- Email: [email protected]
Rationale and Design of MARQUEE: A Phase III, Randomized, Double-Blind Study of Tivantinib Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Patients With Locally Advanced or Metastatic, Nonsquamous, Non–Small-Cell Lung Cancer
Current Trial
Rationale and Design of MARQUEE: A Phase III, Randomized, Double-Blind Study of Tivantinib Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Patients With Locally Advanced or Metastatic, Nonsquamous, Non–Small-Cell Lung Cancer Giorgio V. Scagliotti,1 Silvia Novello,1 Joan H. Schiller,2 Vera Hirsh,3 Lecia V. Sequist,4 Jean-Charles Soria,5 Joachim von Pawel,6 Brian Schwartz,7 Reinhard Von Roemeling,8 Alan B. Sandler9 Abstract We present the rationale and design for MARQUEE, a phase III, randomized, double-blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, non–small-cell lung cancer (NSCLC). The design of MARQUEE is based on preclinical data, the current understanding of the role of cellular N-methyl-N’-nitroso-guanidine human osteosarcoma (MNNG HOS) transforming gene (MET) in NSCLC, and clinical data from a randomized phase II study. The available evidence suggests that dual inhibition of MET and the epidermal growth factor receptor (EGFR) may overcome resistance to EGFR inhibitors. In the phase II study, the combination of tivantinib plus erlotinib significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus erlotinib in the subset of patients with nonsquamous histology, a population enriched for MET overexpression. The primary endpoint in MARQUEE is OS. Secondary and exploratory objectives include determination of PFS, OS in molecular subgroups (defined by EGFR and KRAS mutation status, amplification or overexpression of MET, and serum hepatocyte growth factor), and safety. All patients will be tested for biomarkers, and the results will provide a wealth of information on the role of tivantinib in treating nonsquamous NSCLC. Clinical Lung Cancer, Vol. 13, No. 5, 391-5 © 2012 Elsevier Inc. All rights reserved. Keywords: Epidermal growth factor receptor, Hepatocyte growth factor receptor, MET, Tyrosine kinase inhibitors
Introduction Despite recent advances in treatment, non–small-cell lung cancer (NSCLC) remains the leading global cause of cancer-related death. Most patients have advanced disease at diagnosis, with a median
Trial number: NCT01244191; registration date: November 17, 2010
survival of only 10-12 months despite aggressive therapy.1,2 Therefore, improving treatment strategies and outcomes continues to be a major priority. Recent efforts have focused on targeted therapies or treatments that specifically inhibit critical signaling pathways. A success-
8
Daiichi Sankyo, Inc, Parsippany, NJ Oregon Health and Science University, Portland, OR
9 1
University of Turin, San Luigi Hospital, Orbassano (Turin), Italy University of Texas Southwestern Medical Center, Dallas, TX 3 McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada 4 Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 5 Institute Gustave Roussy and University, Paris-Sud, France 6 Asklepios Klinikum Gauting, Munich, Germany 7 ArQule, Inc, Woburn, MA 2
1525-7304/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. doi: 10.1016/j.cllc.2012.01.003
Submitted: Dec 1, 2011; Revised: Jan 13, 2012; Accepted: Jan 23, 2012; Epub: Mar 30, 2012 Address for correspondence: Giorgio V. Scagliotti, MD, PhD, Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano (Turin), Italy Fax: ⫹39-0119038616; e-mail contact: [email protected]
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Phase III Study of Tivantinib Plus Erlotinib in NSCLC ful example is represented by inhibition of the epidermal growth factor receptor (EGFR) pathway, particularly in patients with activating EGFR mutations, which confer an oncogene-addicted biology and render these tumors susceptible to EGFR blockade. However, resistance to EGFR inhibitors and cancer progression invariably develop.3 The cellular N-methyl-N’-nitroso-guanidine (MET) receptor tyrosine kinase appears to play an important role in cancer cell proliferation, migration, invasion, and metastasis.4 Dysregulation of MET signaling through overexpression or gene amplification and/or expression of the ligand, hepatocyte growth factor (HGF), has been reported in a wide range of tumor types and correlates with poor clinical prognosis in NSCLC and other solid tumors.5 The role of MET in the pathophysiology of NSCLC has been explored based on animal models and human NSCLC cell lines overexpressing MET and sensitive to MET inhibitors. In 1 small study, MET expression was observed in 100% (n ⫽ 23) of primary tumors and 89% (n ⫽ 9) of NSCLC cell lines examined.6 MET was also expressed in 67% (n ⫽ 9) of adenocarcinomas, and activated phospho-MET (p-MET) was observed preferentially along the invasive fronts of NSCLC tumor tissue. Notably, p-MET expression was reported to be higher in lung cancer compared with other solid tumors.4,6 In NSCLC, increased MET gene copy number (GCN) is observed in approximately 20% of tumors,7 and MET overexpression and/or amplification is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) irrespective of secondary EGFR mutations.3,8,9 Several agents are being developed to specifically target MET, including monoclonal antibodies and oral TKIs. These MET inhibitors are currently in clinical trials in lung cancer and other malignancies, and several phase I and phase II trials have been completed. Notably, 2 large phase II trials have been reported that combined a MET inhibitor with erlotinib in patients with previously treated NSCLC.10,11 The rationale for dual inhibition of EGFR and MET for the treatment of NSCLC is largely based on evidence that MET is associated with resistance to erlotinib and gefitinib and data from preclinical models demonstrating additive or synergistic antitumor activity.12,13 Dual inhibition of MET and EGFR has also demonstrated activity in preclinical models of EGFR-resistant NSCLC.14 In addition, a