- Email: [email protected]
Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer
original articles
Annals of Oncology Annals of Oncology 25: 1578–1584, 2014 doi:10.1093/annonc/mdu174 Published online 14 May 2014
Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer 1 Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; 2Prince of Songkla University, Songkhla, Thailand; 3Hematology Oncology Associates, Port St Lucie, USA; 4Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 5US Oncology Research, Houston; 6Virginia Cancer Specialists, Fairfax; 7 Compass Oncology, Vancouver, USA; 8Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China; 9Department of Medical Oncology, National Cancer Centre, Singapore, Republic of Singapore; 10Eisai Inc., Woodcliff Lake, USA; 11Eisai Ltd, Hatfield, UK; 12Ocala Oncology, Ocala, USA
Received 12 September 2013; revised 16 April 2014; accepted 23 April 2014
Background: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. Patients and methods: Eligible patients were randomized to eribulin mesylate 2.0 mg/m2 on day 1 with erlotinib 150 mg on days 2–16 (21-day regimen) or eribulin mesylate 1.4 mg/m2 on days 1 and 8 with erlotinib 150 mg on days 15–28 (28-day regimen). The primary end point was objective response rate (ORR). Results: One hundred and twenty-three patients received ≥1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%–24%] and 17% (95% CI 8%–29%), and disease control rates were 48% (95% CI 35%–61%) and 63% (95% CI 50%–75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. Conclusion: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155. Key words: biomarker, eribulin, erlotinib, non-small-cell lung cancer, platinum-based doublet chemotherapy
introduction Lung cancer is the most common cause of cancer death worldwide [1]. Most patients are diagnosed at an advanced stage and their 5-year survival rates are low [2]. Standard first-line therapy for patients without a known driver oncogene is platinum-based doublet chemotherapy; second-line therapy is single-agent docetaxel or pemetrexed. However, the magnitude of improvement in overall survival (OS) is limited [3–7]. Combining anti-cancer agents with different mechanisms of action may improve efficacy while maintaining tolerability. *Correspondence to: Prof. Tony Mok, Department of Clinical Oncology, The Chinese University of Hong Kong, State Key Laboratory of South China, Sha Tin, Hong Kong, China. Tel: +852-2632-1032; Fax: +852-2632-5816; E-mail: [email protected]. edu.hk
Early studies investigating concomitant administration of cytotoxic drugs and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) did not indicate synergism [8–11]. However, recent evidence suggests that sequential administration, involving intermittent EGFR-TKI dosing intercalated between chemotherapy cycles, may improve treatment outcome [12–14]. A placebo-controlled, randomized phase II study of sequential administration of gemcitabine/platinum chemotherapy followed by 14 days’ erlotinib or placebo as first-line treatment showed significant prolongation of progression-free survival (PFS) [12]. The non-taxane microtubule dynamics inhibitor eribulin mesilate (International Non-proprietary Name eribulin) is indicated in the EU as monotherapy for the treatment of patients with advanced stage breast cancer who have progressed after at least
© 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
T. S. Mok1*, S. L. Geater2, N. Iannotti3, S. Thongprasert4, A. Spira5,6, D. Smith5,7, V. Lee8, W. T. Lim9, L. Reyderman10, B. Wang10, P. Gopalakrishna11, F. Garzon10, L. Xu10 & C. Reynolds5,12
original articles
Annals of Oncology
patients and methods study design In this open-label, multicentre, phase II study, patients were randomized (1:1) to receive eribulin mesylate 2.0 mg/m2 (eribulin 1.75 mg/m2 expressed as free base) on day 1 with erlotinib 150 mg on days 2–16 of a 21-day cycle or eribulin mesylate 1.4 mg/m2 (eribulin 1.23 mg/m2 expressed as free base) on days 1 and 8 with erlotinib 150 mg on days 15–28 of a 28-day cycle. Eribulin was administered as an intravenous infusion in 2–5 min and erlotinib given orally. Patients were randomized via a central interactive voice response system. Randomization was stratified by race (Asian, non-Asian), tumour histology (squamous, non-squamous), and smoking history [never smoker (<100 cigarettes ever), history of smoking]. Treatment continued until disease progression, unacceptable toxicity, death, or as long as clinically appropriate. Grade 3 or 4 toxicities were managed by dose reduction or interruption. Study approval was obtained from participating centres’ Institutional Review Board or Independent Ethics Committee. The study was conducted using Good Clinical Practice in accordance with the Principles of the World Medical Association Declaration of Helsinki 2008, the International Conference on Harmonisation guidelines (CPMP/ICH/135/95), and the United States Code of Federal Regulations (US 21 CFR). All patients provided written informed consent.
patients and study objectives Key inclusion criteria were: 18 years or older; histologically confirmed NSCLC with measurable disease; ≥1 prior platinum-based doublet chemotherapy for recurrent/advanced NSCLC; disease progression during or after last anti-cancer therapy; Eastern Cooperative Oncology Group performance status ≤2; adequate bone marrow, liver, and renal function. Exclusion criteria included: prior therapy with eribulin or EGFR-TKI; known brain metastases unless treated and stable; and pre-existing neuropathy grade >2. The primary efficacy end point was ORR. Secondary efficacy end points were PFS, duration of response (DOR), disease control rate (DCR), and OS. Clinical benefit rate (CBR) was an exploratory efficacy end point. Safety, pharmacokinetic (PK), and exploratory biomarker analyses were also carried out.
assessments efficacy and safety. Tumour response was assessed by the investigator (with Response Evaluation Criteria in Solid Tumors [17]) every 8 weeks or sooner if progressive disease (PD) was suspected. Complete responses (CRs) and partial responses (PRs) required confirmation by scanning after 4 weeks or more. DCR and CBR included CR, PR, or stable disease (SD; ≥7 weeks
Volume 25 | No. 8 | August 2014
for DCR; ≥6 months for CBR). DOR was time from first documented evidence of response (CR or PR) until PD or death. PFS was time from randomization until date of PD or death. OS was time from randomization until death due to any cause, last date known alive, or study cut-off (censored). Adverse events (AEs) and serious AEs (SAEs) were assessed according to the National Cancer Institute Common Terminology Criteria for AEs (version 4).
pharmacokinetics. Sampling was carried out for the first 12 subjects in each dose regimen enrolled at sites able to perform PK assessments. Blood samples were collected 5 min pre-dose, and 5 min, 0.25, 0.5, 1, 2, 4, 6–8, 24–26, 72–120, and 168 h after day 1 administration of eribulin in cycles 1 and 2. Plasma concentrations of eribulin were quantified by a validated liquid chromatographytandem mass spectrometry method [18]. PK parameters were estimated using non-compartmental analysis of plasma concentration–time data.
exploratory analyses: biomarker assessments. Archival tumour specimens (paraffin blocks or unstained slides) were sent to a central laboratory (Genzyme Genetics, now LabCorp Integrated Oncology). Formalinfixed, paraffin-embedded sections were analysed for EGFR expression by standard immunohistochemistry procedure and for EGFR gene amplification and/or high polysomy by fluorescence in situ hybridization using EGFRCEP7® dual-colour DNA probe (Vysis®). Tumour DNA from tissue samples was analysed for KRAS mutation in codons 12 and 13 by single-nucleotide primer extension and for EGFR mutation by polymerase chain reaction amplification and bidirectional gene sequencing of exons 18–21 of the tyrosine kinase domain.
