- Email: [email protected]
Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma
original articles 9. Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003; 38(3): 207–215. 10. Ikai I, Arii S, Okazaki M et al. Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan. Hepatol Res 2007; 37(9): 676–691. 11. Imamura H, Matsuyama Y, Tanaka E et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003; 38(2): 200–207. 12. Shiina S, Tateishi R, Arano T et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2012; 107(4): 569–577. 13. Ishikawa T, Michitaka I, Kamimura H et al. Oral branched-chain amino acids administration improves impaired liver dysfunction after radiofrequency ablation
Annals of Oncology
14. 15.
16.
17.
therapy for hepatocellular carcinoma. Hepatogastroenterology 2009; 56(94–95): 1491–1495. Sasaki A, Kai S, Iwashita Y et al. Microsatellite distribution and indication for locoregional therapy in small hepatocellular carcinoma. Cancer 2005; 103(2): 299–306. Yoshikawa M, Ono N, Yodono H et al. Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol Res 2008; 38(5): 474–483. Osuga K, Arai Y, Anai H et al. Phase I/II multicenter study of transarterial chemoembolization with a cisplatin fine powder and porous gelatin particles for unresectable hepatocellular carcinoma: Japan Interventional Radiology in Oncology Study Group Study 0401. J Vasc Interv Radiol 2012; 23(10): 1278–1285. Kim HC, Lee JH, Chung JW et al. Transarterial chemoembolization with additional cisplatin infusion for hepatocellular carcinoma invading the hepatic vein. J Vasc Interv Radiol 2013; 24(2): 274–283.
Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma D. Propper1*, I. Davidenko2, J. Bridgewater3, L. Kupcinskas4, A. Fittipaldo5, C. Hillenbach6, B. Klughammer6 & M. Ducreux7 1
Barts Cancer Institute, Queen Mary University of London, London, UK; 2State Medical Institution Clinical Oncology Dispensary, Krasnodar, Russia; 3University College London Cancer Institute, London, UK; 4Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; 5Roche Products Ltd, Welwyn Garden City, UK; 6F. Hoffmann-La Roche Ltd, Basel, Switzerland; 7Institut Gustave Roussy, Villejuif, France
Received 8 January 2014; revised 22 April 2014; accepted 23 April 2014
Background: A prospective, randomized phase II study, with mandatory tumor sampling at current disease stage, aimed to identify biomarkers predictive of improved progression-free survival (PFS) in patients with pancreatic cancer treated with erlotinib. Patients and methods: Patients with histologically/cytologically confirmed, unresectable, locally advanced/metastatic pancreatic cancer, who had failed on or were unsuitable for first-line chemotherapy, underwent a tumor biopsy and were then randomized to receive once-daily erlotinib 150 mg or placebo. The primary end point was identification of biomarkers predicting improved PFS with erlotinib. Secondary end points included PFS, overall survival, response and toxicity. Results: At data cut-off, 207 patients were enrolled and analyzed. Prespecified biomarker analyses of EGFR protein expression, EGFR gene copy number/mutations/polymorphisms and KRAS mutations did not identify any subgroups with a detrimental effect or a strong benefit for PFS with erlotinib. In the primary analysis, the median PFS was 6.1 versus 5.9 weeks in the erlotinib and placebo arms, respectively [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.63–1.10; P = 0.1909]. However, observed baseline imbalances indicated worse prognosis in the erlotinib arm. After adjustment for baseline characteristics, a significant PFS benefit for erlotinib was observed (HR 0.68; 95% CI 0.50–0.91; P = 0.0102). Exploratory biomarker analyses showed patients with high baseline serum amphiregulin levels might benefit from erlotinib. Conclusion: This study in patients with inoperable pancreatic cancer did not identify any prespecified biomarkers predictive of PFS benefit with erlotinib. Exploratory analyses suggested high amphiregulin might predict PFS benefit from erlotinib. ClinicalTrials.gov number: NCT00674973. Key words: pancreatic cancer, biomarkers, erlotinib, predictive markers, personalized therapy
*Correspondence to: Dr David Propper, Department of Medical Oncology, Barts Cancer Institute, Queen Mary University of London, 7th Floor, Gloucester House, West Smithfield, London EC1A 7BE, UK. Tel: +44-203-465-5051; Fax: +44-203-465-6051; E-mail: d.j. [email protected]
© 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/ at University of California, San Francisco on December 3, 2014
Annals of Oncology 25: 1384–1390, 2014 doi:10.1093/annonc/mdu176 Published online 14 May 2014
original articles
Annals of Oncology
introduction
patients and methods patients Eligible patients were aged ≥18 years with histologically or cytologically confirmed, unresectable, locally advanced or metastatic pancreatic cancer who had measurable disease [by Response Evaluation Criteria in Solid Tumors (RECIST)] that was accessible for biopsy, and who had failed on prior chemotherapy or were deemed unsuitable for first-line chemotherapy. All patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2, a life expectancy of ≥6 weeks and adequate hematologic, renal and hepatic function. Key exclusion criteria included resectable pancreatic cancer, other malignancies within the last 5 years (except adequately treated cervical cancer, or basal or squamous-cell skin cancer) or major surgery <2 weeks before randomization. Spinal cord compression or central nervous system metastases were excluded by mandatory computed tomography scanning or magnetic resonance imaging in the 4 weeks before randomization.
study design The MARK study was an international, phase II, multicenter, randomized, placebo-controlled, double-blind study in patients with advanced pancreatic
Volume 25 | No. 7 | July 2014
efficacy, biomarker and safety analyses The primary objective of the study was to identify biomarkers predictive of improved PFS in patients treated with erlotinib. Secondary efficacy end points were PFS in the overall population, overall survival (OS), objective response rate (as measured by RECIST) and disease control rate (DCR). Clinical assessments were conducted every 3 weeks during treatment until week 24, and every 12 weeks thereafter. Response assessments were carried out after 6 weeks of treatment, then every 6 weeks until week 24. After week 24, response assessments were carried out every 12 weeks. The same target lesions were to be assessed at each time point using the same imaging technique. EGFR protein expression by immunohistochemistry (IHC), EGFR gene copy number by FISH, EGFR and KRAS mutations (both using commercially available cobas® tests and carried out at Roche Molecular Systems, Pleasanton, CA) were analyzed using tissue from the tumor samples taken at baseline (see supplementary material, available at Annals of Oncology online). Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 (NCI-CTCAE) [6].
