China Medical University Hospital and China Medical University, Taichung, Taiwan; 6Department of Oncology and Radiotherapy, Medical
University of Gdansk, Gdansk; 7Department of Pneumology, Oncology and
Allergology, Medical University of Lublin, Lublin, Poland; 8Lung Unit, Royal Marsden Hospital,
London, UK; 9Department of Medical Oncology, Hospital de la Princesa, Madrid, Spain; 10Department of Pfizer Oncology, Pfizer, Inc., Groton, USA; 11Department of Clinical and Biological Sciences, Institut de Cancérologie Gustave Roussy and INSERM Unit 981, Villejuif, France; 12Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Ontario, Canada
Received 17 June 2014; revised 26 September 2014; accepted 30 September 2014 Background: Figitumumab (CP-751,871) is a fully human IgG2 monoclonal antibody that inhibits the insulin-like growth
factor 1 receptor. This multicenter, randomized, phase III study investigated the efficacy of figitumumab plus erlotinib compared
with erlotinib alone in patients with pretreated, nonsmall-cell lung cancer (NSCLC). Patients and methods: Patients (stage IIIB/IV or recurrent disease with
nonadenocarcinoma histology) who had previously
received at least one platinum-based regimen were randomized to receive open-label figitumumab (20 mg/kg) plus
overall survival (OS).
Results: Of 583 patients randomized, 579 received treatment. The study was closed early by an independent data
safety monitoring committee due to results crossing the prespecified futility boundary. At the final analysis, median OS
was 5.7 months for figitumumab plus erlotinib and 6.2 months for erlotinib alone [hazard ratio (HR) 1.09; 95% confidence
interval (CI) 0.91–1.31; P = 0.35]. Median progression-free survival was 2.1 months for figitumumab plus erlotinib and 2.6
months for erlotinib alone (HR 1.08; 95% CI 0.90–1.29; P = 0.43). Treatment-related nonfatal serious adverse events occurred
in 18% and 5% of patients in the figitumumab arm or erlotinib alone arm, respectively. There were nine treatmentrelated
deaths (three related to both drugs, four related to erlotinib alone and two related to figitumumab).
Conclusions: The addition of figitumumab to erlotinib did not improve OS in patients with advanced, pretreated, nonadenocarcinoma
NSCLC. Clinical development of figitumumab has been discontinued. Clinical Trial ID: NCT00673049.
Key words: figitumumab, erlotinib, nonsmall-cell lung cancer introduction
Most patients with advanced nonsmall-cell lung cancer (NSCLC) and activating mutations in the epidermal growth factor receptor (EGFR) gene respond initially to EGFR tyrosine kinase inhibitors (TKIs), but invariably become resistant over time. Sensitivity loss may involve signaling between EGFR and the insulin-like growth factor 1 receptor (1R) [1, 2]. Targeting both EGFR and IGF-1R delays or prevents resistance to EGFR TKIs in various cancer cells [2, 3], enhances antiproliferative activity against breast cancer and malignant glioma cells [4, 5] and inhibits tumor growth in NSCLC xenograft models [6]. In EGFR-overexpressing NSCLC cells, IGF-1R inhibition abolishes erlotinib resistance, reduces proliferation and promotes apoptosis [7]. These data provide a strong rationale for combining agents that target EGFR and IGF-1R against NSCLC.
*Correspondence to: Prof. Giorgio V. Scagliotti, Department of Oncology, University of
Orbassano, Turin, Italy. Tel: +39-11-9026-414; Fax: +39-11-9015-184; E-mail: giorgio. [email protected]
original articles
original articles Annals of Oncology 26: 497–504, 2015 doi:10.1093/annonc/mdu517
Published online 13 November 2014
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]. Downloaded from http://annonc.oxfordjournals.org/ by guest on May 12, 2015 Figitumumab (CP-751,871) is a fully human IgG2 monoclonal
antibody inhibiting IGF-1R. In phase I studies, it was well tolerated alone or with chemotherapy [8, 9]. A phase II study suggested activity in combination with paclitaxel and carboplatin against NSCLC, particularly in squamous cell histology [10].
However, corrected data ( published 2012) showed it was less effective than previously reported [11].