statistical analyses For efficacy end points, primary analyses were based on the intent-to-treat population (all randomized patients). The safety population included all randomized patients who received at least one dose of study drug, and had at least one post-baseline safety evaluation. The PK population comprised all patients who received at least one dose of study drug and had evaluable PK data. Biomarker analyses were carried out on patients with evaluable biomarker samples. Approximately 100 patients were to be randomized; however, according to a protocol amendment, enrolment of non-Asian patients was stopped and additional Asian patients were enrolled to allow for the recruitment of ≥30% Asian patients in order to enrol the requisite number of patients with EGFR mutation [19]. For each study arm, the 90% one-sided confidence interval (CI) would have 80% power to exclude the historical control ORR of 9% for erlotinib alone if the sample size was 50 patients and the ORR was 20% for the combination. The decision rule for this study was to identify a combination regimen with a potentially higher ORR than single-agent erlotinib; an observation of the ORR of 20% or above would imply a 90% confidence that there is potential synergy between the two agents. Data cut-off for the primary analysis occurred when the last patient completed the week 16 tumour assessment or was off-study. The sample size was not powered for formal statistical treatment comparisons; both regimens were experimental. ORRs were computed with 90% one-sided and 95% two-sided CIs using the Clopper–Pearson method [20]. The median PFS, DOR, and OS were calculated with two-sided 95% CIs using the Kaplan–Meier method. For DCR and CBR, the corresponding exact Clopper–Pearson 95% two-sided CIs were computed. Safety data were summarized using descriptive statistics. Planned exploratory analyses evaluated the correlation between biomarkers and best ORR (Fisher’s exact test; ORR ‘Yes’ defined as ‘CR’ or ‘PR’, ORR ‘No’ defined as ‘SD’ or ‘PD’), PFS (Kaplan–Meier’s curve, log-rank test), and reduction in tumour volume (Wilcoxon’s test).
doi:10.1093/annonc/mdu174 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
two chemotherapeutic regimens. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments [15]. A phase II study of singleagent eribulin as second-line therapy for NSCLC reported an objective response rate (ORR) of 10% [16]. We postulated that an intercalated combination of eribulin and erlotinib would be efficacious in patients with advanced NSCLC and unknown EGFR mutation status. Eribulin mesylate is administered on days 1 and 8 within every 21-day cycle. We modified this regimen to accommodate at least 14 days of erlotinib in the intercalated combination. The objective of this randomized phase II study was to evaluate the efficacy and tolerability of these two intercalated regimens of eribulin and erlotinib in patients with advanced NSCLC previously treated with platinum-based doublet chemotherapy.
original articles
Annals of Oncology
results patients Between 22 February 2010 and 14 December 2010, 123 eligible patients were randomized to the 21-day (n = 63) or 28-day (n = 60) regimen (Figure 1) at 38 sites (23, United States; 15, Asia). Baseline demographics and disease characteristics (Table 1) were similar between arms.
study drug exposure
assessments efficacy. The ORR was 13% (lower bound of 90% CI, 8; 95% CI, 6–24) for the 21-day and 17% (lower bound of 90% CI, 11; 95%
safety. With both regimens, all patients reported AEs and the incidences of grade ≥3 AEs were 84% for the 21-day regimen and 80% for the 28-day regimen. The total number of deaths considered to be treatment-related was 5 (21-day: febrile neutropenia, acute respiratory failure, and pneumonia; 28-day: febrile neutropenia and pneumonia). Other AEs were mostly disease-related. The incidences of AEs (all grades) are summarized in supplementary Table S2, available at Annals of Oncology online. Most common grade ≥3 AEs for the 21- and 28-day regimens included neutropenia (56% versus 48%), asthenia/fatigue (13% versus 12%), and dyspnoea (10% for both regimens). Febrile neutropenia
Subjects enrolled N = 164
Subjects randomized n = 123
Treated n = 123
21-day regimen n = 63
28-day regimen n = 60
Treatment ongoing at cut-off date Discontinued treatment at cut-off date Reason for discontinuation of treatment: Disease progression (completed treatment) Adverse event Subject choice Lost to follow-up Administrative/other
Analysis populations: Intent-to-treat Per protocol Response evaluable Safety Pharmacokinetics
Screen failures (n = 41) Reason: Inclusion/exclusion criteria n = 31 Adverse event n=2 Lost to follow-up n=0 Withdrawn consent n=3 Other n=5
n = 63 n = 51 n = 62 n = 63 n = 22
n=1 n = 62 n = 37 n = 15 n=6 n=0 n=4
Treatment ongoing at cut-off date Discontinued treatment at cut-off date Reason for discontinuation of treatment: Disease progression (completed treatment) Adverse event Subject choice Lost to follow-up Administrative/other
Analysis populations: Intent-to-treat Per protocol Response evaluable Safety Pharmacokinetics
n=2 n = 58 n = 40 n=8 n=5 n=0 n=5
n = 60 n = 52 n = 58 n = 60 n = 16
Figure 1. CONSORT diagram.
| Mok et al.
Volume 25 | No. 8 | August 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Of the 123 patients randomized into the study, all patients in both treatment regimens received at least one dose of study drug. The median number of cycles received per patient was 3 (range, 1–44 cycles) for the 21-day and 4 (range, 1–33) for the 28-day regimen. Dose delays, omissions, and reductions were undertaken in 20 (32%), 0, and 20 (32%) patients, respectively, for the 21-day regimen, and in 20 (33%), 7 (12%), and 16 (27%) patients, respectively, for the 28-day regimen.
CI, 8–29; one-sided P-value of 0.041 compared with the prespecified reference ORR of 9%) for the 28-day regimen (supplementary Table S1, available at Annals of Oncology online). The DCR was higher with the 28-day (63%) compared with the 21-day (48%) regimen, although the CBR was similar. The median DOR was 9.4 months (95% CI, 2.7–censored) for the 21day regimen. The median DOR for the 28-day regimen was 9.7 months (95% CI 5.6–censored). The median PFS was 3.5 and 3.8 months, and the median OS 7.6 and 8.5 months for the 21- and 28-day regimen, respectively (Figure 2A and B).
original articles
Annals of Oncology
Table 1. Baseline patient demographics and disease characteristics (intent-to-treat population) Characteristic
21-day regimen (n = 63)
63.5 (39–87)
33 (55) 27 (45) 35 (58) 23 (38) 2 (3)
44 (73) 16 (27) 2 (3) 2 (3) 1 (2) 0 6 (10) 12 (20) 37 (62) 15 (25) 40 (67) 5 (8) 46 (77) 14 (23) 34 (57) 11 (18) 15 (25)
All data are n (%) unless otherwise stated. ECOG, Eastern Cooperative Oncology Group.
occurred in more patients on the 21-day regimen than the 28-day regimen (17% versus 5%). More patients on the 21-day regimen required dose reductions due to AEs (40% versus 27% for the 28day regimen), and the incidence of SAEs also appeared to be higher (60% versus 45%), including a higher incidence of SAEs requiring/ prolonging hospitalization (59% versus 35%). More patients on the 21-day regimen experienced AEs leading to study drug withdrawal (24% versus 10% for the 28-day regimen). A total of 15 patients had AEs resulting in death.
pharmacokinetics. Eribulin PK parameters were similar to those defined previously [21], and comparable between the 21- and 28-day dosing regimens (supplementary Table S3, available at Annals of Oncology online). The mean elimination half-life in cycle 1 ranged from 27 to 32 h.