statistical analyses In this study, the hypothesis was that the survival distribution function for PFS was the same for erlotinib compared with placebo. The null hypothesis was tested using an unstratified log-rank test at the one-sided 5% level with no adjustment of P-values for multiple testing. However, P-values given within this paper are two-sided. A sample size of 200 patients was chosen to provide an adequate sample, taking into account that the study was conducted in a population in which it is clinically challenging to obtain tumor biopsy samples and to treat with placebo. Patients were assigned 1:1 to erlotinib or placebo using an adaptive randomization method [7] to ensure a balanced stratification for smoking status (current smoker versus former smoker versus never smoker), ECOG PS (0–1 versus 2) and geographic region (Asian versus non-Asian). The primary analysis for efficacy was the Full Analysis Set (FAS), which was defined as all randomized patients. The safety population was defined as all patients who received at least one dose of study medication and had a safety follow-up, whether withdrawn prematurely or not. The efficacy results were evaluated by prespecified biomarker status including EGFR protein expression [IHC positive (>10% of cells with membrane staining) versus negative], EGFR gene copy number [FISH positive ( probe clusters in >10% of cells) versus negative], EGFR mutation status (activating mutation positive versus wild-type), KRAS mutation status (classical mutation positive versus wild-type) and EGFR polymorphisms (long versus short). Additional post hoc exploratory analyses were conducted (see supplementary material, available at Annals of Oncology online, for methodology). Rash analysis included patients alive at day 21, thus excluding those who progressed too quickly to develop rash. The designation ‘early rash’ was used to limit the analysis to erlotinib-related rash only.
doi:10.1093/annonc/mdu176 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Changes to oncogenes and tumor suppressor genes, as well as activation of pathways involved in cell-cycle control, are considered to have a role in the development of pancreatic cancer [1]. Molecularly targeted therapies may therefore have potential for improving outcomes in advanced pancreatic cancer [2]. Erlotinib (Tarceva®, F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor that was approved in combination with gemcitabine as first-line therapy for locally advanced or metastatic pancreatic cancer based on the results of the pivotal phase III PA.3 trial [3]. The survival prolongation from erlotinib in PA.3 was modest. An exploratory analysis of outcomes to identify predictive biomarkers, specifically KRAS mutation status and EGFR gene copy number, in the 26% of patients in PA.3 for whom tissue was available, showed longer survival for patients whose tumors had a low EGFR gene copy number [assessed by fluorescence in situ hybridization (FISH)], although this did not reach statistical significance [4]. An exploratory study in the second-line setting found that erlotinib was associated with disease stabilization in 3 out of 10 patients, which persisted for up to 12 months [5]. These observations suggested that single-agent erlotinib might have benefit in selected patients and there may be predictive biomarkers that could identify such patients. This ongoing randomized, phase II, double-blind, placebocontrolled, biomarker identification, post-approval commitment trial for erlotinib in patients with advanced pancreatic carcinoma (BO21129; bio Marker trial; MARK) was designed to identify biomarkers that might predict improved progression-free survival (PFS) in response to erlotinib. In order to gage the true predictive value of the biomarkers being assessed, it was necessary to administer erlotinib as monotherapy in a placebo-controlled setting; therefore, the trial was designed to administer erlotinib predominantly as a second-line treatment and included only those patients who had either already received first-line gemcitabine-based therapy for advanced pancreatic cancer or were unsuitable to receive such therapy.
cancer. Mandatory tumor biopsies were obtained after screening to establish baseline biomarker status. Serum samples were collected from patients at baseline, 3 weeks after commencing erlotinib and after treatment discontinuation. Patients were randomly assigned to receive erlotinib 150 mg/day or placebo. Dose reductions were permitted for toxicity that could not be controlled by optimal supportive care. Treatment continued until disease progression, unacceptable toxicity, withdrawal or death. At disease progression, investigators could request unblinding of the randomized treatment; those receiving erlotinib were treated at the investigator’s discretion and those on placebo were eligible to receive open-label erlotinib 150 mg/day or other active treatment. The study was conducted in accordance with the principles of the Declaration of Helsinki and Guidelines for Good Clinical Practice. All patients provided written informed consent before trial entry and the study was approved by the ethics committee or institutional review board at each site.
original articles
Annals of Oncology
The cut-off date for the final analysis was 6 months after the last patient was randomized. The study is currently ongoing and will end when the last patient has stopped randomized treatment with erlotinib or placebo and completed their final visit before withdrawal or the start of the open-label extension phase.
results patients
Patients randomized (n = 207)
Placebo (n = 103)
Completed AE Death PD Failure to return Refused Tx
Open-label erlotinib* (n = 57)
Completed AE Death PD Refused Tx Other
Erlotinib (n = 104)
Completed AE Death PD Other protocol violation Refused Tx
(n = 100) (n = 2) (n = 19) (n = 77) (n = 1) (n = 1)
(n = 102) (n = 9) (n = 15) (n = 72) (n = 1) (n = 5)
No open-label erlotinib (n = 43)
(n = 56) (n = 4) (n = 16) (n = 30) (n = 5) (n = 1)
Patients ongoing at data cutoff (n = 1)
Patients ongoing at data cutoff (n = 3)
Patients ongoing at data cutoff (n = 2)
Figure 1. CONSORT diagram. *Patients who had progressed on placebo were given the opportunity to switch to erlotinib in the open-label extension phase of the study, if deemed beneficial to the patient. AE, adverse event; PD, progressive disease; Tx, treatment.
| Propper et al.
Volume 25 | No. 7 | July 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
At the data cut-off on 22 December 2010, 207 patients had been enrolled and randomized (104 to erlotinib, 103 to placebo; Figure 1). The study was conducted in 49 centers across 15 countries. The first patient was randomized on 24 June 2008, and the last patient was randomized on 22 June 2010. Five patients remained on blinded treatment as of the data cut-off. All 207 patients were included in both the efficacy and safety analyses. Overall patient characteristics are listed in Table 1. Baseline characteristics, including stratification factors and line of therapy, were generally well matched between treatment arms. However, there
were a number of imbalances in baseline characteristics that were small in themselves, but overall indicated a worse prognosis in the erlotinib arm, namely patients randomized to erlotinib were older (40% aged ≥65 years versus 30%), more likely to have ≥10% weight loss in the past 6 months (37% versus 26%), more frequently had poorly differentiated disease (32% versus 21%) and reported more pancreatic pain (75% versus 59%). Also, patients randomized to erlotinib had a shorter median time since first diagnosis than those randomized to placebo (6.95 versus 8.77 months, respectively). Biomarker status was generally similar between the erlotinib and placebo arms: 69% of the patients in both arms had EGFR IHC-positive tumors, and nearly half of the patients had a longer CA repeat of EGFR intron 1 polymorphism (48% versus 42% in the erlotinib and placebo arms, respectively) (supplementary Table S1, available at Annals of Oncology online). No patients in the study had EGFR activating mutation-positive tumors. At disease progression, 53% of patients (57/102) in the placebo arm received open-label erlotinib, while only 18% of patients (19/104) in the erlotinib arm received further active therapies.