This prospective, randomized, phase III study was initiated in 2008 to compare overall survival (OS) with figitumumab plus erlotinib to erlotinib alone in pretreated patients with advanced NSCLC. Based on the original analysis of the phase II study [10], the population was limited to nonadenocarcinoma NSCLC.
methods patients
Eligible patients were ≥18 years old, had histologically or cytologically confirmed advanced NSCLC and stage IIIB, stage IV or recurrent disease.
Patients had primary histology of predominantly squamous cell, large cell or adenosquamous carcinoma and had previously received ≥1 platinum-based regimen. Patients aged ≥70 years were eligible if they had received ≥1 singleagent therapy. At least 1 and 2 weeks, respectively, must have elapsed since
the last radiotherapy or systemic therapy, with all acute toxicities resolved to National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI CTCAE v3.0) grade ≤1. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) [12], and adequate organ function. Exclusion criteria included uncontrolled hypertension or diabetes [defined as glycosylated hemoglobin (HbA1c) level
>8%], symptomatic brain metastases, other active malignancies, pregnancy or breast-feeding. A protocol amendment limited enrollment to patients
with HbA1c <5.7% to reduce the risk of hyperglycemia, but was not implemented fully before study termination. Anticancer therapies for the primary
diagnosis other than study treatment were not allowed. Medications for best supportive care and other concomitant systemic therapies were permitted, including insulin and other antidiabetic agents.
The study was conducted in accordance with the International
Conference on Harmonization Good Clinical Practice guidelines, the declaration of Helsinki, and applicable local requirements/laws. Approval from the
institutional review board or independent ethics committee was obtained for each center. All patients provided written informed consent.
study design and treatment
Patients were randomized 1 : 1 to receive open-label figitumumab plus erlotinib (investigational arm) or erlotinib alone (control arm). Randomization
was stratified by gender, ECOG performance status (0/1 versus 2) and region (United States/Canada versus Europe versus rest of the world).
The primary end point was OS (the time from randomization to death from any cause). Secondary end points included progression-free survival (PFS), tumor response (RECIST v1.0; complete plus partial responses) and safety. All patients received erlotinib 150 mg/day ≥1 h before or 2 h after food. In the investigational arm, patients received figitumumab 20 mg/kg i.v. on
day 1 of each 3-week cycle with an additional dose on day 2 of cycle 1 to expedite steady-state drug levels. Treatment continued until disease progression,
unmanageable toxicity or 17 cycles (longer if the investigator and
sponsor considered that it was providing clinical benefit). Patients in the control arm who discontinued erlotinib because of disease progression could receive figitumumab alone (labelled as ‘crossover’), as phase I studies in other malignancies suggested possible benefits of monotherapy with
acceptable toxicity [9, 13]. Patients in the investigational arm who discontinued erlotinib could continue on single-agent figitumumab and vice versa
until progression. study procedures
Tumors were assessed at 6, 9, 12, 15 and 18 weeks after randomization and every 6 weeks thereafter, with objective responses confirmed ≥4 weeks after initial observation. Off-treatment tumor assessments were to be carried out at least once every 8 weeks until objective disease progression. After progression, patients were to be followed for survival monthly by telephone until
death or ∼14 months after accrual completion. Adverse events (AEs) were graded using NCI CTCAE v3.0 and collected until 150 days after the last
dose of study drugs, withdrawal of consent or initiation of subsequent anticancer therapy. Clinical and laboratory assessments occurred at baseline, day
1 of each cycle and end of treatment. statistical analysis
The primary OS analysis was a 0.024-level stratified log-rank test, with one interim analysis. The primary PFS analysis was a 0.001-level stratified logrank test with no interim. Statistical analyses were undertaken by Pfizer, the study sponsor. The supplementary Material, available at Annals of Oncology online, provides additional detail.
results
patients and treatment exposure
Between 5 June 2008 and 2 March 2010, 583 patients were randomized and 579 received treatment (figitumumab plus erlotinib:
n = 289; erlotinib alone: n = 290; Figure 1). Baseline
characteristics generally were well balanced between treatments (Table 1). Fewer than 10% of patients in each arm received ≥3 prior treatment regimens.