Volume 25 | No. 8 | August 2014
exploratory analyses: biomarker assessments. Sixty patients (21day, 34; 28-day, 26) were assessed for biomarker analyses (7 PR, 30 SD, 10 PD, 13 not evaluable). Twenty-one patients (36%) had tumours that tested EGFR FISH-positive (29 negative, 8 undetermined, 2 missing). EGFR protein expression was detected in 46 patients (77%) (6 negative, 8 unknown). EGFR mutations were detected in 8 patients (13%) (35 wild type, 17 unknown), and KRAS mutations were detected in 15 patients (25%) (30 wild-type, 15 unknown), respectively. Four of the eight patients (50%) with EGFRmutant tumours responded, with DORs of 2.0 (censored), 7.2, 7.4, and 20.4 months. Positive correlations with ORR (P = 0.018) and reduction in tumour volume (P = 0.016) were observed (Table 2). No other significant associations were observed between the studied biomarkers and efficacy parameters.
discussion This randomized phase II study confirmed the feasibility of combining eribulin with erlotinib in an intercalated manner with the 28-day regimen meeting our predefined criteria for a positive result. However, ORRs of 13% and 17% suggest similar efficacy for the two regimens, supported by similar survival outcomes. Our findings suggest that addition of the EGFR-TKI erlotinib does not improve the treatment outcome of eribulin in these patients (no selection by biomarker status) with advanced NSCLC. This may best be explained by the fact that most of the patients in this study did not harbour activating EGFR mutations. When this study was designed, it was unclear whether the intercalated combination of chemotherapy and EGFR-TKI would improve treatment outcomes in patients with or without EGFR mutation. Recent data from NVALT-10 [22] and FASTACT 2 [23] suggest that patients without activating EGFR mutations are unlikely to benefit from the combination. In NVALT-10, intercalated combination of single-agent chemotherapy and erlotinib improved PFS of patients with non-squamous cell carcinoma but not those with squamous cell carcinoma. Although biomarker analysis for EGFR mutation was not available in NVALT-10, it is reasonable to postulate that the majority of patients with squamous cell carcinoma had EGFR mutation-negative tumours. Wu et al. [23] reported similar findings in their randomized phase III study, whereby the benefit of intercalated combination of gemcitabine/platinum and erlotinib was confined to patients with EGFR-mutant tumours. The majority of patients in the current study were white with a history of smoking; only eight (13%) of the tested population had EGFRmutant disease. Thus, our findings also show that addition of EGFR-TKI to chemotherapy fails to improve treatment outcome in patients without EGFR mutation. Both regimens were generally well tolerated, with no additional safety considerations with the combination. The 21-day regimen was associated with a relatively higher incidence of dose reduction and SAEs. Erlotinib induces cytochrome P450
doi:10.1093/annonc/mdu174 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Age, years [median 62.0 (35–87) (range)] Gender Male 33 (52) Female 30 (48) Race White 35 (56) Asian 24 (38) Black or African 4 (6) American Primary tumour type Non-squamous 48 (76) Squamous 15 (24) Disease stage at diagnosis IA 0 IB 1 (2) IIA 2 (3) IIB 2 (3) IIIA 7 (11) IIIB 7 (11) IV 44 (70) ECOG performance status 0 16 (25) 1 40 (64) 2 7 (11) Smoking history Former smoker 47 (75) Never smoker 16 (25) Number of previous anti-cancer regimens 1 37 (59) 2 21 (33) ≥3 4 (6)
28-day regimen (n = 60)
There was a dose-related increase in eribulin exposure: the mean area under the concentration–time curve (AUC) from time zero to infinity for cycle 1 was 851.5 and 1276.5 ng·h/ml following 1.4 and 2 mg/m2 dose administration, respectively. Dose-normalized exposure was similar on day 1 of cycles 1 and 2 of both regimens, indicating lack of eribulin accumulation on subsequent dosing.
original articles
Annals of Oncology
A 1.0
21-day regimen Censored: 21-day regimen
28-day regimen Censored: 28-day regimen
0.9 0.8
Probability
0.7 0.6 3.8 months
0.5 0.4
3.5 months
0.2 0.1 0.0 0
2
4
6
8
12
10
14
16
18
20
22
24
26
28
30
Progression-free survival (months) Patients at risk (n = ): 21-day regimen 63 52 36 30 23 19 15 15 13 13 8 7 6 4 3 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 0 28-day regimen 60 55 40 36 22 22 17 16 11 11 9 8 7 6 5 5 5 5 5 5 5 5 5 5 5 5 4 3 2 1 0 21-day regimen
Number of patients 63
Events 53 (84.1%)
Censored 10 (15.9%)
Median PFS (95% CI) 3.5 (1.9, 4.7)
28-day regimen
60
48 (80.0%)
12 (20.0%)
3.8 (3.3, 5.5)
B 1.0
21-day regimen Censored: 21-day regimen
28-day regimen Censored: 28-day regimen
0.9 0.8
Probability
0.7 0.6 8.5 months
0.5 7.6 months 0.4 0.3 0.2 0.1 0.0 0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
Overall survival (months) Patients at risk (n = ): 21-day regimen 63 59 54 51 47 44 40 37 28 28 25 23 23 21 20 18 17 16 13 12 11 11 10 10 8 8 6 6 5 3 3 3 2 2 1 0 0 28-day regimen 60 58 53 49 42 42 37 34 29 25 23 22 21 20 18 18 18 17 16 16 16 16 15 14 14 14 14 14 13 11 11 8 4 3 2 2 0 21-day regimen
Number of patients 63
Events 58 (92.1%)
Censored 5 (7.9%)
Mean overall survival (95% CI) 7.6 (6.3, 11.0)
28-day regimen
60
44 (73.3%)
16 (26.7%)
8.5 (6.2, 13.1)
Figure 2. Kaplan–Meier analysis of (A) progression-free survival and (B) overall survival (intent-to-treat population). CI, confidence interval; PFS, progression-free survival.
| Mok et al.
Volume 25 | No. 8 | August 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
0.3
original articles
Annals of Oncology
Table 2. Summary of efficacy by EGFR mutation status (intent-totreat population with evaluable biomarker data) Efficacy parameter
Result by EGFR mutation status EGFR mutation EGFR wild type positive (n = 8) (n = 35)a
Best objective response, n (%) Partial response 4 (50) Stable disease 4 (50) Disease progression 0 Not evaluable 0
0.59 (0.24–1.41) P = 0.23
a
n = 26 evaluable for tumour shrinkage. CI, confidence interval; EGFR, epidermal growth factor receptor.