original articles
Annals of Oncology
Table 1. Baseline demographic and clinical characteristics in the overall population Characteristic
Erlotinib (n = 104)
57 (25–88) 31 (30) 72 (70) 59 (57) 44 (43) 86 (83) 17 (17) 27 (26) 75 (74) 98 (95) 5 (5) 29 (28) 49 (48) 25 (24) 34 (33) 69 (67) 8.77 (0.1–63.7) 1.08 (0.1–10.0) 15 (15) 88 (85) 10 (10) 38 (37) 22 (21) 33 (32) 61 (59) 42 (41)
ECOG, Eastern Cooperative Oncology Group. Total n = 173. b Smoking status: patients who had stopped smoking <1 year ago were counted as current smokers. c First-line treatment was defined as any patient who did not report taking palliative chemotherapy. a
efficacy
safety and tolerability
The median PFS in the overall population was similar in the erlotinib and placebo arms [median 6.1 versus 5.9 weeks, respectively; hazard ratio (HR) 0.83 (95% confidence interval (CI), 0.63–1.10); log-rank P = 0.1909; Figure 2]; however, the primary model did not adjust for baseline imbalances. The adjusted
Safety data were available for all 207 patients in the study (supplementary Table S2, available at Annals of Oncology online). The AE profile for erlotinib was comparable with previous experience with the drug. In this study, there were no cases of interstitial lung disease (ILD) with erlotinib; however, one case
Volume 25 | No. 7 | July 2014
doi:10.1093/annonc/mdu176 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Age, years Median (range) 62 (33–90) Age, n (%) ≥65 years 42 (40) <65 years 62 (60) Gender, n (%) Male 59 (57) Female 45 (43) ECOG performance status, n (%)a 0/1 88 (85) 2 16 (15) Weight loss in past 6 months, n (%) >10% 38 (37) ≤10% 65 (63) Region, n (%) Non-Asia 98 (94) Asia 6 (6) Smoking status, n (%)b Current smoker 29 (28) Never smoker 48 (46) Former smoker 27 (26) First-line treatment, n (%)c Yes 36 (35) No 68 (65) Months since first diagnosis Median (range) 6.95 (0.3–53.9) Months since progressiona Median (range) 0.97 (0.2–9.8) Stage at screening, n (%) Local 20 (19) Metastatic 84 (81) Histologic grade, n (%) Well differentiated 11 (11) Moderately differentiated 32 (31) Poorly differentiated 33 (32) Unknown 28 (27) Pain related to pancreatic cancer Yes 78 (75) No 26 (25)
Placebo (n = 103)
post hoc analysis of PFS correcting for baseline prognostic differences, including smoking status, pain related to pancreatic cancer, location of the primary tumor in the tail, and lesions in the pancreas, liver and other sites, showed a statistically significant effect with erlotinib [adjusted HR 0.68 (95% CI 0.50–0.91); P = 0.0102 using Wald’s test]. No significant difference was observed between erlotinib and placebo in the pre-planned, unadjusted OS analysis [4.0 versus 3.1 months, respectively; HR 1.04 (95% CI 0.77–1.39); log-rank P = 0.8137; Figure 2], but a post hoc, adjusted analysis showed a trend in favor of erlotinib [adjusted HR 0.83 (95% CI 0.60–1.16); P = 0.2867 using Wald’s test). Efficacy analyses by skin rash (supplementary Figure S1, available at Annals of Oncology online) and biomarker subgroups are presented in full in the supplementary material, available at Annals of Oncology online. No statistically significant difference in the median PFS was observed between the study arms in the overall population or according to stratification factor or tumor biomarker status within the pre-planned unadjusted analysis (Figure 2; supplementary Figures S2–S5, available at Annals of Oncology online). However, an adjusted analysis of biomarker subgroups using the post hoc model showed HRs for the EGFR IHC-positive subgroup and the short EGFR CA-SSR1 polymorphism subgroup were 0.64 (95% CI 0.42–0.98) and 0.63 (95% CI 0.41–0.95), respectively (supplementary Table S4, available at Annals of Oncology online). Pre-planned and post hoc analyses of OS did not identify any of the pre-planned tumor biomarkers that predicted a detrimental effect or a strong benefit with erlotinib. The factors identified by the stepwise selection of the Cox regression for OS in the FAS were smoking status, weight loss, pancreatic pain, location of the primary tumor in the tail, weight and tumor characteristics at screening (tumor size, number of target lesions, presence of non-target lesions, presence of tumors in the pancreas, liver and other sites). Different factors for PFS and OS were identified, as PFS is more driven by speed of tumor growth, while OS is more dependent on general health indicators such as weight. An adjusted post hoc analysis of additional serum biomarkers (Figure 3) showed that erlotinib provided a greater PFS and OS benefit than placebo for patients with high levels of amphiregulin [PFS-adjusted HR 0.51 (95% CI 0.33–0.80); OS-adjusted HR 0.55 (95% CI 0.34–0.92)], and likely no benefit for patients with low levels of amphiregulin [PFS-adjusted HR 0.94 (95% CI 0.60–1.47); OS-adjusted HR 1.26 (95% CI 0.74–2.16)]. In addition, erlotinib provided a greater PFS benefit but no significant difference in OS versus placebo in patients with low levels of EGF, or high levels of TGF-α (Figure 3). No complete responses were reported in this study, although partial responses were observed in 1% and 4% of erlotinib- and placebo-treated patients, respectively. DCR was higher with erlotinib compared with placebo (28% versus 18%, P = 0.1077), although the difference did not reach statistical significance.
original articles
Annals of Oncology
Proportion without event
A 1.0
Erlotinib (n = 104, median = 6.1) Placebo (n = 103, median = 5.9)
0.8
HR 0.83 (0.63 – 1.10) Log-rank P = 0.1909
0.6
Adjusted post-hoc analysis* HR 0.68 (0.50 – 0.91) Log-rank P = 0.0102 (Wald’s test)
0.4
0.2
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96 102 108 114
0 2
0 2
0 2
Duration of progression-free survival (weeks) No. of patients at risk 104 59 Erlotinib 103 48 Placebo
28 18
18 9
8 7
6 6
3 5
1 5
1 5
1 4
1 3
1 3
0 2
0 2
0 2
0 1
0 0
Proportion without event
B 1.0
Erlotinib (n = 104, median = 4.0) Placebo (n = 103, median = 3.1)
0.8
HR 1.04 (0.77 – 1.39) Log-rank P = 0.8137
0.6
Adjusted post-hoc analysis* HR 0.83 (0.60 – 1.16) Log-rank P = 0.2867 (Wald’s test)
0.4
0.2
0
3
6
9
12
15
18
21
24
27
30
0 2
0 2
0 0
0 0
Duration of survival (months) No. of patients at risk Erlotinib 104 Placebo 103
59 51
29 28
13 17
8 12
4 7
1 2
Figure 2. Progression-free survival (PFS) and overall survival (OS) by treatment arm. *The Kaplan–Meier curve shown is not adjusted for imbalances in baseline characteristics.
(1.0%) of ILD was observed in the placebo arm. No new safety signals were observed.
discussion This randomized, phase II, biomarker study in patients with advanced, pre-treated pancreatic cancer did not identify a population subset with a strong benefit or detrimental effect after treatment with erlotinib in this population with poor prognosis. The pre-planned, unadjusted analysis for PFS did not demonstrate a significant benefit for erlotinib. However, the study was not powered to detect a significant difference and a post hoc, adjusted analysis, taking into account imbalances in baseline characteristics, showed a statistically significant effect of erlotinib on PFS [adjusted HR 0.68 (95% CI 0.50–0.91); P = 0.0102].
| Propper et al.