Enrollment was closed permanently in March 2010 by Data Safety Monitoring Committee (DSMC) recommendation
because the results of the interim analysis crossed the prespecified futility boundary, indicating that the addition of figitumumab to erlotinib did not improve OS. Patients could continue study treatment if considered in their best interest, and if the local authorities permitted, but figitumumab was no longer offered to patients who progressed on single-agent erlotinib. Follow-up for survival continued until 31 March 2011. Three
patients continued on treatment after this date (two in the figitumumab arm and one in the control arm) and are shown here
as ongoing; additionally six patients were ongoing in safety or long-term follow-up.
Patients in the figitumumab arm received a median of three cycles of figitumumab and two cycles of erlotinib (range 1–37 for both), and patients in the control arm received a median of four cycles of erlotinib (range 1–26). In the figitumumab arm, figitumumab doses were delayed in 12% of patients and reduced in 5%; erlotinib doses were reduced in 21%. In the control arm,
14% of patients had dose reductions; 29% crossed over to figitumumab after progression and completed a median of two
cycles; 2% of these patients had dose reductions. efficacy
At the final analysis, 483 patients had died (241 figitumumab and 242 control). Median OS was 5.7 versus 6.2 months [HR
| Scagliotti et al. Volume 26 | No. 3 | March 2015
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Downloaded from http://annonc.oxfordjournals.org/ by guest on May 12, 2015 1.09; 95% confidence interval (CI) 0.91–1.31; P = 0.35;
Figure 2A]. No benefit of figitumumab on OS was demonstrated by gender, ECOG performance status, histology, smoking status, HbA1c and regional subset (supplementary Figure S1, available at Annals of Oncology online). Median OS in patients with baseline HbA1c <5.7% was 6.9 months with figitumumab and 6.5
months with erlotinib alone; for patients with HbA1c ≥5.7%, median OS was 4.6 and 6.1 months, respectively. Median PFS was 2.1 months with figitumumab and 2.6 months with erlotinib alone (HR 1.08; 95% CI 0.90–1.29; P = 0.43; Figure 2B).
Objective response rate was 5.5% versus 3.8% (P = 0.34; Table 2).
safety
The most common all-causality AEs in both study arms were rash, diarrhea and decreased appetite (Table 3). Grade 3/4 AEs that differed most between study arms included fatigue, asthenia, decreased appetite and dehydration. Any-grade rash occurred in a similar number of patients in each arm and was
rarely severe. Hyperglycemia occurred more frequently with figitumumab but was mostly mild in severity. Antidiabetic agent
use increased in figitumumab-treated patients from 8% before enrollment to 19% on-study (versus 10% at baseline and 11% on control treatment). The incidence of most AEs was similar in patients with baseline HbA1c <5.7% and ≥5.7% (supplementary Assigned to study treatment (n=583)
Randomized to figitumumab + erlotinib Not treated
Treated with erlotinib alone in error Treated with figitumumab + erlotinib
Ongoing at cut-off date (n=293) (n=3) (n=1) (n=289) (n=7) (n=290) (n=1) (n=290)a (n=1) (n=83) (n=1) (n=1) (n=209) (n=18) (n=7) (n=7) (n=8) (n=15) (n=23) (n=167) (n=5) (n=18) (n=2) (n=82) (n=71) (n=3) (n=3) (n=5) (n=0) (n=83) (n=83) (n=83) (n=1) (n=290) (n=290) (n=14) (n=206)
(n=40) (n=20) (n=26) (n=25) (n=141) (n=9) (n=26) (n=40) (n=24) (n=23) (n=30) (n=139) (n=7) (n=23) (n=282) (n=234) (n=9) (n=25) (n=1) (n=293) (n=289) (n=13)
Reasons for figitumumab discontinuation Reasons for study discontinuation
Patient died
AE related to figitumumab AE unrelated to figitumumab
Global deterioration of health status Objective progression or relapse Other
Patient refusal
Reasons for erlotinib discontinuation Patient died
AE related to erlotinib AE unrelated to erlotinib
Objective progression or relapse Other
Patient refusal Death
Lost to follow-up
No longer willing to participate Other
Study terminated by sponsor
(patients still alive when data collection ceased in March 2011)
Analyzed for efficacy Analyzed for safety
Randomized to erlotinib alone Not treated
Treated with erlotinib alone Ongoing at cut-off date Crossover
aIncludes 1 patient randomized to figitumumab arm treated with erlotinib alone in error
Reasons for figitumumab discontinuation Other
Reasons for erlotinib discontinuation Patient died
AE related to erlotinib AE unrelated to erlotinib
Global deterioration of health status Lost to follow-up
Objective progression or relapse Other
Patient refusal
Reasons for study discontinuation Death
Lost to follow-up
No longer willing to participate Other
Study terminated by sponsor Analyzed for efficacy
Analyzed for safety Analyzed for efficacy Analyzed for safety
Figitumumab after progression on erlotinib Treated with figitumumab alone
Ongoing at cut-off date
Reasons for study discontinuation Death
Lost to follow-up
No longer willing to participate ceased in March 2011)
(patients still alive when data collection Study terminated by sponsor
ceased in March 2011)
(patients still alive when data collection
Figure 1. Patient disposition. AE, adverse event.