(CYP)3A4 and decreases exposure (AUC) of co-administered drugs that are CYP3A4 substrates. Eribulin is a CYP3A4 substrate; however, metabolism has been shown to be a minor contribution to eribulin clearance [21]. Prolonged (>7 days) administration of the CYP inducer erlotinib will result in enzyme induction; however, in the current study, eribulin exposure (AUC) and clearance were comparable when eribulin was administered alone (day 1, cycle 1) or after extended administration of erlotinib (day 1, cycle 2). This indicates that CYP3A4 induction does not have a substantial effect on eribulin exposure and that eribulin efficacy will not be compromised when administered with erlotinib according to the dosing regimen tested. These results are in agreement with another study which demonstrated that co-administration with rifampicin, a strong CYP3A4 inducer, also had no effect on eribulin exposure [24]. Given the positive primary result and slightly better tolerance, the 28-day regimen should be considered for future investigation. The combination of chemotherapy and EGFR-TKI has been controversial. Our study demonstrates the feasibility of combining a novel cytotoxic chemotherapy with EGFR-TKI in an intercalated manner. However, addition of EGFR-TKI is unlikely to improve treatment outcomes in patients without EGFR mutation. Future investigation should explore the combination in patients with EGFR-mutant disease in comparison with single-agent EGFR-TKI.
acknowledgements We thank all the patients and investigators who participated in this study (see Appendix). We also thank Annette Smith, PhD, from Complete Medical Communications, who provided medical writing support, and Oxford PharmaGenesis™ Ltd (UK), who provided additional medical writing support for the manuscript revisions. All funding for medical writing support was provided by Eisai.
Volume 25 | No. 8 | August 2014
This study was funded by Eisai Ltd (NCT01104155).
disclosure TSM is an advisor for AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, Bristol-Myers Squibb, BeiGene, AVEO Oncology, Pfizer, Taiho, Boehringer Ingelheim, GlaxoSmithKline Biologicals, and Clovis Oncology, is a member of the speakers’ bureau for Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, Merck Serono, and Pfizer, and is currently conducting research sponsored by AstraZeneca. LR, BW, PG, FG, and LX are employees of Eisai Ltd. CR has previously been on the speakers bureaus for Boehringer Ingelheim, Eisai, and Genentech. SLG, NI, ST, AS, DS, VL, and WTL have declared no conflicts of interest.
references 1. Ferlay J, Shin HR, Bray F et al. GLOBOCAN 2008 v2.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 10. http://globocan.iarc.fr (11 December 2012, date last accessed). 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29. 3. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22: 1589–1597. 4. Shepherd FA, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18: 2095–2103. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–132. 6. Kim ES, Hirsh V, Mok T et al. Gefitinib versus docetaxel in previously treated nonsmall-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008; 372: 1809–1818. 7. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 8. Gatzemeier U, Pluzanska A, Szczesna A et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25: 1545–1552. 9. Herbst RS, Prager D, Hermann R et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23: 5892–5899. 10. Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004; 22: 785–794. 11. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 2004; 22: 777–784. 12. Mok TS, Wu YL, Yu CJ et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced nonsmall-cell lung cancer. J Clin Oncol 2009; 27: 5080–5087. 13. Sangha R, Davies AM, Lara PN, Jr et al. Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: results of a phase I/ II trial. J Thorac Oncol 2011; 6: 2112–2119. 14. Li T, Lara PN, Jr, Mack PC et al. Intercalation of erlotinib and pemetrexed in the treatment of non-small cell lung cancer. Curr Drug Targets 2010; 11: 85–94. 15. Cortes J, O’Shaughnessy J, Loesch D et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011; 377: 914–923.
doi:10.1093/annonc/mdu174 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Tumour shrinkage (% tumour change from baseline to nadir), mean (95% CI) Hazard ratio for progression-free survival (95% CI)
2 (6) 17 (49) 7 (20) 9 (26) P = 0.018 −36 (−56 to −17) −10 (−21 to 1) P = 0.016
funding
original articles
23. Wu YL, Lee JS, Thongprasert S et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol 2013; 14: 777–786. 24. Devriese LA, Witteveen PE, Wanders J et al. Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin. Br J Clin Pharmacol 2013; 75: 507–515.
appendix investigators Hong Kong: VL, TSM; Korea: J.-H. Kim, S.-W. Kim, J.-S. Lee, J.-S. Lee, K.-C. Park; Malaysia: S.H. How, M.H. Saw, J. Low; Singapore: A. Chang, D. Lim; Taiwan: Y.-M. Chen, T.-C. Hsia, W.-C. Su, C.-H. Yang; Thailand: C. Koowattanapaisan, SLG, S. Sorraritchingchai, ST; United States: V. Armenio, R. Axelrod, L. Bazhenova, D. Bodkin, J. Cantrell, A. Chaudhry, L.-C. Chen, S. Gadgeel, S. Goel, R. Govindan, M. Gupta, NI, R. Jotte, D. Martincic, J. Muscato, M. Neubauer, J. Paschold, CR, R. Robles, P.J. Rosen, R. Ruxer, M. Savin, DS, AS, R. Yanagihara.
Annals of Oncology 25: 1584–1590, 2014 doi:10.1093/annonc/mdu172 Published online 13 June 2014
SNPs in the transforming growth factor-β pathway as predictors of outcome in advanced lung adenocarcinoma with EGFR mutations treated with gefitinib L. Zhang1, Q. X. Li1, H. L. Wu1, X. Lu2, M. Yang3, S. Y. Yu1 & X. L. Yuan1* Departments of 1Oncology; 2Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province; 3College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
Received 30 March 2014; revised 15 April 2014; accepted 23 April 2014
Background: The aim of this study was to evaluate whether genetic variations in the transforming growth factor-β (TGF-β) pathway influenced clinical outcome of advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations treated with gefitinib. Patients and methods: Two hundred six patients with advanced lung adenocarcinomas were enrolled in this study. EGFR mutation in these tumors was detected. Among them, 106 patients with EGFR mutation and 37 of 100 patients with wild type were treated with gefitinib. Genotype of 33 single-nucleotide polymorphisms (SNPs) from 13 genes involved in the TGF-β signaling pathway was determined, and their association with survival time was analyzed. Univariate and multivariate analyses were carried out to assess the role of biological/clinical parameters in progression-free survival (PFS) and overall survival (OS) using Pearson’s χ 2 test, log-rank test, and Cox proportional hazards model. Results: Among SNPs analyzed, multivariate analysis showed the cytidylate and thymidine (CT) genotype of SMAD3: rs11632964 was associated with a longer OS and PFS when the entire cohort of 143 patients were included; the association was significant in the patients with EGFR mutant tumors (30.8 versus 17.5 months; log-rank P = 0.020; and 20.8 *Correspondence to: Dr Xianglin Yuan, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei 430030, China. Tel: +86-27-8366 3406; Fax: +86-27-8366 2834; E-mail: [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
16. Spira AI, Iannotti NO, Savin MA et al. A phase II study of eribulin mesylate (E7389) in patients with advanced, previously treated non-small-cell lung cancer. Clin Lung Cancer 2012; 13: 31–38. 17. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247. 18. Desjardins C, Saxton P, Lu SX et al. A high-performance liquid chromatographytandem mass spectrometry method for the clinical combination study of carboplatin and anti-tumor agent eribulin mesylate (E7389) in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 875: 373–382. 19. Shigematsu H, Lin L, Takahashi T et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005; 97: 339–346. 20. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934; 26: 404–413. 21. Dubbelman AC, Rosing H, Jansen RS et al. Mass balance study of [14C]eribulin in patients with advanced solid tumors. Drug Metab Dispos 2012; 40: 313–321. 22. Aerts JG, Codrington H, Burgers S et al. A randomized phase II study comparing erlotinib (E) versus E alternating with chemotherapy in relapsed non-small cell lung cancer (NSCLC) patients. The NVALT10 study. Ann Oncol 2012; 23(Suppl. 9): abstr LBA29.