KRAS wild-type disease and EGFR activating mutations have been associated with improved response to EGFR-targeted therapies in other tumors [8–11]. In this study, the results in the subgroups with KRAS mutations or EGFR wild-type disease were similar to the overall population (HR 0.79, 0.90 and 0.73, respectively). A post hoc adjusted analysis of serum biomarkers showed that patients with elevated baseline levels of amphiregulin, which is a potent mitogen acting at the EGFR in pancreatic cancer cells [12], derived a greater PFS and OS benefit from erlotinib versus placebo, while no difference was seen in those who had low levels of amphiregulin. In addition, a greater PFS benefit with erlotinib was observed in patients with low levels of EGF or high levels of TGF-α. A definitive mechanism for the effect of these markers on clinical efficacy has not been established. High amphiregulin
Volume 25 | No. 7 | July 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
0
original articles
Annals of Oncology
A HR (95% CI) All
Total no. of patients
0.68 (0.50–0.91)
206
Low (£median)
0.94 (0.60–1.47)
99
High (>median)
0.51 (0.33–0.80)
99
Low (£median)
0.53 (0.34–0.83)
101
High (>median)
0.84 (0.54–1.30)
100
Low (£median)
0.66 (0.43–1.03)
101
High (>median)
0.67 (0.44–1.03)
100
Low (£median)
0.68 (0.43–1.08)
100
High (>median)
0.51 (0.32–0.81)
98
Amphiregulin
EGF
sHER2
0.4
0.6
1
2
HR Favors erlotinib
Favors placebo
B HR (95% CI) All
Total no. of patients
0.83 (0.60–1.16)
201
Low (£median)
1.26 (0.74–2.16)
99
High (>median)
0.55 (0.34–0.92)
94
Low (£median)
0.61 (0.38–0.99)
98
High (>median)
0.87 (0.52–1.46)
98
Low (£median)
0.65 (0.38–1.10)
98
High (>median)
0.85 (0.52–1.39)
98
Low (£median)
0.90 (0.54–1.49)
97
High (>median)
0.65 (0.37–1.15)
96
Amphiregulin
EGF
sHER2
TGF-a
0.4
0.6
1
2
HR Favors erlotinib
Favors placebo
Figure 3. Summary of exploratory serum biomarker analyses for progression-free survival (PFS) and overall survival (OS)-adjusted post hoc analysis.
levels may indicate a poor prognosis, since it stimulates EGFR coupling to cell proliferation (as does TGF-α) [13]. Amphiregulin may also alter EGFR internalization and degradation, favoring accumulation of EGFR at the cell surface [14], thus making cells more susceptible to EGFR tyrosine-kinase inhibitors, while EGF competitively antagonizes amphiregulin and internalizes EGFR. In this study, conducted in patients with a poor prognosis, there was no significant difference between the erlotinib and placebo arms in the unstratified analysis of OS. However, it should be
Volume 25 | No. 7 | July 2014
noted that approximately half of the patients in the placebo arm received open-label erlotinib after progression and this cross-over may have influenced the results of the OS analysis. The safety and tolerability profile of erlotinib in this study was as expected, and the incidence of AEs such as rash and gastrointestinal disturbances was consistent with previous experience with erlotinib in pancreatic cancer and other tumors [3, 9–11], with no new safety signals observed. In contrast with previous studies [15], skin rash was not predictive of improved
doi:10.1093/annonc/mdu176 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
TGF-a
original articles
acknowledgements Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. The authors would like to thank all patients who participated in the study and the clinical personnel involved in tumor sampling, data collection and analysis. John Bridgewater was supported in part by the UCLH/UCL Biomedical Research Centre.
funding This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland [no grant number].
disclosure DP, ID and LK have no conflicts of interest. JB has received honoraria from Merck and participated as an advisor for Roche. AF, CH and BK are paid employees of F. Hoffmann-La Roche Ltd. AF and BK also own stock in F. Hoffmann-La Roche Ltd. MD has received honoraria from Roche, Merck Serono and Novartis; has acted as a consultant/advisor for Roche, Merck Serono and Amgen; and has received research funding from Roche and Chugai.
references 1. Samuel N, Hudson TJ. The molecular and cellular heterogenecity of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2011; 9: 77–87. 2. Burris H, III, Rocha-Lima C. New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. Oncologist 2008; 13: 289–298.
| Propper et al.
3. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960–1966. 4. Cunha Santos G, Dhani N, Tu D et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer 2010; 116: 5599–5607. 5. Epelbaum R, Schnaider J, Gluzman A et al. Erlotinib as a single-agent therapy in patients with advanced pancreatic cancer. Presented at the American Society of Clinical Oncology Gastrointestinal Symposium, Orlando, FL, 19–21 January 2007. Abstract 202. 6. Common Terminology Criteria for Adverse Events v3.0 (CTCAE): The NCI Common Terminology Criteria for Adverse Events. Bethesda, MD: Cancer Therapy Evaluation Program, 2006. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/ctcaev3.pdf (11 June 2014, date last accessed). 7. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975; 31: 103–115. 8. Van Cutsem E, Köhne C-H, Lang I et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29: 2011–2019. 9. Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958–967. 10. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957. 11. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG- 0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735–742. 12. Yokoyama M, Ebert M, Funatomi H et al. Amphiregulin is a potent mitogen in human pancreatic-cancer cells—correlation with patient survival. Int J Oncol 1995; 6: 625–631. 13. Wilson KJ, Mill C, Lambert S et al. EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors 2012; 30: 107–116. 14. Willmarth NE, Baillo A, Dziubinski ML et al. Altered EGFR localization and degradation in human breast cancer cells with an amphiregulin/EGFR autocrine loop. Cell Signal 2009; 21: 212–219. 15. Wacker B, Nagrani T, Weinberg J et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007; 13: 3913–3921. 16. Duffy MJ, Sturgeon C, Lamerz R et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol 2010; 21: 441–447. 17. Lee J, Jang KT, Ki CS et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer 2007; 109: 1561–1569. 18. Jamieson NB, Carter CR, McKay CJ et al. Tissue biomarkers for prognosis in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. Clin Cancer Res 2011; 17: 3316–3331.
Volume 25 | No. 7 | July 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
PFS in this study, perhaps because of improved early intervention and effective prophylactic use of emollient creams. To date, there is limited evidence to support the use of predictive biomarkers for patients with pancreatic cancer who could benefit from targeted therapies. CA19-9 is an adverse prognostic marker [16]. KRAS mutations may also adversely affect prognosis [17], as may Bcl-2-associated X protein (BAX), Bcl-2, survivin, Ki-67, cyclooxygenase-2, E-cadherin and S100 calcium-binding proteins, in particular S100A2 [18]. The observation based on the exploratory analyses from this study, that patients with elevated baseline levels of amphiregulin obtained a greater PFS and OS benefit with erlotinib, suggests some potential value for this biomarker in pancreatic cancer. Further research is still needed, however, to identify those patients with advanced pancreatic cancer who may benefit most from erlotinib.