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Downloaded from http://annonc.oxfordjournals.org/ by guest on May 12, 2015 Tables S2 and 3, available at Annals of Oncology online), except
hyperglycemia, which was more common in the latter. Five patients discontinued figitumumab due to hyperglycemia and three of them also discontinued erlotinib.
Among crossover patients, all-causality AEs were generally similar to those in the figitumumab plus erlotinib arm, with the exception of gastrointestinal events, which were somewhat less frequent with single-agent figitumumab (Table 3). The most frequent treatment-related AEs with single-agent figitumumab
were rash (40%), decreased appetite (18%), asthenia (14%) and
hyperglycemia (13%). One crossover patient discontinued figitumumab due to hyperglycemia.
The most common (all-causality) serious AEs (SAEs) in the figitumumab and erlotinib arms, respectively, were: dehydration (5% versus 2%), diarrhea (4% versus 1%), dyspnea (4% versus 1%) and pneumonia (3% versus 4%). Nonfatal treatment-related SAEs occurred in 18% versus 5%, respectively.
Nine deaths were considered treatment-related; five in the figitumumab arm, of which three were related to both drugs (pulmonary hemorrhage, cardiac arrest, acute respiratory distress syndrome) and two to erlotinib only (intestinal ischemia,
were related to erlotinib (respiratory failure, pneumonia Table 1. Patient characteristics at baseline (all randomized, as randomized)
Patient characteristic Figitumumab arm (N = 293) Control arm (N = 290) No. % No. % Gender, male 228 78 225 78 Age, years Median 62.0 62.0 Range 33–85 29–87 Ethnicity White 249 85 238 82 Black 7 2 7 2 Asian 21 7 23 8 Other/not specified 16 5 22 8 Region United States/Canada 50 17 49 17 European Union 155 53 152 52 Rest ofWorld 88 30 89 31 ECOG performance status 0–1 237 81 236 82 2 56 19 54 19 Disease stage Stage IIIB 62 21 55 19 Stage IV 230 78 235 81 Not reported 1 <1.0 0 0 Smoking status Never smoked 16 6 26 9 Current smoker 94 32 101 35 Ex-smokera 183 63 163 56 Histology Squamous cell 263 90 263 91 Large cell 20 7 19 7 Adenosquamous 9 3 8 3 Not reported 1 <1.0 0 0 Prior treatments
Surgery 86 30 93 32 Radiation 129 44 137 47 Systemic 292 100 290 100
aPatients who had not had a cigarette within the last year or longer. ECOG, Eastern Cooperative Oncology Group.
0 10 20 30 40 0 10 20 30 40 50 60 70 80 90 100 Survival probability (%) Survival time (months)
Randomized group Figitumumab Censored figitumumab Control Figitumumab Figitumumab Control Control Censored control
Number of patients at risk 293 290 206 237 146 163 102 109 74 79 58
58 45 35 33 27 22 23 13 12 7 7 3 3 0 1 0
Median OS, months (95% Cl) 5.7 (4.8, 6.7) 6.2 (5.8, 7.2) Hazard ratio (95% Cl) P value 1.09 (0.91–1.31) 0.35 0 10 20 30 0 10 20 30 40 50 60 70 80 90 100
Progression-free survival probability (%) Survival time (months)
Randomized group Figitumumab Censored figitumumab Control
Figitumumab Figitumumab
Control Control
Censored control
Number of patients at risk 293 290 108 130 44 61 20 32 13 16 9 10 5 5 5 3 3 1 2 1 1 1 0 1 0 Median PFS, months (95% Cl) 2.1 (1.9, 2.6) 2.6 (2.1, 2.8) Hazard ratio (95% Cl) P value 1.08 (0.90–1.29) 0.43 B A
Figure 2. Kaplan–Meier plot for (A) overall survival; (B) progression-free survival (as-randomized population). CI, confidence interval; OS, overall survival; PFS, progression-free survival.