phase Ib/II trial of the MET inhibitor cabozantinib plus erlotinib in patients with NSCLC demonstrated activity in patients previously treated with erlotinib.15 These studies suggest that combined inhibition of EGFR and MET may overcome resistance to EGFR inhibitors. Tivantinib is a TKI that specifically targets MET and has been studied extensively in a wide range of tumor types, including NSCLC, both as single-agent therapy and in combination with erlotinib.16-18 In a phase I trial combining tivantinib with erlotinib in patients with advanced solid tumors, 6 of 8 patients with NSCLC achieved prolonged stable disease, and the combination was well tolerated.16 Subsequently, a global, randomized, double-blind, placebo-controlled phase II trial was conducted to evaluate erlotinib plus tivantinib (ET) in previously treated patients with EGFR TKInaive advanced NSCLC.10 Patients (n ⫽ 167) were randomized to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP), and the primary end point was progression-free survival (PFS). Median PFS in the intent-totreat (ITT) population was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.57-
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1.16; P ⫽ .24). However, significant improvement in PFS was observed in the ITT population after adjusting for key prognostic factors (HR, 0.68; 95% CI, 0.47-0.98; P ⫽ .04). More importantly, a planned subset analysis demonstrated significant improvement in both PFS (adjusted HR, 0.61; 95% CI, 0.39-0.98; P ⫽ .04) and overall survival (OS) (adjusted HR, 0.58; 95% CI, 0.34-0.99; P ⫽ .04) in patients with nonsquamous histology who were treated with ET (Figure 1).10 This hypothesis-generating exploratory analysis suggests that nonsquamous tumors may be enriched for MET expression. Indeed, biomarker analysis showed that among nonsquamous tumors 75% were MET-positive by immunohistochemistry (IHC), compared with only 12% of squamous tumors (Daiichi Sankyo, Inc, data on file). This is consistent with existing literature suggesting that activation of the HGF-MET pathway occurs more frequently and may play a more critical role in tumor progression and metastasis in nonsquamous cell NSCLC.6,19 Despite small patient numbers, significant improvement in PFS (HR, 0.18; 95% CI, 0.050.70; P ⬍ .01) was also observed in the subset of patients with KRAS mutations (Figure 2),10 and a trend toward PFS improvement was observed in patients with wild type EGFR (HR, 0.7; 95% CI, 0.441.10; P ⫽ .12). Finally, an exploratory analysis of time to development of new metastases demonstrated a significant delay of metastasis among patients treated with ET (median, 7.3 versus 3.6 months; HR, 0.49; 95% CI, 0.31-0.78; P ⫽ .01 in the ITT population), and this effect was more pronounced in the nonsquamous subset. Consistent with the phase I study, ET was well tolerated. Common adverse events included low-grade rash, diarrhea, fatigue, nausea, vomiting, and dyspnea; rates of overall or serious adverse events were similar for ET and EP. Based on these encouraging data, we designed the MARQUEE trial, a phase III, randomized, double-blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, NSCLC (Figure 3). The primary objective of this study is to determine whether the combination of tivantinib plus erlotinib can improve OS in a population of nonsquamous NSCLC patients. Of note, this trial will collect tissue from all randomized patients and assess key biomarkers such as EGFR and KRAS mutation status to gain a better understanding of the clinical benefit of tivantinib plus erlotinib in specific molecular subsets of patients.
Patients and Methods Key Eligibility Criteria Entry criteria are limited to patients with histologically or cytologically confirmed, surgically unresectable, locally advanced or metastatic (stage IIIB/IV) nonsquamous NSCLC with measurable disease and documented disease progression after last prior therapy. Eligible patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1, must have received 1 or 2 prior lines of systemic anticancer therapy for advanced or metastatic disease, 1 of which must have been a platinum-doublet, and must not have received any prior therapy with an EGFR or MET inhibitor. Patients must demonstrate adequate bone marrow, liver, and renal function. Patients with clinically unstable brain metastases, history of cardiac disease, uncontrolled hypertension, or other currently active malignancies are ex-
Giorgio V. Scagliotti et al Figure 1 Progression-Free and Overall Survival. Kaplan-Meier Estimate of (A) Progression-Free Survival and (B) Overall Survival in Patients With Nonsquamous Tumor Histology Treated With Erlotinib Plus Tivantinib or Erlotinib Plus Placebo
Progression-Free Survival (proportion)
A 1.0 0.8
Events 46 36
n 59 58
Censored 13 22 Placebo
95% CI 56-112 105-218
Median 68 132 Tivantinib
0.6 HR: 0.71; 95% CI 0.46-1.10 Log-rank P = .12 Adjusted HR: 0.61 (95% CI 0.47-0.98); P < .05a
0.4 0.2
0
B
Placebo Tivantinib
50
100 150 200 250 300 350 400 450 500 550 600 Time, days
1.0 Overall Survival (proportion)
Placebo 0.8
Tivantinib
HR: 0.72; 95% CI 0.44-1.17 Log-rank P = .18 Adjusted HR: 0.58 (95% CI 0.34-0.99); P < .05a
0.6 0.4 0.2 Placebo Tivantinib 0
50
Events 35 31
n 59 58
Censored 24 27
Median 208 302
95% CI 148-336 236-NR
100 150 200 250 300 350 400 450 500 550 600 Time, days Patients, n
Erlotinib + Tivantinib Erlotinib + Placebo
58 59
Median PFS, months
Median OS, months
4.4 2.3
9.9 6.8
a Hazard ratios were adjusted by Cox proportional hazards model for sex, prior chemotherapy, best prior response, time from diagnosis, and mutation status of the epidermal growth factor receptor gene. Abbreviations: HR ⫽ hazard ratio; OS ⫽ overall survival; PFS ⫽ progression-free survival. From Sequist L, et al: J Clin Oncol 2011; 29 (24):3307-3315; emphasis added. 10 Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
cluded. All patients must have available tumor tissue and sign institutional review board-approved informed consent forms.