Annals of Oncology
Annals of Oncology
14. 15.
16.
17.
therapy for hepatocellular carcinoma. Hepatogastroenterology 2009; 56(94–95): 1491–1495. Sasaki A, Kai S, Iwashita Y et al. Microsatellite distribution and indication for locoregional therapy in small hepatocellular carcinoma. Cancer 2005; 103(2): 299–306. Yoshikawa M, Ono N, Yodono H et al. Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma. Hepatol Res 2008; 38(5): 474–483. Osuga K, Arai Y, Anai H et al. Phase I/II multicenter study of transarterial chemoembolization with a cisplatin fine powder and porous gelatin particles for unresectable hepatocellular carcinoma: Japan Interventional Radiology in Oncology Study Group Study 0401. J Vasc Interv Radiol 2012; 23(10): 1278–1285. Kim HC, Lee JH, Chung JW et al. Transarterial chemoembolization with additional cisplatin infusion for hepatocellular carcinoma invading the hepatic vein. J Vasc Interv Radiol 2013; 24(2): 274–283.
Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma D. Propper1*, I. Davidenko2, J. Bridgewater3, L. Kupcinskas4, A. Fittipaldo5, C. Hillenbach6, B. Klughammer6 & M. Ducreux7 1
Barts Cancer Institute, Queen Mary University of London, London, UK; 2State Medical Institution Clinical Oncology Dispensary, Krasnodar, Russia; 3University College London Cancer Institute, London, UK; 4Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; 5Roche Products Ltd, Welwyn Garden City, UK; 6F. Hoffmann-La Roche Ltd, Basel, Switzerland; 7Institut Gustave Roussy, Villejuif, France
Received 8 January 2014; revised 22 April 2014; accepted 23 April 2014
Background: A prospective, randomized phase II study, with mandatory tumor sampling at current disease stage, aimed to identify biomarkers predictive of improved progression-free survival (PFS) in patients with pancreatic cancer treated with erlotinib. Patients and methods: Patients with histologically/cytologically confirmed, unresectable, locally advanced/metastatic pancreatic cancer, who had failed on or were unsuitable for first-line chemotherapy, underwent a tumor biopsy and were then randomized to receive once-daily erlotinib 150 mg or placebo. The primary end point was identification of biomarkers predicting improved PFS with erlotinib. Secondary end points included PFS, overall survival, response and toxicity. Results: At data cut-off, 207 patients were enrolled and analyzed. Prespecified biomarker analyses of EGFR protein expression, EGFR gene copy number/mutations/polymorphisms and KRAS mutations did not identify any subgroups with a detrimental effect or a strong benefit for PFS with erlotinib. In the primary analysis, the median PFS was 6.1 versus 5.9 weeks in the erlotinib and placebo arms, respectively [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.63–1.10; P = 0.1909]. However, observed baseline imbalances indicated worse prognosis in the erlotinib arm. After adjustment for baseline characteristics, a significant PFS benefit for erlotinib was observed (HR 0.68; 95% CI 0.50–0.91; P = 0.0102). Exploratory biomarker analyses showed patients with high baseline serum amphiregulin levels might benefit from erlotinib. Conclusion: This study in patients with inoperable pancreatic cancer did not identify any prespecified biomarkers predictive of PFS benefit with erlotinib. Exploratory analyses suggested high amphiregulin might predict PFS benefit from erlotinib. ClinicalTrials.gov number: NCT00674973. Key words: pancreatic cancer, biomarkers, erlotinib, predictive markers, personalized therapy
*Correspondence to: Dr David Propper, Department of Medical Oncology, Barts Cancer Institute, Queen Mary University of London, 7th Floor, Gloucester House, West Smithfield, London EC1A 7BE, UK. Tel: +44-203-465-5051; Fax: +44-203-465-6051; E-mail: d.j. [email protected]
© 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/ at University of California, San Francisco on December 3, 2014
Annals of Oncology 25: 1384–1390, 2014 doi:10.1093/annonc/mdu176 Published online 14 May 2014
original articles
Annals of Oncology
introduction
patients and methods patients Eligible patients were aged ≥18 years with histologically or cytologically confirmed, unresectable, locally advanced or metastatic pancreatic cancer who had measurable disease [by Response Evaluation Criteria in Solid Tumors (RECIST)] that was accessible for biopsy, and who had failed on prior chemotherapy or were deemed unsuitable for first-line chemotherapy. All patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–2, a life expectancy of ≥6 weeks and adequate hematologic, renal and hepatic function. Key exclusion criteria included resectable pancreatic cancer, other malignancies within the last 5 years (except adequately treated cervical cancer, or basal or squamous-cell skin cancer) or major surgery <2 weeks before randomization. Spinal cord compression or central nervous system metastases were excluded by mandatory computed tomography scanning or magnetic resonance imaging in the 4 weeks before randomization.
study design The MARK study was an international, phase II, multicenter, randomized, placebo-controlled, double-blind study in patients with advanced pancreatic
Volume 25 | No. 7 | July 2014
efficacy, biomarker and safety analyses The primary objective of the study was to identify biomarkers predictive of improved PFS in patients treated with erlotinib. Secondary efficacy end points were PFS in the overall population, overall survival (OS), objective response rate (as measured by RECIST) and disease control rate (DCR). Clinical assessments were conducted every 3 weeks during treatment until week 24, and every 12 weeks thereafter. Response assessments were carried out after 6 weeks of treatment, then every 6 weeks until week 24. After week 24, response assessments were carried out every 12 weeks. The same target lesions were to be assessed at each time point using the same imaging technique. EGFR protein expression by immunohistochemistry (IHC), EGFR gene copy number by FISH, EGFR and KRAS mutations (both using commercially available cobas® tests and carried out at Roche Molecular Systems, Pleasanton, CA) were analyzed using tissue from the tumor samples taken at baseline (see supplementary material, available at Annals of Oncology online). Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 (NCI-CTCAE) [6].
statistical analyses In this study, the hypothesis was that the survival distribution function for PFS was the same for erlotinib compared with placebo. The null hypothesis was tested using an unstratified log-rank test at the one-sided 5% level with no adjustment of P-values for multiple testing. However, P-values given within this paper are two-sided. A sample size of 200 patients was chosen to provide an adequate sample, taking into account that the study was conducted in a population in which it is clinically challenging to obtain tumor biopsy samples and to treat with placebo. Patients were assigned 1:1 to erlotinib or placebo using an adaptive randomization method [7] to ensure a balanced stratification for smoking status (current smoker versus former smoker versus never smoker), ECOG PS (0–1 versus 2) and geographic region (Asian versus non-Asian). The primary analysis for efficacy was the Full Analysis Set (FAS), which was defined as all randomized patients. The safety population was defined as all patients who received at least one dose of study medication and had a safety follow-up, whether withdrawn prematurely or not. The efficacy results were evaluated by prespecified biomarker status including EGFR protein expression [IHC positive (>10% of cells with membrane staining) versus negative], EGFR gene copy number [FISH positive ( probe clusters in >10% of cells) versus negative], EGFR mutation status (activating mutation positive versus wild-type), KRAS mutation status (classical mutation positive versus wild-type) and EGFR polymorphisms (long versus short). Additional post hoc exploratory analyses were conducted (see supplementary material, available at Annals of Oncology online, for methodology). Rash analysis included patients alive at day 21, thus excluding those who progressed too quickly to develop rash. The designation ‘early rash’ was used to limit the analysis to erlotinib-related rash only.