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Downloaded from http://annonc.oxfordjournals.org/ by guest on May 12, 2015 aspiration/renal failure/acute cardiac arrest), and two to figitumumab
after crossover (pulmonary hemorrhage, cerebral hemorrhage) (supplementary Table S1, available at Annals of
Oncology online).
In the figitumumab arm, 7% of patients discontinued treatment due to figitumumab-related AEs and 8% due to erlotinibrelated AEs. In the control arm, 2% of patients discontinued
treatment due to erlotinib-related AEs. discussion
In this randomized, phase III study, adding figitumumab to
erlotinib failed to improve survival over erlotinib alone in pretreated patients with advanced NSCLC, causing the DSMC to
close the study early due to a survival HR that crossed the prespecified futility boundary. No significant difference was found
between study arms for PFS.
These results are disappointing given preclinical findings that suggested blockade of IGF-1R signaling may sensitize tumors to inhibition of EGFR [4–7]. However, the results are consistent with another study showing that erlotinib combined with an IGF-1R-targeted antibody did not prolong survival and was associated with higher toxicity than erlotinib alone in unselected patients with advanced, pretreated NSCLC [14].
The response rate in our study was low in both arms, possibly reflecting the advanced stage of NSCLC and nonadenocarcinoma histology. We did not assess EGFR status in tumor tissue
samples, but our patients were unlikely to harbor EGFR mutations based on their nonadenocarcinoma histology. The tumor
response rate in the erlotinib arm of our study (3.8%) was similar to that (3%) in the EGFR-negative subgroup of erlotinib recipients in the pivotal registration study [15]. Our protocol included optional collection of tissue samples for exploratory biomarker analysis, but too few samples were collected. Certain AEs (notably nausea/vomiting, diarrhea, decreased appetite/weight, asthenia, mucosal inflammation, dehydration and hyperglycemia) and SAEs (dehydration, diarrhea and
dyspnea) were more common with figitumumab. For patients who crossed over from erlotinib to figitumumab, AEs reported
after commencing figitumumab were documented in the figitumumab crossover arm, not the erlotinib control arm. Therefore,
AE rates may be underestimated in the control arm. Rash was the most common any-grade AE reported and is a known toxicity of erlotinib.
Hyperglycemia, mostly transient, is a known side-effect of figitumumab [8, 9] and other IGF-1R inhibitors [16, 17]. Here,
hyperglycemia (any grade) occurred in 15% (6% grade 3/4) of patients receiving figitumumab versus 4% (<1% grade 3/4) receiving erlotinib alone. In an exploratory analysis, OS in patients
with baseline HbA1c ≥5.7% was slightly worse with figitumumab than with erlotinib alone, while OS for patients with
HbA1c <5.7% appeared similar.
A phase III clinical trial of figitumumab plus carboplatin and paclitaxel for advanced nonadenocarcinoma NSCLC was also closed early due to futility [18]. Initially, it was reported that a subset of figitumumab-treated patients with elevated circulating IGF-1 experienced longer PFS than those treated with chemotherapy alone. However, these data were subsequently retracted,
and no biomarkers have been clearly associated with anti-IGF-1R activity [19].
When our study was designed, there was a good preclinical rationale for combining figitumumab with erlotinib in NSCLC.