Study Design Patients will be stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status and will be randomized to receive either tivantinib (360 mg twice daily, orally) plus erlotinib (150 mg once daily, orally) or matching placebo plus erlotinib (150 mg once daily, orally) until disease progression or unacceptable toxicity. Before starting study treatment, EGFR and KRAS mutation status, baseline tumor measurement per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (spiral computed tomography or magnetic resonance imaging with ⱕ5 mm cuts), safety
testing, and a 12-lead electrocardiogram will be completed. Tumor tissue will also be tested for MET expression by IHC and for MET GCN by fluorescence in situ hybridization, and serum will be tested for circulating HGF. Tumor response and disease progression will be evaluated every 8 weeks based on investigator-assessed RECIST. The primary objective of this study is to evaluate OS in the ITT population. Secondary and exploratory endpoints include evaluation of PFS in the ITT population and OS in EGFR-wild type, KRAS-mutant, and MET-positive subgroups, and to further characterize the safety of tivantinib in combination with erlotinib. Additional exploratory objectives include patient-reported outcomes and population pharmacokinetics, pharmacodynamics, and pharmacogenomics.
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Phase III Study of Tivantinib Plus Erlotinib in NSCLC Figure 2 Cox Proportional Hazard Ratio Analysis of Median Progression-Free Survival by Patient Subgroup
Median PFS (95% CI), months n/N
Erlotinib + Tivantinib
Erlotinib + Placebo
Squamous cell
26/24
3.2 (1.9-4.2)
2.0 (1.8-4.9)
Non-squamous cell
58/59
4.4 (3.5-7.3)
2.3 (1.9-3.7)
c-MET FISH > 4
19/18
3.6 (1.9-5.7)
3.6 (1.7-3.8)
c-MET FISH > 5
8/11
5.6 (3.8-NE)
3.6 (1.8-7.3)
EGFR mutant
6/11
5.6 (1.9-7.5)
4.9 (1.9-8.4)
EGFR wt
51/48
3.2 (1.9-4.2)
1.9 (1.8-2.3)
KRAS mutant
10/5
2.3 (1.8-NE)
1.0 (0.3-1.9)
KRAS wt
49/45
3.6 (1.9-4.2)
2.3 (1.9-3.7)
Unadjusted HR 1.05 0.71 0.71 0.45 1.23 0.70 0.18 1.01 0
0.5
1.0
Favors Erlotinib + Tivantinib
1.5
2.0
5.0
Favors Erlotinin + Placebo
Abbreviations: FISH ⫽ fluorescence in situ hybridization; HR ⫽ hazard ratio; PFS ⫽ progression-free survival; wt ⫽ wild type. Data from Sequist L, et al.10
Figure 3 Schematic Diagram of the MARQUEE Study Design
Who progressed after 1 or 2 prior lines of chemotherapy, 1 of which must be a platinum-doublet (target N = 988) Endpoints Primary: OS in ITT population Secondary: OS in EGFR wt patients PFS in ITT population Safety of tivantinib + erlotinib Exploratory: PK and PD analysis Biologic subgroup analysis QOL/FACT-L
Arm A: Tivantinib + Erlotinib PO BID PO QD
Randomized (1:1)
Patients with non-squamous NSCLC
Arm B: Placepbo + Erlotinib PO BID PO QD Stratification by EGFR and KRAS mutational status Number of previous therapies Sex Smoking status Assuming 7 months’ median survival with control, this study is designed to assess 33% improvement in median OS in the tivantinib plus erlotinib arm, with 90% power at 2-sided significance level of 0.01.