Annals of Oncology
Annals of Oncology Annals of Oncology 25: 1578–1584, 2014 doi:10.1093/annonc/mdu174 Published online 14 May 2014
Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer 1 Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; 2Prince of Songkla University, Songkhla, Thailand; 3Hematology Oncology Associates, Port St Lucie, USA; 4Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 5US Oncology Research, Houston; 6Virginia Cancer Specialists, Fairfax; 7 Compass Oncology, Vancouver, USA; 8Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China; 9Department of Medical Oncology, National Cancer Centre, Singapore, Republic of Singapore; 10Eisai Inc., Woodcliff Lake, USA; 11Eisai Ltd, Hatfield, UK; 12Ocala Oncology, Ocala, USA
Received 12 September 2013; revised 16 April 2014; accepted 23 April 2014
Background: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. Patients and methods: Eligible patients were randomized to eribulin mesylate 2.0 mg/m2 on day 1 with erlotinib 150 mg on days 2–16 (21-day regimen) or eribulin mesylate 1.4 mg/m2 on days 1 and 8 with erlotinib 150 mg on days 15–28 (28-day regimen). The primary end point was objective response rate (ORR). Results: One hundred and twenty-three patients received ≥1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%–24%] and 17% (95% CI 8%–29%), and disease control rates were 48% (95% CI 35%–61%) and 63% (95% CI 50%–75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. Conclusion: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155. Key words: biomarker, eribulin, erlotinib, non-small-cell lung cancer, platinum-based doublet chemotherapy
introduction Lung cancer is the most common cause of cancer death worldwide [1]. Most patients are diagnosed at an advanced stage and their 5-year survival rates are low [2]. Standard first-line therapy for patients without a known driver oncogene is platinum-based doublet chemotherapy; second-line therapy is single-agent docetaxel or pemetrexed. However, the magnitude of improvement in overall survival (OS) is limited [3–7]. Combining anti-cancer agents with different mechanisms of action may improve efficacy while maintaining tolerability. *Correspondence to: Prof. Tony Mok, Department of Clinical Oncology, The Chinese University of Hong Kong, State Key Laboratory of South China, Sha Tin, Hong Kong, China. Tel: +852-2632-1032; Fax: +852-2632-5816; E-mail: [email protected]. edu.hk
Early studies investigating concomitant administration of cytotoxic drugs and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) did not indicate synergism [8–11]. However, recent evidence suggests that sequential administration, involving intermittent EGFR-TKI dosing intercalated between chemotherapy cycles, may improve treatment outcome [12–14]. A placebo-controlled, randomized phase II study of sequential administration of gemcitabine/platinum chemotherapy followed by 14 days’ erlotinib or placebo as first-line treatment showed significant prolongation of progression-free survival (PFS) [12]. The non-taxane microtubule dynamics inhibitor eribulin mesilate (International Non-proprietary Name eribulin) is indicated in the EU as monotherapy for the treatment of patients with advanced stage breast cancer who have progressed after at least
© 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
T. S. Mok1*, S. L. Geater2, N. Iannotti3, S. Thongprasert4, A. Spira5,6, D. Smith5,7, V. Lee8, W. T. Lim9, L. Reyderman10, B. Wang10, P. Gopalakrishna11, F. Garzon10, L. Xu10 & C. Reynolds5,12
original articles
Annals of Oncology
patients and methods study design In this open-label, multicentre, phase II study, patients were randomized (1:1) to receive eribulin mesylate 2.0 mg/m2 (eribulin 1.75 mg/m2 expressed as free base) on day 1 with erlotinib 150 mg on days 2–16 of a 21-day cycle or eribulin mesylate 1.4 mg/m2 (eribulin 1.23 mg/m2 expressed as free base) on days 1 and 8 with erlotinib 150 mg on days 15–28 of a 28-day cycle. Eribulin was administered as an intravenous infusion in 2–5 min and erlotinib given orally. Patients were randomized via a central interactive voice response system. Randomization was stratified by race (Asian, non-Asian), tumour histology (squamous, non-squamous), and smoking history [never smoker (<100 cigarettes ever), history of smoking]. Treatment continued until disease progression, unacceptable toxicity, death, or as long as clinically appropriate. Grade 3 or 4 toxicities were managed by dose reduction or interruption. Study approval was obtained from participating centres’ Institutional Review Board or Independent Ethics Committee. The study was conducted using Good Clinical Practice in accordance with the Principles of the World Medical Association Declaration of Helsinki 2008, the International Conference on Harmonisation guidelines (CPMP/ICH/135/95), and the United States Code of Federal Regulations (US 21 CFR). All patients provided written informed consent.
patients and study objectives Key inclusion criteria were: 18 years or older; histologically confirmed NSCLC with measurable disease; ≥1 prior platinum-based doublet chemotherapy for recurrent/advanced NSCLC; disease progression during or after last anti-cancer therapy; Eastern Cooperative Oncology Group performance status ≤2; adequate bone marrow, liver, and renal function. Exclusion criteria included: prior therapy with eribulin or EGFR-TKI; known brain metastases unless treated and stable; and pre-existing neuropathy grade >2. The primary efficacy end point was ORR. Secondary efficacy end points were PFS, duration of response (DOR), disease control rate (DCR), and OS. Clinical benefit rate (CBR) was an exploratory efficacy end point. Safety, pharmacokinetic (PK), and exploratory biomarker analyses were also carried out.
assessments efficacy and safety. Tumour response was assessed by the investigator (with Response Evaluation Criteria in Solid Tumors [17]) every 8 weeks or sooner if progressive disease (PD) was suspected. Complete responses (CRs) and partial responses (PRs) required confirmation by scanning after 4 weeks or more. DCR and CBR included CR, PR, or stable disease (SD; ≥7 weeks
Volume 25 | No. 8 | August 2014
for DCR; ≥6 months for CBR). DOR was time from first documented evidence of response (CR or PR) until PD or death. PFS was time from randomization until date of PD or death. OS was time from randomization until death due to any cause, last date known alive, or study cut-off (censored). Adverse events (AEs) and serious AEs (SAEs) were assessed according to the National Cancer Institute Common Terminology Criteria for AEs (version 4).
pharmacokinetics. Sampling was carried out for the first 12 subjects in each dose regimen enrolled at sites able to perform PK assessments. Blood samples were collected 5 min pre-dose, and 5 min, 0.25, 0.5, 1, 2, 4, 6–8, 24–26, 72–120, and 168 h after day 1 administration of eribulin in cycles 1 and 2. Plasma concentrations of eribulin were quantified by a validated liquid chromatographytandem mass spectrometry method [18]. PK parameters were estimated using non-compartmental analysis of plasma concentration–time data.
exploratory analyses: biomarker assessments. Archival tumour specimens (paraffin blocks or unstained slides) were sent to a central laboratory (Genzyme Genetics, now LabCorp Integrated Oncology). Formalinfixed, paraffin-embedded sections were analysed for EGFR expression by standard immunohistochemistry procedure and for EGFR gene amplification and/or high polysomy by fluorescence in situ hybridization using EGFRCEP7® dual-colour DNA probe (Vysis®). Tumour DNA from tissue samples was analysed for KRAS mutation in codons 12 and 13 by single-nucleotide primer extension and for EGFR mutation by polymerase chain reaction amplification and bidirectional gene sequencing of exons 18–21 of the tyrosine kinase domain.