Table 2. Efficacy results (all randomized, as randomized)
Variable Figitumumab arm (N = 293) Control arm (N = 290) Hazard ratio (95% CI)a P Overall survival
Deaths, n (%) 241 (82) 242 (83)
Median survival, months (95% CI)c 5.7 (4.8–6.7) 6.2 (5.8–7.2) 1.09 (0.91–1.31) 0.35b PFS (investigator assessment)
Events, n (%) 228 (78) 251 (87)
Objective progression 166 (57) 225 (78)
Death without objective progression 62 (21) 26 (9)
Median PFS, months (95% CI)c 2.1 (1.9–2.6) 2.6 (2.1–2.8) 1.08 (0.90–1.29) 0.43b Best overall response (investigator assessment)d
Complete response, n (%) 0 1 (<1) Partial response, n (%) 16 (5) 10 (3)
Stable disease, n (%) 113 (39) 130 (45)
Objective response rate, % (95% CI)e 5.5 (3.2–8.7) 3.8 (1.9–6.7) 1.67 (−1.7 to 5.1f) 0.34g
Results represent final analysis as of 31 March 2011. aCox proportional hazards model versus control.
bTwo-sided stratified log-rank test stratified by gender, ECOG performance status and region.
cKaplan–Meier estimate, Brookmeyer and Crowley Method. dConfirmed no sooner than 4 weeks after initial observation. eExact CI.
fBased on a normal approximation. gPearson χ2 test.
CI, confidence interval; PFS, progression-free survival.
Volume 26 | No. 3 | March 2015 doi:10.1093/annonc/mdu517 | Annals of Oncology original articles
Downloaded from http://annonc.oxfordjournals.org/ by guest on May 12, 2015 Table 3. Most common treatment-emergent (all-causality) adverse events (≥10% of patients for any grade or >5% of patients for grade 3 and 4)
Grade 3 Grade 4 Any gradec Figitumumab arm (N = 289)a Control arm (N = 290)a Figitumumab crossover armb (N = 83) Figitumumab arm (N = 289)a Control arm (N = 290)a Figitumumab crossover armb (N = 83) Figitumumab arm (N = 289)a Control arm (N = 290)a Figitumumab
crossover armb (N = 83)
Adverse event No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) Any adverse event
(excluding grade 5) 109 (38) 84 (29) 26 (31) 71 (25) 52 (18) 21 (25) 268 (93) 271 (93) 80 (96) Rash 20 (7) 13 (4) 0 0 0 0 141 (49) 152 (52) 33 (40) Diarrhea 23 (8) 8 (3) 0 0 0 0 127 (44) 106 (37) 10 (12) Decreased appetite 30 (10) 13 (4) 4 (5) 0 0 0 117 (40) 71 (24) 32 (39) Dyspnea 16 (6) 15 (5) 3 (4) 8 (3) 4 (1) 0 60 (21) 62 (21) 25 (30) Fatigue 22 (8) 5 (2) 4 (5) 3 (1) 0 1 (1) 65 (22) 54 (19) 17 (21) Cough 2 (1) 3 (1) 3 (4) 0 0 0 43 (15) 51 (18) 21 (25) Asthenia 31 (11) 11 (4) 9 (11) 3 (1) 2 (1) 0 82 (28) 47 (16) 25 (30) Nausea 5 (2) 2 (1) 0 0 0 0 55 (19) 36 (12) 8 (10) Hemoptysis 5 (2) 2 (1) 1 (1) 0 2 (1) 0 34 (12) 35 (12) 10 (12) Weight decreased 5 (2) 4 (1) 4 (5) 0 0 0 65 (22) 33 (11) 19 (23) Pruritus 1 (<1) 3 (1) 0 0 0 0 21 (7) 31 (11) 3 (4) Anemia 5 (2) 6 (2) 5 (6) 0 1 (<1) 0 31 (11) 29 (10) 12 (14) Chest pain 7 (2) 3 (1) 5 (6) 3 (1) 0 0 34 (12) 28 (10) 22 (27) Vomiting 2 (1) 1 (<1) 0 0 0 1 (1) 51 (18) 25 (9) 8 (10) Dry skin 0 0 0 0 0 0 30 (10) 24 (8) 7 (8) Pyrexia 0 1 (<1) 0 0 0 0 29 (10) 23 (8) 6 (7) Hyperglycemia 9 (3) 1 (<1) 4 (5) 7 (2) 0 1 (1) 43 (15) 13 (4) 13 (16) Mucosal inflammation 2 (1) 1 (<1) 0 0 0 0 33 (11) 11 (4) 0 Dehydration 15 (5) 5 (2) 2 (2) 1 (<1) 0 0 28 (10) 12 (4) 3 (4) Headache 0 1 (<1) 0 0 0 0 13 (4) 14 (5) 9 (11) Constipation 1 (<1) 0 0 0 0 0 17 (6) 19 (7) 9 (11) Back pain 5 (2) 3 (1) 0 0 0 0 19 (7) 25 (9) 9 (11)
aTen patients did not receive treatment and were not included in safety analyses. bPatients receiving single-agent figitumumab after progression on erlotinib. For these patients, adverse events that were reported after the start of figitumumab treatment are reported under the figitumumab
crossover group, and adverse events reported after the start of erlotinib but before figitumumab start are reported under the control arm.