Abbreviations: BID ⫽ twice daily; EGFR ⫽ epidermal growth factor receptor; FACT-L ⫽ Functional Assessment of Cancer Therapy-Lung; ITT ⫽ intent-to-treat; NSCLC ⫽ non–small-cell lung cancer; OS ⫽ overall survival; PD ⫽ pharmacodynamics; PFS ⫽ progression-free survival; PK ⫽ pharmacokinetics; PO ⫽ orally; QD ⫽ once daily; QOL ⫽ quality of life; TKI ⫽ tyrosine kinase inhibitor; wt ⫽ wild type.
Statistical Considerations Assuming 7-month median OS in the placebo plus erlotinib arm, the study is designed with 90% power to detect 33% improvement in median OS (ie, HR, 0.75) at a 2-sided significance level of .01. Allowing for 1 planned interim analysis to assess efficacy, a total of
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988 patients is projected. Assuming accrual over 18 months with a maximum treatment plus follow-up period of 30 months, 735 events are required for the primary analysis of OS. The interim analysis will be performed when 50% of the planned number of events are observed (ie, 368 deaths) using the spending function methodology of
Giorgio V. Scagliotti et al Lan-DeMets family with O’Brien-Fleming parameters for early stopping for efficacy or futility.
Conclusion The MARQUEE trial is a global, phase III, randomized trial with a solid preclinical rationale and robust early phase clinical data in support of the patient selection strategy. Patients who are most likely to benefit from dual inhibition of EGFR and MET have been selected for inclusion in this study based on results of the phase II study. This trial is currently ongoing. Successful accrual to date, which requires tissue from all patients and molecular testing for EGFR and KRAS mutation status before randomization, supports the feasibility of the study design. The outcomes of MARQUEE will have clinical implications with respect to establishing the role of MET inhibitors in treating advanced nonsquamous NSCLC and will provide a wealth of information to better understand which patients are most likely to benefit from dual inhibition of the EGFR and MET pathways.
Acknowledgments Financial support provided by Daiichi Sankyo, Inc, a member of the Daiichi Sankyo Group, Daiichi Sankyo Co, Ltd, Tokyo, Japan. The authors thank Jeffrey S. Riegel, PhD, at Accuverus, Beachwood, OH, for editorial support.
Disclosure Giorgio Scagliotti: Consultant for Eli Lilly honoraria from AstraZeneca, Eli Lilly, Pfizer, Roche, AVEO, ARIAD, and Boehringer Ingelheim. Joan Schiller: Consultant for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, GSK, Eli Lilly, Pfizer, Merck-Serono, MSD, Roche, and Sanofi-Aventis. Vera Hirsh: Member of Daiichi Sankyo, Inc., advisory board. Lecia Sequist: Consultant for Clovis Oncology, Celgene, and GSK; uncompensated consultant for Daiichi Sankyo, Inc., and Merrimack Pharmaceuticals. Jean-Charles Soria: Honoraria from Abbott, Amgen, AstraZeneca, BMS, GSK, Lilly, Pfizer, Merck-Serono, MSD, Roche, and Sanofi-Aventis. Joachim von Pawel: Consultant for Daiichi Sankyo, Inc. Brian Schwartz: Employee of ArQule, Inc. Reinhard Von Roemeling: Employee of Daiichi Sankyo, Inc. Alan Sandler: Grants and research support from Abraxis, Daiichi Sankyo, Inc., Eli Lilly, Pfizer, and Synta; consultant or Advisory Board member for Abraxis, Agennix, Allos Therapeutics, Aveo, Boehringer Ingelheim, Celgene, Clovis Oncology, Daiichi Sankyo, Inc., Eli Lilly, Genentech, GlaxoSmithKline, Hoffman LaRoche, OxiGene, Pfizer, and Roche; member of Speaker’s Bureau for Eli Lilly, Genentech, and Quintiles; honoraria
from Agennix, Boehringer Ingelheim, Celgene, Chugai (Roche), Daiichi Sankyo, Inc., Eli Lilly, Genentech, GlaxoSmithKline, OxiGene, Roche, and Quintiles; legal consulting for Genentech, Pfizer, OSI Pharmaceuticals, and Roche. Silvia Novello states no conflicts of interest.