doi:10.1093/annonc/mdu176 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Changes to oncogenes and tumor suppressor genes, as well as activation of pathways involved in cell-cycle control, are considered to have a role in the development of pancreatic cancer [1]. Molecularly targeted therapies may therefore have potential for improving outcomes in advanced pancreatic cancer [2]. Erlotinib (Tarceva®, F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor that was approved in combination with gemcitabine as first-line therapy for locally advanced or metastatic pancreatic cancer based on the results of the pivotal phase III PA.3 trial [3]. The survival prolongation from erlotinib in PA.3 was modest. An exploratory analysis of outcomes to identify predictive biomarkers, specifically KRAS mutation status and EGFR gene copy number, in the 26% of patients in PA.3 for whom tissue was available, showed longer survival for patients whose tumors had a low EGFR gene copy number [assessed by fluorescence in situ hybridization (FISH)], although this did not reach statistical significance [4]. An exploratory study in the second-line setting found that erlotinib was associated with disease stabilization in 3 out of 10 patients, which persisted for up to 12 months [5]. These observations suggested that single-agent erlotinib might have benefit in selected patients and there may be predictive biomarkers that could identify such patients. This ongoing randomized, phase II, double-blind, placebocontrolled, biomarker identification, post-approval commitment trial for erlotinib in patients with advanced pancreatic carcinoma (BO21129; bio Marker trial; MARK) was designed to identify biomarkers that might predict improved progression-free survival (PFS) in response to erlotinib. In order to gage the true predictive value of the biomarkers being assessed, it was necessary to administer erlotinib as monotherapy in a placebo-controlled setting; therefore, the trial was designed to administer erlotinib predominantly as a second-line treatment and included only those patients who had either already received first-line gemcitabine-based therapy for advanced pancreatic cancer or were unsuitable to receive such therapy.
cancer. Mandatory tumor biopsies were obtained after screening to establish baseline biomarker status. Serum samples were collected from patients at baseline, 3 weeks after commencing erlotinib and after treatment discontinuation. Patients were randomly assigned to receive erlotinib 150 mg/day or placebo. Dose reductions were permitted for toxicity that could not be controlled by optimal supportive care. Treatment continued until disease progression, unacceptable toxicity, withdrawal or death. At disease progression, investigators could request unblinding of the randomized treatment; those receiving erlotinib were treated at the investigator’s discretion and those on placebo were eligible to receive open-label erlotinib 150 mg/day or other active treatment. The study was conducted in accordance with the principles of the Declaration of Helsinki and Guidelines for Good Clinical Practice. All patients provided written informed consent before trial entry and the study was approved by the ethics committee or institutional review board at each site.
original articles
Annals of Oncology
The cut-off date for the final analysis was 6 months after the last patient was randomized. The study is currently ongoing and will end when the last patient has stopped randomized treatment with erlotinib or placebo and completed their final visit before withdrawal or the start of the open-label extension phase.
results patients
Patients randomized (n = 207)
Placebo (n = 103)
Completed AE Death PD Failure to return Refused Tx
Open-label erlotinib* (n = 57)
Completed AE Death PD Refused Tx Other
Erlotinib (n = 104)
Completed AE Death PD Other protocol violation Refused Tx
(n = 100) (n = 2) (n = 19) (n = 77) (n = 1) (n = 1)
(n = 102) (n = 9) (n = 15) (n = 72) (n = 1) (n = 5)
No open-label erlotinib (n = 43)
(n = 56) (n = 4) (n = 16) (n = 30) (n = 5) (n = 1)
Patients ongoing at data cutoff (n = 1)
Patients ongoing at data cutoff (n = 3)
Patients ongoing at data cutoff (n = 2)
Figure 1. CONSORT diagram. *Patients who had progressed on placebo were given the opportunity to switch to erlotinib in the open-label extension phase of the study, if deemed beneficial to the patient. AE, adverse event; PD, progressive disease; Tx, treatment.
| Propper et al.
Volume 25 | No. 7 | July 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
At the data cut-off on 22 December 2010, 207 patients had been enrolled and randomized (104 to erlotinib, 103 to placebo; Figure 1). The study was conducted in 49 centers across 15 countries. The first patient was randomized on 24 June 2008, and the last patient was randomized on 22 June 2010. Five patients remained on blinded treatment as of the data cut-off. All 207 patients were included in both the efficacy and safety analyses. Overall patient characteristics are listed in Table 1. Baseline characteristics, including stratification factors and line of therapy, were generally well matched between treatment arms. However, there
were a number of imbalances in baseline characteristics that were small in themselves, but overall indicated a worse prognosis in the erlotinib arm, namely patients randomized to erlotinib were older (40% aged ≥65 years versus 30%), more likely to have ≥10% weight loss in the past 6 months (37% versus 26%), more frequently had poorly differentiated disease (32% versus 21%) and reported more pancreatic pain (75% versus 59%). Also, patients randomized to erlotinib had a shorter median time since first diagnosis than those randomized to placebo (6.95 versus 8.77 months, respectively). Biomarker status was generally similar between the erlotinib and placebo arms: 69% of the patients in both arms had EGFR IHC-positive tumors, and nearly half of the patients had a longer CA repeat of EGFR intron 1 polymorphism (48% versus 42% in the erlotinib and placebo arms, respectively) (supplementary Table S1, available at Annals of Oncology online). No patients in the study had EGFR activating mutation-positive tumors. At disease progression, 53% of patients (57/102) in the placebo arm received open-label erlotinib, while only 18% of patients (19/104) in the erlotinib arm received further active therapies.