cAll rows include grade 5 events except as noted. | Scagliotti et al. Volume 26 | No. 3 | March 2015
original articles Annals of Oncology
However, without phase II combination data, information may have been insufficient to predict success in phase III.
Figitumumab development has been discontinued. acknowledgements
The authors thank the participating patients and their families, as well as the network of investigators (Appendix), research nurses, study coordinators, and operations staff. They also wish to posthumously acknowledge the contribution of Dr Valentina Tzekova, University Hospital Queen Joanna, Sofia, Bulgaria, to the study.We also thank Jose Rodrigues Pereira, Piotr Koralewski and Andrzej Kazarnowicz for their contributions to the study. funding
Medical writing support was provided by Nicola Crofts at ACUMED (Tytherington, UK) and was funded by Pfizer, Inc. disclosure
Employment or leadership position: RJB (Pfizer); SG (Pfizer); KM (Pfizer); Consultant or advisory role: F. Barlesi (Pfizer); F. Blackhall (Pfizer, Roche); SP (Pfizer, Roche); FAS (Pfizer); Stock ownership: RJB (Pfizer), SG (Pfizer), KM (Pfizer); Honoraria: F. Barlesi (Pfizer); F. Blackhall (Pfizer); SP (Pfizer); GVS (Eli Lilly, AstraZeneca, Roche, Pfizer); FAS (Pfizer); J.-C. S. (Pfizer); Research funding: F. Blackhall (Pfizer, Roche). All remaining authors have declared no conflicts of interest. references
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appendix
Investigators: Stephane Holbrechts, Didier Verhoeven, Carlos Moreira Ferreira, Helio Pinczowski, Jose Rodrigues Pereira, Gilberto Schwartsmann, Krassimir Dimitrov Koynov, Tatyana Vasileva Koynova, Violina Taskova, Constanta Velinova Timcheva, Valentina Ilieva Tzekova, Victor Cohen, Frances Shepherd, Osvaldo Aren, Kamil Klenha, Petr Klepetko, Jan Novotny, Petr Zatloukal, Fabrice Barlesi, Benjamin Besse, Eric Dansin, Pierre Fournel, Herve Lena, Fabrice Paganin, Gilles Robinet, Denis Moro-Sibilot, Vassilis Georgoulias, Christos N. Papandreou, Istvan Albert, Gabor Kovacs, Zsolt Szekely Papai, Janos Strausz, Ahmad Hudoyo, Benjamin P. Margono, Kenneth J. O’Byrne, Seamus O’Reilly, JaniceWalshe, Alessandra Bearz, Eugenio Cammilluzzi, Pierfranco Conte, Adolfo
Favaretto, Cesare Gridelli, Alberto Ravaioli, Giorgio Scagliotti, Heung Tae Kim, Joo-Hang Kim, Sang-We Kim, Alinta
Kazarnowicz, Piotr Koralewski, Janusz Milanowski, Jerzy Tujakowski, Hector A. Velez Cortes, Tudor Eliade Ciuleanu,
Volume 26 | No. 3 | March 2015 doi:10.1093/annonc/mdu517 | Annals of Oncology original articles
Downloaded from http://annonc.oxfordjournals.org/ by guest on May 12, 2015 Anghel-Adrian Udrea, Constantin Volovat, Alexander
P. Chuprina, Irina S. Davidenko, Dmitry Gladyshev, Vera Andreevna Gorbunova, Bogan N. Kotiv, Anatoly Makhson, Georgey M. Manikhas, Dmitriy P. Udovitsa, Svetislav Jelic, Dragana Jovanovic, Branislav Perin, Branko Zakotnik, Raymond Abratt, Michiel Christoffel Botha, L. Goedhals, Felipe Cardenal Alemany, Natividad Martinez Banaclocha, Joaquim Bosch Barrera, Pilar Lopez Criado, Luis De la Cruz Merino, Lara Iglesias Docampo, Yolanda Garcia Garcia, Ramon Garcia Gomez, Emilio Esteban Gonzalez, Luis Gonzalo Paz-Ares Rodriguez, Margarita Majem Tarruella, Silvia Catot Tort, Richard Cathomas, Cornelia Droege, Alfred Joseph Zippelius, Te-Chun Hsia, Han-Pin Kuo, Tsai Chun-Ming, Igor