References 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542-50. 2. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26:3543-51. 3. Cataldo VD, Gibbons DL, Pérez-Soler R, et al. Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N Engl J Med 2011; 364:947-55. 4. Ma PC, Tretiakova MS, MacKinnon AC, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 2008; 47:1025-37. 5. Okuda K, Sasaki H, Yukiue H, et al. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci 2008; 99:2280-5. 6. Ma PC, Jagadeeswaran R, Jagadeesh S, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res 2005; 65:1479-88. 7. Lutterbach B, Zeng Q, Davis LJ, et al. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res 2007; 67:2081-8. 8. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007; 104:20932-7. 9. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316: 1039-43. 10. Sequist LV, von Pawel J, Garmey EG, et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol 2011;29:3307-15. 11. Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. J Clin Oncol 2011; 29(Suppl): Abstract 7505. 12. Fournel M, Dupont I, Bonfils C, et al. Potent preclinical anti-tumor activity of MGCD265, an orally active Met/VEGFR multitargeted kinase inhibitor in phase II clinical development, in combination with an EGFR inhibitor. Presented at: AACR 101st Annual Meeting; April 12-17, 2010; Washington, DC. Abstract 3612. 13. Mark M, Zhang Y-W, Su Y, et al. Combination efficacy with MetMAb and erlotinib in a NSCLC tumor model highlight therapeutic opportunities for c-Met inhibitors in combination with EGFR inhibitors. Presented at: AACR 99th Annual Meeting; April 12-16, 2008; San Diego, CA. Abstract 1336. 14. Janne PA, Wax M, Leach JW, et al. Targeting MET with XL184 to reverse EGFR tyrosine kinase inhibitor (TKI) resistance in NSCLC: impact of preclinical studies on clinical trial design. EJC Suppl 2008; 6: Abstract 174. 15. Wakelee HA, Gettinger SN, Engelman JA, et al. A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib (E) in patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol 2010; 28(Suppl): Abstract 3017. 16. Goldman JW, Laux I, Chai F, et al. Phase 1 dose-escalation trial evaluating the combination of the selective MET inhibitor tivantinib (ARQ 197) plus erlotinib. Cancer [Epub ahead of print]. 17. Rosen LS, Senzer N, Mekhail T, et al. A phase I dose-escalation study of tivantinib (ARQ 197) in adult patients with metastatic solid tumors. Clin Cancer Res 2011; 17:7754-64. 18. Yap TA, Olmos D, Brunetto AT, et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol 2011; 29:1271-9. 19. Tsao MS, Yang Y, Marcus A, et al. Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non-small-cell lung cancer. Hum Pathol 2001; 32:57-65.
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Rationale and Design of MARQUEE: A Phase III, Randomized, Double-Blind Study of Tivantinib Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Patients With Locally Advanced or Metastatic, Nonsquamous, Non–Small-Cell Lung Cancer Giorgio V. Scagliotti,1 Silvia Novello,1 Joan H. Schiller,2 Vera Hirsh,3 Lecia V. Sequist,4 Jean-Charles Soria,5 Joachim von Pawel,6 Brian Schwartz,7 Reinhard Von Roemeling,8 Alan B. Sandler9 Abstract We present the rationale and design for MARQUEE, a phase III, randomized, double-blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, non–small-cell lung cancer (NSCLC). The design of MARQUEE is based on preclinical data, the current understanding of the role of cellular N-methyl-N’-nitroso-guanidine human osteosarcoma (MNNG HOS) transforming gene (MET) in NSCLC, and clinical data from a randomized phase II study. The available evidence suggests that dual inhibition of MET and the epidermal growth factor receptor (EGFR) may overcome resistance to EGFR inhibitors. In the phase II study, the combination of tivantinib plus erlotinib significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus erlotinib in the subset of patients with nonsquamous histology, a population enriched for MET overexpression. The primary endpoint in MARQUEE is OS. Secondary and exploratory objectives include determination of PFS, OS in molecular subgroups (defined by EGFR and KRAS mutation status, amplification or overexpression of MET, and serum hepatocyte growth factor), and safety. All patients will be tested for biomarkers, and the results will provide a wealth of information on the role of tivantinib in treating nonsquamous NSCLC. Clinical Lung Cancer, Vol. 13, No. 5, 391-5 © 2012 Elsevier Inc. All rights reserved. Keywords: Epidermal growth factor receptor, Hepatocyte growth factor receptor, MET, Tyrosine kinase inhibitors
Introduction Despite recent advances in treatment, non–small-cell lung cancer (NSCLC) remains the leading global cause of cancer-related death. Most patients have advanced disease at diagnosis, with a median
Trial number: NCT01244191; registration date: November 17, 2010
survival of only 10-12 months despite aggressive therapy.1,2 Therefore, improving treatment strategies and outcomes continues to be a major priority. Recent efforts have focused on targeted therapies or treatments that specifically inhibit critical signaling pathways. A success-
8
Daiichi Sankyo, Inc, Parsippany, NJ Oregon Health and Science University, Portland, OR
9 1
University of Turin, San Luigi Hospital, Orbassano (Turin), Italy University of Texas Southwestern Medical Center, Dallas, TX 3 McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada 4 Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 5 Institute Gustave Roussy and University, Paris-Sud, France 6 Asklepios Klinikum Gauting, Munich, Germany 7 ArQule, Inc, Woburn, MA 2
1525-7304/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. doi: 10.1016/j.cllc.2012.01.003
Submitted: Dec 1, 2011; Revised: Jan 13, 2012; Accepted: Jan 23, 2012; Epub: Mar 30, 2012 Address for correspondence: Giorgio V. Scagliotti, MD, PhD, Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano (Turin), Italy Fax: ⫹39-0119038616; e-mail contact: [email protected]