original articles
Annals of Oncology
Table 1. Baseline demographic and clinical characteristics in the overall population Characteristic
Erlotinib (n = 104)
57 (25–88) 31 (30) 72 (70) 59 (57) 44 (43) 86 (83) 17 (17) 27 (26) 75 (74) 98 (95) 5 (5) 29 (28) 49 (48) 25 (24) 34 (33) 69 (67) 8.77 (0.1–63.7) 1.08 (0.1–10.0) 15 (15) 88 (85) 10 (10) 38 (37) 22 (21) 33 (32) 61 (59) 42 (41)
ECOG, Eastern Cooperative Oncology Group. Total n = 173. b Smoking status: patients who had stopped smoking <1 year ago were counted as current smokers. c First-line treatment was defined as any patient who did not report taking palliative chemotherapy. a
efficacy
safety and tolerability
The median PFS in the overall population was similar in the erlotinib and placebo arms [median 6.1 versus 5.9 weeks, respectively; hazard ratio (HR) 0.83 (95% confidence interval (CI), 0.63–1.10); log-rank P = 0.1909; Figure 2]; however, the primary model did not adjust for baseline imbalances. The adjusted
Safety data were available for all 207 patients in the study (supplementary Table S2, available at Annals of Oncology online). The AE profile for erlotinib was comparable with previous experience with the drug. In this study, there were no cases of interstitial lung disease (ILD) with erlotinib; however, one case
Volume 25 | No. 7 | July 2014
doi:10.1093/annonc/mdu176 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Age, years Median (range) 62 (33–90) Age, n (%) ≥65 years 42 (40) <65 years 62 (60) Gender, n (%) Male 59 (57) Female 45 (43) ECOG performance status, n (%)a 0/1 88 (85) 2 16 (15) Weight loss in past 6 months, n (%) >10% 38 (37) ≤10% 65 (63) Region, n (%) Non-Asia 98 (94) Asia 6 (6) Smoking status, n (%)b Current smoker 29 (28) Never smoker 48 (46) Former smoker 27 (26) First-line treatment, n (%)c Yes 36 (35) No 68 (65) Months since first diagnosis Median (range) 6.95 (0.3–53.9) Months since progressiona Median (range) 0.97 (0.2–9.8) Stage at screening, n (%) Local 20 (19) Metastatic 84 (81) Histologic grade, n (%) Well differentiated 11 (11) Moderately differentiated 32 (31) Poorly differentiated 33 (32) Unknown 28 (27) Pain related to pancreatic cancer Yes 78 (75) No 26 (25)
Placebo (n = 103)
post hoc analysis of PFS correcting for baseline prognostic differences, including smoking status, pain related to pancreatic cancer, location of the primary tumor in the tail, and lesions in the pancreas, liver and other sites, showed a statistically significant effect with erlotinib [adjusted HR 0.68 (95% CI 0.50–0.91); P = 0.0102 using Wald’s test]. No significant difference was observed between erlotinib and placebo in the pre-planned, unadjusted OS analysis [4.0 versus 3.1 months, respectively; HR 1.04 (95% CI 0.77–1.39); log-rank P = 0.8137; Figure 2], but a post hoc, adjusted analysis showed a trend in favor of erlotinib [adjusted HR 0.83 (95% CI 0.60–1.16); P = 0.2867 using Wald’s test). Efficacy analyses by skin rash (supplementary Figure S1, available at Annals of Oncology online) and biomarker subgroups are presented in full in the supplementary material, available at Annals of Oncology online. No statistically significant difference in the median PFS was observed between the study arms in the overall population or according to stratification factor or tumor biomarker status within the pre-planned unadjusted analysis (Figure 2; supplementary Figures S2–S5, available at Annals of Oncology online). However, an adjusted analysis of biomarker subgroups using the post hoc model showed HRs for the EGFR IHC-positive subgroup and the short EGFR CA-SSR1 polymorphism subgroup were 0.64 (95% CI 0.42–0.98) and 0.63 (95% CI 0.41–0.95), respectively (supplementary Table S4, available at Annals of Oncology online). Pre-planned and post hoc analyses of OS did not identify any of the pre-planned tumor biomarkers that predicted a detrimental effect or a strong benefit with erlotinib. The factors identified by the stepwise selection of the Cox regression for OS in the FAS were smoking status, weight loss, pancreatic pain, location of the primary tumor in the tail, weight and tumor characteristics at screening (tumor size, number of target lesions, presence of non-target lesions, presence of tumors in the pancreas, liver and other sites). Different factors for PFS and OS were identified, as PFS is more driven by speed of tumor growth, while OS is more dependent on general health indicators such as weight. An adjusted post hoc analysis of additional serum biomarkers (Figure 3) showed that erlotinib provided a greater PFS and OS benefit than placebo for patients with high levels of amphiregulin [PFS-adjusted HR 0.51 (95% CI 0.33–0.80); OS-adjusted HR 0.55 (95% CI 0.34–0.92)], and likely no benefit for patients with low levels of amphiregulin [PFS-adjusted HR 0.94 (95% CI 0.60–1.47); OS-adjusted HR 1.26 (95% CI 0.74–2.16)]. In addition, erlotinib provided a greater PFS benefit but no significant difference in OS versus placebo in patients with low levels of EGF, or high levels of TGF-α (Figure 3). No complete responses were reported in this study, although partial responses were observed in 1% and 4% of erlotinib- and placebo-treated patients, respectively. DCR was higher with erlotinib compared with placebo (28% versus 18%, P = 0.1077), although the difference did not reach statistical significance.
original articles
Annals of Oncology
Proportion without event
A 1.0
Erlotinib (n = 104, median = 6.1) Placebo (n = 103, median = 5.9)
0.8
HR 0.83 (0.63 – 1.10) Log-rank P = 0.1909
0.6
Adjusted post-hoc analysis* HR 0.68 (0.50 – 0.91) Log-rank P = 0.0102 (Wald’s test)
0.4
0.2
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96 102 108 114
0 2
0 2
0 2
Duration of progression-free survival (weeks) No. of patients at risk 104 59 Erlotinib 103 48 Placebo
28 18
18 9
8 7
6 6
3 5
1 5
1 5
1 4
1 3
1 3
0 2
0 2
0 2
0 1
0 0
Proportion without event
B 1.0
Erlotinib (n = 104, median = 4.0) Placebo (n = 103, median = 3.1)
0.8
HR 1.04 (0.77 – 1.39) Log-rank P = 0.8137
0.6
Adjusted post-hoc analysis* HR 0.83 (0.60 – 1.16) Log-rank P = 0.2867 (Wald’s test)
0.4
0.2
0
3
6
9
12
15
18
21
24
27
30
0 2
0 2
0 0
0 0
Duration of survival (months) No. of patients at risk Erlotinib 104 Placebo 103
59 51
29 28
13 17
8 12
4 7
1 2
Figure 2. Progression-free survival (PFS) and overall survival (OS) by treatment arm. *The Kaplan–Meier curve shown is not adjusted for imbalances in baseline characteristics.
(1.0%) of ILD was observed in the placebo arm. No new safety signals were observed.
discussion This randomized, phase II, biomarker study in patients with advanced, pre-treated pancreatic cancer did not identify a population subset with a strong benefit or detrimental effect after treatment with erlotinib in this population with poor prognosis. The pre-planned, unadjusted analysis for PFS did not demonstrate a significant benefit for erlotinib. However, the study was not powered to detect a significant difference and a post hoc, adjusted analysis, taking into account imbalances in baseline characteristics, showed a statistically significant effect of erlotinib on PFS [adjusted HR 0.68 (95% CI 0.50–0.91); P = 0.0102].
| Propper et al.