statistical analyses For efficacy end points, primary analyses were based on the intent-to-treat population (all randomized patients). The safety population included all randomized patients who received at least one dose of study drug, and had at least one post-baseline safety evaluation. The PK population comprised all patients who received at least one dose of study drug and had evaluable PK data. Biomarker analyses were carried out on patients with evaluable biomarker samples. Approximately 100 patients were to be randomized; however, according to a protocol amendment, enrolment of non-Asian patients was stopped and additional Asian patients were enrolled to allow for the recruitment of ≥30% Asian patients in order to enrol the requisite number of patients with EGFR mutation [19]. For each study arm, the 90% one-sided confidence interval (CI) would have 80% power to exclude the historical control ORR of 9% for erlotinib alone if the sample size was 50 patients and the ORR was 20% for the combination. The decision rule for this study was to identify a combination regimen with a potentially higher ORR than single-agent erlotinib; an observation of the ORR of 20% or above would imply a 90% confidence that there is potential synergy between the two agents. Data cut-off for the primary analysis occurred when the last patient completed the week 16 tumour assessment or was off-study. The sample size was not powered for formal statistical treatment comparisons; both regimens were experimental. ORRs were computed with 90% one-sided and 95% two-sided CIs using the Clopper–Pearson method [20]. The median PFS, DOR, and OS were calculated with two-sided 95% CIs using the Kaplan–Meier method. For DCR and CBR, the corresponding exact Clopper–Pearson 95% two-sided CIs were computed. Safety data were summarized using descriptive statistics. Planned exploratory analyses evaluated the correlation between biomarkers and best ORR (Fisher’s exact test; ORR ‘Yes’ defined as ‘CR’ or ‘PR’, ORR ‘No’ defined as ‘SD’ or ‘PD’), PFS (Kaplan–Meier’s curve, log-rank test), and reduction in tumour volume (Wilcoxon’s test).
doi:10.1093/annonc/mdu174 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
two chemotherapeutic regimens. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments [15]. A phase II study of singleagent eribulin as second-line therapy for NSCLC reported an objective response rate (ORR) of 10% [16]. We postulated that an intercalated combination of eribulin and erlotinib would be efficacious in patients with advanced NSCLC and unknown EGFR mutation status. Eribulin mesylate is administered on days 1 and 8 within every 21-day cycle. We modified this regimen to accommodate at least 14 days of erlotinib in the intercalated combination. The objective of this randomized phase II study was to evaluate the efficacy and tolerability of these two intercalated regimens of eribulin and erlotinib in patients with advanced NSCLC previously treated with platinum-based doublet chemotherapy.
original articles
Annals of Oncology
results patients Between 22 February 2010 and 14 December 2010, 123 eligible patients were randomized to the 21-day (n = 63) or 28-day (n = 60) regimen (Figure 1) at 38 sites (23, United States; 15, Asia). Baseline demographics and disease characteristics (Table 1) were similar between arms.
study drug exposure
assessments efficacy. The ORR was 13% (lower bound of 90% CI, 8; 95% CI, 6–24) for the 21-day and 17% (lower bound of 90% CI, 11; 95%
safety. With both regimens, all patients reported AEs and the incidences of grade ≥3 AEs were 84% for the 21-day regimen and 80% for the 28-day regimen. The total number of deaths considered to be treatment-related was 5 (21-day: febrile neutropenia, acute respiratory failure, and pneumonia; 28-day: febrile neutropenia and pneumonia). Other AEs were mostly disease-related. The incidences of AEs (all grades) are summarized in supplementary Table S2, available at Annals of Oncology online. Most common grade ≥3 AEs for the 21- and 28-day regimens included neutropenia (56% versus 48%), asthenia/fatigue (13% versus 12%), and dyspnoea (10% for both regimens). Febrile neutropenia
Subjects enrolled N = 164
Subjects randomized n = 123
Treated n = 123
21-day regimen n = 63
28-day regimen n = 60
Treatment ongoing at cut-off date Discontinued treatment at cut-off date Reason for discontinuation of treatment: Disease progression (completed treatment) Adverse event Subject choice Lost to follow-up Administrative/other
Analysis populations: Intent-to-treat Per protocol Response evaluable Safety Pharmacokinetics
Screen failures (n = 41) Reason: Inclusion/exclusion criteria n = 31 Adverse event n=2 Lost to follow-up n=0 Withdrawn consent n=3 Other n=5
n = 63 n = 51 n = 62 n = 63 n = 22
n=1 n = 62 n = 37 n = 15 n=6 n=0 n=4
Treatment ongoing at cut-off date Discontinued treatment at cut-off date Reason for discontinuation of treatment: Disease progression (completed treatment) Adverse event Subject choice Lost to follow-up Administrative/other
Analysis populations: Intent-to-treat Per protocol Response evaluable Safety Pharmacokinetics
n=2 n = 58 n = 40 n=8 n=5 n=0 n=5
n = 60 n = 52 n = 58 n = 60 n = 16
Figure 1. CONSORT diagram.
| Mok et al.
Volume 25 | No. 8 | August 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Of the 123 patients randomized into the study, all patients in both treatment regimens received at least one dose of study drug. The median number of cycles received per patient was 3 (range, 1–44 cycles) for the 21-day and 4 (range, 1–33) for the 28-day regimen. Dose delays, omissions, and reductions were undertaken in 20 (32%), 0, and 20 (32%) patients, respectively, for the 21-day regimen, and in 20 (33%), 7 (12%), and 16 (27%) patients, respectively, for the 28-day regimen.
CI, 8–29; one-sided P-value of 0.041 compared with the prespecified reference ORR of 9%) for the 28-day regimen (supplementary Table S1, available at Annals of Oncology online). The DCR was higher with the 28-day (63%) compared with the 21-day (48%) regimen, although the CBR was similar. The median DOR was 9.4 months (95% CI, 2.7–censored) for the 21day regimen. The median DOR for the 28-day regimen was 9.7 months (95% CI 5.6–censored). The median PFS was 3.5 and 3.8 months, and the median OS 7.6 and 8.5 months for the 21- and 28-day regimen, respectively (Figure 2A and B).
original articles
Annals of Oncology
Table 1. Baseline patient demographics and disease characteristics (intent-to-treat population) Characteristic
21-day regimen (n = 63)
63.5 (39–87)
33 (55) 27 (45) 35 (58) 23 (38) 2 (3)
44 (73) 16 (27) 2 (3) 2 (3) 1 (2) 0 6 (10) 12 (20) 37 (62) 15 (25) 40 (67) 5 (8) 46 (77) 14 (23) 34 (57) 11 (18) 15 (25)
All data are n (%) unless otherwise stated. ECOG, Eastern Cooperative Oncology Group.
occurred in more patients on the 21-day regimen than the 28-day regimen (17% versus 5%). More patients on the 21-day regimen required dose reductions due to AEs (40% versus 27% for the 28day regimen), and the incidence of SAEs also appeared to be higher (60% versus 45%), including a higher incidence of SAEs requiring/ prolonging hospitalization (59% versus 35%). More patients on the 21-day regimen experienced AEs leading to study drug withdrawal (24% versus 10% for the 28-day regimen). A total of 15 patients had AEs resulting in death.
pharmacokinetics. Eribulin PK parameters were similar to those defined previously [21], and comparable between the 21- and 28-day dosing regimens (supplementary Table S3, available at Annals of Oncology online). The mean elimination half-life in cycle 1 ranged from 27 to 32 h.