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Phase III Study of Tivantinib Plus Erlotinib in NSCLC ful example is represented by inhibition of the epidermal growth factor receptor (EGFR) pathway, particularly in patients with activating EGFR mutations, which confer an oncogene-addicted biology and render these tumors susceptible to EGFR blockade. However, resistance to EGFR inhibitors and cancer progression invariably develop.3 The cellular N-methyl-N’-nitroso-guanidine (MET) receptor tyrosine kinase appears to play an important role in cancer cell proliferation, migration, invasion, and metastasis.4 Dysregulation of MET signaling through overexpression or gene amplification and/or expression of the ligand, hepatocyte growth factor (HGF), has been reported in a wide range of tumor types and correlates with poor clinical prognosis in NSCLC and other solid tumors.5 The role of MET in the pathophysiology of NSCLC has been explored based on animal models and human NSCLC cell lines overexpressing MET and sensitive to MET inhibitors. In 1 small study, MET expression was observed in 100% (n ⫽ 23) of primary tumors and 89% (n ⫽ 9) of NSCLC cell lines examined.6 MET was also expressed in 67% (n ⫽ 9) of adenocarcinomas, and activated phospho-MET (p-MET) was observed preferentially along the invasive fronts of NSCLC tumor tissue. Notably, p-MET expression was reported to be higher in lung cancer compared with other solid tumors.4,6 In NSCLC, increased MET gene copy number (GCN) is observed in approximately 20% of tumors,7 and MET overexpression and/or amplification is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) irrespective of secondary EGFR mutations.3,8,9 Several agents are being developed to specifically target MET, including monoclonal antibodies and oral TKIs. These MET inhibitors are currently in clinical trials in lung cancer and other malignancies, and several phase I and phase II trials have been completed. Notably, 2 large phase II trials have been reported that combined a MET inhibitor with erlotinib in patients with previously treated NSCLC.10,11 The rationale for dual inhibition of EGFR and MET for the treatment of NSCLC is largely based on evidence that MET is associated with resistance to erlotinib and gefitinib and data from preclinical models demonstrating additive or synergistic antitumor activity.12,13 Dual inhibition of MET and EGFR has also demonstrated activity in preclinical models of EGFR-resistant NSCLC.14 In addition, a phase Ib/II trial of the MET inhibitor cabozantinib plus erlotinib in patients with NSCLC demonstrated activity in patients previously treated with erlotinib.15 These studies suggest that combined inhibition of EGFR and MET may overcome resistance to EGFR inhibitors. Tivantinib is a TKI that specifically targets MET and has been studied extensively in a wide range of tumor types, including NSCLC, both as single-agent therapy and in combination with erlotinib.16-18 In a phase I trial combining tivantinib with erlotinib in patients with advanced solid tumors, 6 of 8 patients with NSCLC achieved prolonged stable disease, and the combination was well tolerated.16 Subsequently, a global, randomized, double-blind, placebo-controlled phase II trial was conducted to evaluate erlotinib plus tivantinib (ET) in previously treated patients with EGFR TKInaive advanced NSCLC.10 Patients (n ⫽ 167) were randomized to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP), and the primary end point was progression-free survival (PFS). Median PFS in the intent-totreat (ITT) population was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.57-
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1.16; P ⫽ .24). However, significant improvement in PFS was observed in the ITT population after adjusting for key prognostic factors (HR, 0.68; 95% CI, 0.47-0.98; P ⫽ .04). More importantly, a planned subset analysis demonstrated significant improvement in both PFS (adjusted HR, 0.61; 95% CI, 0.39-0.98; P ⫽ .04) and overall survival (OS) (adjusted HR, 0.58; 95% CI, 0.34-0.99; P ⫽ .04) in patients with nonsquamous histology who were treated with ET (Figure 1).10 This hypothesis-generating exploratory analysis suggests that nonsquamous tumors may be enriched for MET expression. Indeed, biomarker analysis showed that among nonsquamous tumors 75% were MET-positive by immunohistochemistry (IHC), compared with only 12% of squamous tumors (Daiichi Sankyo, Inc, data on file). This is consistent with existing literature suggesting that activation of the HGF-MET pathway occurs more frequently and may play a more critical role in tumor progression and metastasis in nonsquamous cell NSCLC.6,19 Despite small patient numbers, significant improvement in PFS (HR, 0.18; 95% CI, 0.050.70; P ⬍ .01) was also observed in the subset of patients with KRAS mutations (Figure 2),10 and a trend toward PFS improvement was observed in patients with wild type EGFR (HR, 0.7; 95% CI, 0.441.10; P ⫽ .12). Finally, an exploratory analysis of time to development of new metastases demonstrated a significant delay of metastasis among patients treated with ET (median, 7.3 versus 3.6 months; HR, 0.49; 95% CI, 0.31-0.78; P ⫽ .01 in the ITT population), and this effect was more pronounced in the nonsquamous subset. Consistent with the phase I study, ET was well tolerated. Common adverse events included low-grade rash, diarrhea, fatigue, nausea, vomiting, and dyspnea; rates of overall or serious adverse events were similar for ET and EP. Based on these encouraging data, we designed the MARQUEE trial, a phase III, randomized, double-blind, placebo-controlled study of ARQ 197 plus erlotinib versus placebo plus erlotinib in previously treated subjects with locally advanced or metastatic, nonsquamous, NSCLC (Figure 3). The primary objective of this study is to determine whether the combination of tivantinib plus erlotinib can improve OS in a population of nonsquamous NSCLC patients. Of note, this trial will collect tissue from all randomized patients and assess key biomarkers such as EGFR and KRAS mutation status to gain a better understanding of the clinical benefit of tivantinib plus erlotinib in specific molecular subsets of patients.