KRAS wild-type disease and EGFR activating mutations have been associated with improved response to EGFR-targeted therapies in other tumors [8–11]. In this study, the results in the subgroups with KRAS mutations or EGFR wild-type disease were similar to the overall population (HR 0.79, 0.90 and 0.73, respectively). A post hoc adjusted analysis of serum biomarkers showed that patients with elevated baseline levels of amphiregulin, which is a potent mitogen acting at the EGFR in pancreatic cancer cells [12], derived a greater PFS and OS benefit from erlotinib versus placebo, while no difference was seen in those who had low levels of amphiregulin. In addition, a greater PFS benefit with erlotinib was observed in patients with low levels of EGF or high levels of TGF-α. A definitive mechanism for the effect of these markers on clinical efficacy has not been established. High amphiregulin
Volume 25 | No. 7 | July 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
0
original articles
Annals of Oncology
A HR (95% CI) All
Total no. of patients
0.68 (0.50–0.91)
206
Low (£median)
0.94 (0.60–1.47)
99
High (>median)
0.51 (0.33–0.80)
99
Low (£median)
0.53 (0.34–0.83)
101
High (>median)
0.84 (0.54–1.30)
100
Low (£median)
0.66 (0.43–1.03)
101
High (>median)
0.67 (0.44–1.03)
100
Low (£median)
0.68 (0.43–1.08)
100
High (>median)
0.51 (0.32–0.81)
98
Amphiregulin
EGF
sHER2
0.4
0.6
1
2
HR Favors erlotinib
Favors placebo
B HR (95% CI) All
Total no. of patients
0.83 (0.60–1.16)
201
Low (£median)
1.26 (0.74–2.16)
99
High (>median)
0.55 (0.34–0.92)
94
Low (£median)
0.61 (0.38–0.99)
98
High (>median)
0.87 (0.52–1.46)
98
Low (£median)
0.65 (0.38–1.10)
98
High (>median)
0.85 (0.52–1.39)
98
Low (£median)
0.90 (0.54–1.49)
97
High (>median)
0.65 (0.37–1.15)
96
Amphiregulin
EGF
sHER2
TGF-a
0.4
0.6
1
2
HR Favors erlotinib
Favors placebo
Figure 3. Summary of exploratory serum biomarker analyses for progression-free survival (PFS) and overall survival (OS)-adjusted post hoc analysis.
levels may indicate a poor prognosis, since it stimulates EGFR coupling to cell proliferation (as does TGF-α) [13]. Amphiregulin may also alter EGFR internalization and degradation, favoring accumulation of EGFR at the cell surface [14], thus making cells more susceptible to EGFR tyrosine-kinase inhibitors, while EGF competitively antagonizes amphiregulin and internalizes EGFR. In this study, conducted in patients with a poor prognosis, there was no significant difference between the erlotinib and placebo arms in the unstratified analysis of OS. However, it should be
Volume 25 | No. 7 | July 2014
noted that approximately half of the patients in the placebo arm received open-label erlotinib after progression and this cross-over may have influenced the results of the OS analysis. The safety and tolerability profile of erlotinib in this study was as expected, and the incidence of AEs such as rash and gastrointestinal disturbances was consistent with previous experience with erlotinib in pancreatic cancer and other tumors [3, 9–11], with no new safety signals observed. In contrast with previous studies [15], skin rash was not predictive of improved
doi:10.1093/annonc/mdu176 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
TGF-a
original articles
acknowledgements Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. The authors would like to thank all patients who participated in the study and the clinical personnel involved in tumor sampling, data collection and analysis. John Bridgewater was supported in part by the UCLH/UCL Biomedical Research Centre.
funding This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland [no grant number].
disclosure DP, ID and LK have no conflicts of interest. JB has received honoraria from Merck and participated as an advisor for Roche. AF, CH and BK are paid employees of F. Hoffmann-La Roche Ltd. AF and BK also own stock in F. Hoffmann-La Roche Ltd. MD has received honoraria from Roche, Merck Serono and Novartis; has acted as a consultant/advisor for Roche, Merck Serono and Amgen; and has received research funding from Roche and Chugai.
references 1. Samuel N, Hudson TJ. The molecular and cellular heterogenecity of pancreatic ductal adenocarcinoma. Nat Rev Gastroenterol Hepatol 2011; 9: 77–87. 2. Burris H, III, Rocha-Lima C. New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. Oncologist 2008; 13: 289–298.
| Propper et al.
3. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960–1966. 4. Cunha Santos G, Dhani N, Tu D et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer 2010; 116: 5599–5607. 5. Epelbaum R, Schnaider J, Gluzman A et al. Erlotinib as a single-agent therapy in patients with advanced pancreatic cancer. Presented at the American Society of Clinical Oncology Gastrointestinal Symposium, Orlando, FL, 19–21 January 2007. Abstract 202. 6. Common Terminology Criteria for Adverse Events v3.0 (CTCAE): The NCI Common Terminology Criteria for Adverse Events. Bethesda, MD: Cancer Therapy Evaluation Program, 2006. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/ctcaev3.pdf (11 June 2014, date last accessed). 7. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975; 31: 103–115. 8. Van Cutsem E, Köhne C-H, Lang I et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29: 2011–2019. 9. Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958–967. 10. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957. 11. Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG- 0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12: 735–742. 12. Yokoyama M, Ebert M, Funatomi H et al. Amphiregulin is a potent mitogen in human pancreatic-cancer cells—correlation with patient survival. Int J Oncol 1995; 6: 625–631. 13. Wilson KJ, Mill C, Lambert S et al. EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors 2012; 30: 107–116. 14. Willmarth NE, Baillo A, Dziubinski ML et al. Altered EGFR localization and degradation in human breast cancer cells with an amphiregulin/EGFR autocrine loop. Cell Signal 2009; 21: 212–219. 15. Wacker B, Nagrani T, Weinberg J et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007; 13: 3913–3921. 16. Duffy MJ, Sturgeon C, Lamerz R et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol 2010; 21: 441–447. 17. Lee J, Jang KT, Ki CS et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer 2007; 109: 1561–1569. 18. Jamieson NB, Carter CR, McKay CJ et al. Tissue biomarkers for prognosis in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. Clin Cancer Res 2011; 17: 3316–3331.
Volume 25 | No. 7 | July 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
PFS in this study, perhaps because of improved early intervention and effective prophylactic use of emollient creams. To date, there is limited evidence to support the use of predictive biomarkers for patients with pancreatic cancer who could benefit from targeted therapies. CA19-9 is an adverse prognostic marker [16]. KRAS mutations may also adversely affect prognosis [17], as may Bcl-2-associated X protein (BAX), Bcl-2, survivin, Ki-67, cyclooxygenase-2, E-cadherin and S100 calcium-binding proteins, in particular S100A2 [18]. The observation based on the exploratory analyses from this study, that patients with elevated baseline levels of amphiregulin obtained a greater PFS and OS benefit with erlotinib, suggests some potential value for this biomarker in pancreatic cancer. Further research is still needed, however, to identify those patients with advanced pancreatic cancer who may benefit most from erlotinib.
Annals of Oncology