Volume 25 | No. 8 | August 2014
exploratory analyses: biomarker assessments. Sixty patients (21day, 34; 28-day, 26) were assessed for biomarker analyses (7 PR, 30 SD, 10 PD, 13 not evaluable). Twenty-one patients (36%) had tumours that tested EGFR FISH-positive (29 negative, 8 undetermined, 2 missing). EGFR protein expression was detected in 46 patients (77%) (6 negative, 8 unknown). EGFR mutations were detected in 8 patients (13%) (35 wild type, 17 unknown), and KRAS mutations were detected in 15 patients (25%) (30 wild-type, 15 unknown), respectively. Four of the eight patients (50%) with EGFRmutant tumours responded, with DORs of 2.0 (censored), 7.2, 7.4, and 20.4 months. Positive correlations with ORR (P = 0.018) and reduction in tumour volume (P = 0.016) were observed (Table 2). No other significant associations were observed between the studied biomarkers and efficacy parameters.
discussion This randomized phase II study confirmed the feasibility of combining eribulin with erlotinib in an intercalated manner with the 28-day regimen meeting our predefined criteria for a positive result. However, ORRs of 13% and 17% suggest similar efficacy for the two regimens, supported by similar survival outcomes. Our findings suggest that addition of the EGFR-TKI erlotinib does not improve the treatment outcome of eribulin in these patients (no selection by biomarker status) with advanced NSCLC. This may best be explained by the fact that most of the patients in this study did not harbour activating EGFR mutations. When this study was designed, it was unclear whether the intercalated combination of chemotherapy and EGFR-TKI would improve treatment outcomes in patients with or without EGFR mutation. Recent data from NVALT-10 [22] and FASTACT 2 [23] suggest that patients without activating EGFR mutations are unlikely to benefit from the combination. In NVALT-10, intercalated combination of single-agent chemotherapy and erlotinib improved PFS of patients with non-squamous cell carcinoma but not those with squamous cell carcinoma. Although biomarker analysis for EGFR mutation was not available in NVALT-10, it is reasonable to postulate that the majority of patients with squamous cell carcinoma had EGFR mutation-negative tumours. Wu et al. [23] reported similar findings in their randomized phase III study, whereby the benefit of intercalated combination of gemcitabine/platinum and erlotinib was confined to patients with EGFR-mutant tumours. The majority of patients in the current study were white with a history of smoking; only eight (13%) of the tested population had EGFRmutant disease. Thus, our findings also show that addition of EGFR-TKI to chemotherapy fails to improve treatment outcome in patients without EGFR mutation. Both regimens were generally well tolerated, with no additional safety considerations with the combination. The 21-day regimen was associated with a relatively higher incidence of dose reduction and SAEs. Erlotinib induces cytochrome P450
doi:10.1093/annonc/mdu174 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Age, years [median 62.0 (35–87) (range)] Gender Male 33 (52) Female 30 (48) Race White 35 (56) Asian 24 (38) Black or African 4 (6) American Primary tumour type Non-squamous 48 (76) Squamous 15 (24) Disease stage at diagnosis IA 0 IB 1 (2) IIA 2 (3) IIB 2 (3) IIIA 7 (11) IIIB 7 (11) IV 44 (70) ECOG performance status 0 16 (25) 1 40 (64) 2 7 (11) Smoking history Former smoker 47 (75) Never smoker 16 (25) Number of previous anti-cancer regimens 1 37 (59) 2 21 (33) ≥3 4 (6)
28-day regimen (n = 60)
There was a dose-related increase in eribulin exposure: the mean area under the concentration–time curve (AUC) from time zero to infinity for cycle 1 was 851.5 and 1276.5 ng·h/ml following 1.4 and 2 mg/m2 dose administration, respectively. Dose-normalized exposure was similar on day 1 of cycles 1 and 2 of both regimens, indicating lack of eribulin accumulation on subsequent dosing.
original articles
Annals of Oncology
A 1.0
21-day regimen Censored: 21-day regimen
28-day regimen Censored: 28-day regimen
0.9 0.8
Probability
0.7 0.6 3.8 months
0.5 0.4
3.5 months
0.2 0.1 0.0 0
2
4
6
8
12
10
14
16
18
20
22
24
26
28
30
Progression-free survival (months) Patients at risk (n = ): 21-day regimen 63 52 36 30 23 19 15 15 13 13 8 7 6 4 3 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 0 28-day regimen 60 55 40 36 22 22 17 16 11 11 9 8 7 6 5 5 5 5 5 5 5 5 5 5 5 5 4 3 2 1 0 21-day regimen
Number of patients 63
Events 53 (84.1%)
Censored 10 (15.9%)
Median PFS (95% CI) 3.5 (1.9, 4.7)
28-day regimen
60
48 (80.0%)
12 (20.0%)
3.8 (3.3, 5.5)
B 1.0
21-day regimen Censored: 21-day regimen
28-day regimen Censored: 28-day regimen
0.9 0.8
Probability
0.7 0.6 8.5 months
0.5 7.6 months 0.4 0.3 0.2 0.1 0.0 0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
Overall survival (months) Patients at risk (n = ): 21-day regimen 63 59 54 51 47 44 40 37 28 28 25 23 23 21 20 18 17 16 13 12 11 11 10 10 8 8 6 6 5 3 3 3 2 2 1 0 0 28-day regimen 60 58 53 49 42 42 37 34 29 25 23 22 21 20 18 18 18 17 16 16 16 16 15 14 14 14 14 14 13 11 11 8 4 3 2 2 0 21-day regimen
Number of patients 63
Events 58 (92.1%)
Censored 5 (7.9%)
Mean overall survival (95% CI) 7.6 (6.3, 11.0)
28-day regimen
60
44 (73.3%)
16 (26.7%)
8.5 (6.2, 13.1)
Figure 2. Kaplan–Meier analysis of (A) progression-free survival and (B) overall survival (intent-to-treat population). CI, confidence interval; PFS, progression-free survival.
| Mok et al.
Volume 25 | No. 8 | August 2014
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
0.3
original articles
Annals of Oncology
Table 2. Summary of efficacy by EGFR mutation status (intent-totreat population with evaluable biomarker data) Efficacy parameter
Result by EGFR mutation status EGFR mutation EGFR wild type positive (n = 8) (n = 35)a
Best objective response, n (%) Partial response 4 (50) Stable disease 4 (50) Disease progression 0 Not evaluable 0
0.59 (0.24–1.41) P = 0.23
a
n = 26 evaluable for tumour shrinkage. CI, confidence interval; EGFR, epidermal growth factor receptor.