Patients and Methods Key Eligibility Criteria Entry criteria are limited to patients with histologically or cytologically confirmed, surgically unresectable, locally advanced or metastatic (stage IIIB/IV) nonsquamous NSCLC with measurable disease and documented disease progression after last prior therapy. Eligible patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1, must have received 1 or 2 prior lines of systemic anticancer therapy for advanced or metastatic disease, 1 of which must have been a platinum-doublet, and must not have received any prior therapy with an EGFR or MET inhibitor. Patients must demonstrate adequate bone marrow, liver, and renal function. Patients with clinically unstable brain metastases, history of cardiac disease, uncontrolled hypertension, or other currently active malignancies are ex-
Giorgio V. Scagliotti et al Figure 1 Progression-Free and Overall Survival. Kaplan-Meier Estimate of (A) Progression-Free Survival and (B) Overall Survival in Patients With Nonsquamous Tumor Histology Treated With Erlotinib Plus Tivantinib or Erlotinib Plus Placebo
Progression-Free Survival (proportion)
A 1.0 0.8
Events 46 36
n 59 58
Censored 13 22 Placebo
95% CI 56-112 105-218
Median 68 132 Tivantinib
0.6 HR: 0.71; 95% CI 0.46-1.10 Log-rank P = .12 Adjusted HR: 0.61 (95% CI 0.47-0.98); P < .05a
0.4 0.2
0
B
Placebo Tivantinib
50
100 150 200 250 300 350 400 450 500 550 600 Time, days
1.0 Overall Survival (proportion)
Placebo 0.8
Tivantinib
HR: 0.72; 95% CI 0.44-1.17 Log-rank P = .18 Adjusted HR: 0.58 (95% CI 0.34-0.99); P < .05a
0.6 0.4 0.2 Placebo Tivantinib 0
50
Events 35 31
n 59 58
Censored 24 27
Median 208 302
95% CI 148-336 236-NR
100 150 200 250 300 350 400 450 500 550 600 Time, days Patients, n
Erlotinib + Tivantinib Erlotinib + Placebo
58 59
Median PFS, months
Median OS, months
4.4 2.3
9.9 6.8
a Hazard ratios were adjusted by Cox proportional hazards model for sex, prior chemotherapy, best prior response, time from diagnosis, and mutation status of the epidermal growth factor receptor gene. Abbreviations: HR ⫽ hazard ratio; OS ⫽ overall survival; PFS ⫽ progression-free survival. From Sequist L, et al: J Clin Oncol 2011; 29 (24):3307-3315; emphasis added. 10 Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
cluded. All patients must have available tumor tissue and sign institutional review board-approved informed consent forms.
Study Design Patients will be stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status and will be randomized to receive either tivantinib (360 mg twice daily, orally) plus erlotinib (150 mg once daily, orally) or matching placebo plus erlotinib (150 mg once daily, orally) until disease progression or unacceptable toxicity. Before starting study treatment, EGFR and KRAS mutation status, baseline tumor measurement per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (spiral computed tomography or magnetic resonance imaging with ⱕ5 mm cuts), safety
testing, and a 12-lead electrocardiogram will be completed. Tumor tissue will also be tested for MET expression by IHC and for MET GCN by fluorescence in situ hybridization, and serum will be tested for circulating HGF. Tumor response and disease progression will be evaluated every 8 weeks based on investigator-assessed RECIST. The primary objective of this study is to evaluate OS in the ITT population. Secondary and exploratory endpoints include evaluation of PFS in the ITT population and OS in EGFR-wild type, KRAS-mutant, and MET-positive subgroups, and to further characterize the safety of tivantinib in combination with erlotinib. Additional exploratory objectives include patient-reported outcomes and population pharmacokinetics, pharmacodynamics, and pharmacogenomics.
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Phase III Study of Tivantinib Plus Erlotinib in NSCLC Figure 2 Cox Proportional Hazard Ratio Analysis of Median Progression-Free Survival by Patient Subgroup
Median PFS (95% CI), months n/N
Erlotinib + Tivantinib
Erlotinib + Placebo
Squamous cell
26/24
3.2 (1.9-4.2)
2.0 (1.8-4.9)
Non-squamous cell
58/59
4.4 (3.5-7.3)
2.3 (1.9-3.7)
c-MET FISH > 4
19/18
3.6 (1.9-5.7)
3.6 (1.7-3.8)
c-MET FISH > 5
8/11
5.6 (3.8-NE)
3.6 (1.8-7.3)
EGFR mutant
6/11
5.6 (1.9-7.5)
4.9 (1.9-8.4)
EGFR wt
51/48
3.2 (1.9-4.2)
1.9 (1.8-2.3)
KRAS mutant
10/5
2.3 (1.8-NE)
1.0 (0.3-1.9)
KRAS wt
49/45
3.6 (1.9-4.2)
2.3 (1.9-3.7)
Unadjusted HR 1.05 0.71 0.71 0.45 1.23 0.70 0.18 1.01 0
0.5
1.0
Favors Erlotinib + Tivantinib
1.5
2.0
5.0
Favors Erlotinin + Placebo
Abbreviations: FISH ⫽ fluorescence in situ hybridization; HR ⫽ hazard ratio; PFS ⫽ progression-free survival; wt ⫽ wild type. Data from Sequist L, et al.10
Figure 3 Schematic Diagram of the MARQUEE Study Design
Who progressed after 1 or 2 prior lines of chemotherapy, 1 of which must be a platinum-doublet (target N = 988) Endpoints Primary: OS in ITT population Secondary: OS in EGFR wt patients PFS in ITT population Safety of tivantinib + erlotinib Exploratory: PK and PD analysis Biologic subgroup analysis QOL/FACT-L
Arm A: Tivantinib + Erlotinib PO BID PO QD
Randomized (1:1)
Patients with non-squamous NSCLC
Arm B: Placepbo + Erlotinib PO BID PO QD Stratification by EGFR and KRAS mutational status Number of previous therapies Sex Smoking status Assuming 7 months’ median survival with control, this study is designed to assess 33% improvement in median OS in the tivantinib plus erlotinib arm, with 90% power at 2-sided significance level of 0.01.