Mykolayovych Bondarenko, Oleksan S. Dudnichenko, Oleksan Yu. Popovych, Nataliya L. Voytko, Igor O. Vynnichenko, Fiona Helen Blackhall, Sanjaykumar Batuklal Popat, Michael Seckl, Ian Churchill Anderson, Rita Susan Axelrod, Steven Charles Buck, Vikki Ann Canfield, David Christianson, Grace K. Dy, Mitchell Allen Garrison, Brian Vincent Geister, Narender Rao Gorukanti, Missak Haigentz Jr, Thomas Harris, Nasser Janbay, Clyde Michael Jones, Vinni Juneja, Boriana Kamenova, Anita Kaul, Waseemullah Khan, Anthony Mark Landis, Corey Jay Langer, Bhoomi Mehrotra, Alexander Reed Menter, Alain Catalin Mita, Manish Monga, Raja Abi Ali Fuad Mudad, Stephen Daniel Myers, Gregory Alan Otterson, Sai-Hong Ignatius Ou, Haralambos E. Raftopoulos, Suresh Sakkarai Ramalingam, James R. Rigas, Michael T. Slaughter, Ronald George Steis, Sachdev Prakash Thomas, Guy W. Tillinghast, Roy Timothy Webb, Geoffrey Roger Weiss, David William Zenk, Alfredo Carrato Mena, Carmen Guillen Ponce, Rut Porta Balanya, Jose Miguel Sanchez Torres, Ricardo Hitt Sabag, Raul Manuel Marquez Vazquez.
doi:10.1093/annonc/mdu567 Published online 15 December 2014
Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA–N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy†
N. Li1,2,‡, Z.-F. Zeng3,‡, S.-Y. Wang1,‡*, W. Ou1, X. Ye4, J. Li5, X.-H. He3, B.-B. Zhang6, H. Yang7,
H.-B. Sun8, Q. Fang9 & B.-X. Wang10
Departments of 1Thoracic Surgery; 2Experimental Research; 3Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; 4Department of Thoracic Surgery, Guangdong General Hospital, Guangzhou; 5Department of
Ultrasound, Sun Yat-sen University Cancer Center, Guangzhou; 6Department of Thoracic Surgery, Henan Chest Hospital, Zhengzhou; 7Department of Thyroid and Breast
Surgery, The Central Hospital of Wuhan, Wuhan; 8Department of Thoracic Surgery, Henan Cancer Hospital, Zhengzhou; 9Department of Surgical Oncology, The Central People’s Hospital of Huizhou City, Huizhou; 10Guangzhou Medical University, Guangzhou, China
Received 26 August 2014; revised 26 October 2014; accepted 6 December 2014 Background: This study compared prophylactic cranial irradiation (PCI) with observation in patients with resected stage
IIIA–N2 non-small-cell lung cancer (NSCLC) and high risk of cerebral metastases after adjuvant chemotherapy.
Patients and methods: In this open-label, randomized, phase III trial, patients with fully resected postoperative pathologically
confirmed stage IIIA–N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant
chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point
was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival
(OS), toxicity and quality of life.
†Presented in part as part of a poster highlights session at the 50th Annual Meeting of the
American Society of Clinical Oncology, 30 May–3 June 2014, Chicago, IL, USA. ‡N.L., Z.-F.Z., and S.-Y.W. contributed equally to this article.
*Correspondence to: Prof. Si-Yu Wang, Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China. Tel: +86-20-87343439, Fax: +86-20-87343439. E-mail: [email protected] original articles Annals of Oncology
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]. Downloaded from http://annonc.oxfordjournals.org/ by guest on May 12, 2015