(CYP)3A4 and decreases exposure (AUC) of co-administered drugs that are CYP3A4 substrates. Eribulin is a CYP3A4 substrate; however, metabolism has been shown to be a minor contribution to eribulin clearance [21]. Prolonged (>7 days) administration of the CYP inducer erlotinib will result in enzyme induction; however, in the current study, eribulin exposure (AUC) and clearance were comparable when eribulin was administered alone (day 1, cycle 1) or after extended administration of erlotinib (day 1, cycle 2). This indicates that CYP3A4 induction does not have a substantial effect on eribulin exposure and that eribulin efficacy will not be compromised when administered with erlotinib according to the dosing regimen tested. These results are in agreement with another study which demonstrated that co-administration with rifampicin, a strong CYP3A4 inducer, also had no effect on eribulin exposure [24]. Given the positive primary result and slightly better tolerance, the 28-day regimen should be considered for future investigation. The combination of chemotherapy and EGFR-TKI has been controversial. Our study demonstrates the feasibility of combining a novel cytotoxic chemotherapy with EGFR-TKI in an intercalated manner. However, addition of EGFR-TKI is unlikely to improve treatment outcomes in patients without EGFR mutation. Future investigation should explore the combination in patients with EGFR-mutant disease in comparison with single-agent EGFR-TKI.
acknowledgements We thank all the patients and investigators who participated in this study (see Appendix). We also thank Annette Smith, PhD, from Complete Medical Communications, who provided medical writing support, and Oxford PharmaGenesis™ Ltd (UK), who provided additional medical writing support for the manuscript revisions. All funding for medical writing support was provided by Eisai.
Volume 25 | No. 8 | August 2014
This study was funded by Eisai Ltd (NCT01104155).
disclosure TSM is an advisor for AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, Bristol-Myers Squibb, BeiGene, AVEO Oncology, Pfizer, Taiho, Boehringer Ingelheim, GlaxoSmithKline Biologicals, and Clovis Oncology, is a member of the speakers’ bureau for Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, Merck Serono, and Pfizer, and is currently conducting research sponsored by AstraZeneca. LR, BW, PG, FG, and LX are employees of Eisai Ltd. CR has previously been on the speakers bureaus for Boehringer Ingelheim, Eisai, and Genentech. SLG, NI, ST, AS, DS, VL, and WTL have declared no conflicts of interest.
references 1. Ferlay J, Shin HR, Bray F et al. GLOBOCAN 2008 v2.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 10. http://globocan.iarc.fr (11 December 2012, date last accessed). 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29. 3. Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22: 1589–1597. 4. Shepherd FA, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18: 2095–2103. 5. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–132. 6. Kim ES, Hirsh V, Mok T et al. Gefitinib versus docetaxel in previously treated nonsmall-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008; 372: 1809–1818. 7. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92–98. 8. Gatzemeier U, Pluzanska A, Szczesna A et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25: 1545–1552. 9. Herbst RS, Prager D, Hermann R et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23: 5892–5899. 10. Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004; 22: 785–794. 11. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol 2004; 22: 777–784. 12. Mok TS, Wu YL, Yu CJ et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced nonsmall-cell lung cancer. J Clin Oncol 2009; 27: 5080–5087. 13. Sangha R, Davies AM, Lara PN, Jr et al. Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: results of a phase I/ II trial. J Thorac Oncol 2011; 6: 2112–2119. 14. Li T, Lara PN, Jr, Mack PC et al. Intercalation of erlotinib and pemetrexed in the treatment of non-small cell lung cancer. Curr Drug Targets 2010; 11: 85–94. 15. Cortes J, O’Shaughnessy J, Loesch D et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011; 377: 914–923.
doi:10.1093/annonc/mdu174 |
Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 3, 2014
Tumour shrinkage (% tumour change from baseline to nadir), mean (95% CI) Hazard ratio for progression-free survival (95% CI)
2 (6) 17 (49) 7 (20) 9 (26) P = 0.018 −36 (−56 to −17) −10 (−21 to 1) P = 0.016
funding
original articles
23. Wu YL, Lee JS, Thongprasert S et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol 2013; 14: 777–786. 24. Devriese LA, Witteveen PE, Wanders J et al. Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin. Br J Clin Pharmacol 2013; 75: 507–515.
appendix investigators Hong Kong: VL, TSM; Korea: J.-H. Kim, S.-W. Kim, J.-S. Lee, J.-S. Lee, K.-C. Park; Malaysia: S.H. How, M.H. Saw, J. Low; Singapore: A. Chang, D. Lim; Taiwan: Y.-M. Chen, T.-C. Hsia, W.-C. Su, C.-H. Yang; Thailand: C. Koowattanapaisan, SLG, S. Sorraritchingchai, ST; United States: V. Armenio, R. Axelrod, L. Bazhenova, D. Bodkin, J. Cantrell, A. Chaudhry, L.-C. Chen, S. Gadgeel, S. Goel, R. Govindan, M. Gupta, NI, R. Jotte, D. Martincic, J. Muscato, M. Neubauer, J. Paschold, CR, R. Robles, P.J. Rosen, R. Ruxer, M. Savin, DS, AS, R. Yanagihara.
Annals of Oncology 25: 1584–1590, 2014 doi:10.1093/annonc/mdu172 Published online 13 June 2014
SNPs in the transforming growth factor-β pathway as predictors of outcome in advanced lung adenocarcinoma with EGFR mutations treated with gefitinib L. Zhang1, Q. X. Li1, H. L. Wu1, X. Lu2, M. Yang3, S. Y. Yu1 & X. L. Yuan1* Departments of 1Oncology; 2Transplantation, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province; 3College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
Received 30 March 2014; revised 15 April 2014; accepted 23 April 2014
Background: The aim of this study was to evaluate whether genetic variations in the transforming growth factor-β (TGF-β) pathway influenced clinical outcome of advanced lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations treated with gefitinib. Patients and methods: Two hundred six patients with advanced lung adenocarcinomas were enrolled in this study. EGFR mutation in these tumors was detected. Among them, 106 patients with EGFR mutation and 37 of 100 patients with wild type were treated with gefitinib. Genotype of 33 single-nucleotide polymorphisms (SNPs) from 13 genes involved in the TGF-β signaling pathway was determined, and their association with survival time was analyzed. Univariate and multivariate analyses were carried out to assess the role of biological/clinical parameters in progression-free survival (PFS) and overall survival (OS) using Pearson’s χ 2 test, log-rank test, and Cox proportional hazards model. Results: Among SNPs analyzed, multivariate analysis showed the cytidylate and thymidine (CT) genotype of SMAD3: rs11632964 was associated with a longer OS and PFS when the entire cohort of 143 patients were included; the association was significant in the patients with EGFR mutant tumors (30.8 versus 17.5 months; log-rank P = 0.020; and 20.8 *Correspondence to: Dr Xianglin Yuan, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan, Hubei 430030, China. Tel: +86-27-8366 3406; Fax: +86-27-8366 2834; E-mail: [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
16. Spira AI, Iannotti NO, Savin MA et al. A phase II study of eribulin mesylate (E7389) in patients with advanced, previously treated non-small-cell lung cancer. Clin Lung Cancer 2012; 13: 31–38. 17. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247. 18. Desjardins C, Saxton P, Lu SX et al. A high-performance liquid chromatographytandem mass spectrometry method for the clinical combination study of carboplatin and anti-tumor agent eribulin mesylate (E7389) in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 875: 373–382. 19. Shigematsu H, Lin L, Takahashi T et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005; 97: 339–346. 20. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934; 26: 404–413. 21. Dubbelman AC, Rosing H, Jansen RS et al. Mass balance study of [14C]eribulin in patients with advanced solid tumors. Drug Metab Dispos 2012; 40: 313–321. 22. Aerts JG, Codrington H, Burgers S et al. A randomized phase II study comparing erlotinib (E) versus E alternating with chemotherapy in relapsed non-small cell lung cancer (NSCLC) patients. The NVALT10 study. Ann Oncol 2012; 23(Suppl. 9): abstr LBA29.
Annals of Oncology