Abbreviations: BID ⫽ twice daily; EGFR ⫽ epidermal growth factor receptor; FACT-L ⫽ Functional Assessment of Cancer Therapy-Lung; ITT ⫽ intent-to-treat; NSCLC ⫽ non–small-cell lung cancer; OS ⫽ overall survival; PD ⫽ pharmacodynamics; PFS ⫽ progression-free survival; PK ⫽ pharmacokinetics; PO ⫽ orally; QD ⫽ once daily; QOL ⫽ quality of life; TKI ⫽ tyrosine kinase inhibitor; wt ⫽ wild type.
Statistical Considerations Assuming 7-month median OS in the placebo plus erlotinib arm, the study is designed with 90% power to detect 33% improvement in median OS (ie, HR, 0.75) at a 2-sided significance level of .01. Allowing for 1 planned interim analysis to assess efficacy, a total of
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988 patients is projected. Assuming accrual over 18 months with a maximum treatment plus follow-up period of 30 months, 735 events are required for the primary analysis of OS. The interim analysis will be performed when 50% of the planned number of events are observed (ie, 368 deaths) using the spending function methodology of
Giorgio V. Scagliotti et al Lan-DeMets family with O’Brien-Fleming parameters for early stopping for efficacy or futility.
Conclusion The MARQUEE trial is a global, phase III, randomized trial with a solid preclinical rationale and robust early phase clinical data in support of the patient selection strategy. Patients who are most likely to benefit from dual inhibition of EGFR and MET have been selected for inclusion in this study based on results of the phase II study. This trial is currently ongoing. Successful accrual to date, which requires tissue from all patients and molecular testing for EGFR and KRAS mutation status before randomization, supports the feasibility of the study design. The outcomes of MARQUEE will have clinical implications with respect to establishing the role of MET inhibitors in treating advanced nonsquamous NSCLC and will provide a wealth of information to better understand which patients are most likely to benefit from dual inhibition of the EGFR and MET pathways.
Acknowledgments Financial support provided by Daiichi Sankyo, Inc, a member of the Daiichi Sankyo Group, Daiichi Sankyo Co, Ltd, Tokyo, Japan. The authors thank Jeffrey S. Riegel, PhD, at Accuverus, Beachwood, OH, for editorial support.
Disclosure Giorgio Scagliotti: Consultant for Eli Lilly honoraria from AstraZeneca, Eli Lilly, Pfizer, Roche, AVEO, ARIAD, and Boehringer Ingelheim. Joan Schiller: Consultant for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, GSK, Eli Lilly, Pfizer, Merck-Serono, MSD, Roche, and Sanofi-Aventis. Vera Hirsh: Member of Daiichi Sankyo, Inc., advisory board. Lecia Sequist: Consultant for Clovis Oncology, Celgene, and GSK; uncompensated consultant for Daiichi Sankyo, Inc., and Merrimack Pharmaceuticals. Jean-Charles Soria: Honoraria from Abbott, Amgen, AstraZeneca, BMS, GSK, Lilly, Pfizer, Merck-Serono, MSD, Roche, and Sanofi-Aventis. Joachim von Pawel: Consultant for Daiichi Sankyo, Inc. Brian Schwartz: Employee of ArQule, Inc. Reinhard Von Roemeling: Employee of Daiichi Sankyo, Inc. Alan Sandler: Grants and research support from Abraxis, Daiichi Sankyo, Inc., Eli Lilly, Pfizer, and Synta; consultant or Advisory Board member for Abraxis, Agennix, Allos Therapeutics, Aveo, Boehringer Ingelheim, Celgene, Clovis Oncology, Daiichi Sankyo, Inc., Eli Lilly, Genentech, GlaxoSmithKline, Hoffman LaRoche, OxiGene, Pfizer, and Roche; member of Speaker’s Bureau for Eli Lilly, Genentech, and Quintiles; honoraria
from Agennix, Boehringer Ingelheim, Celgene, Chugai (Roche), Daiichi Sankyo, Inc., Eli Lilly, Genentech, GlaxoSmithKline, OxiGene, Roche, and Quintiles; legal consulting for Genentech, Pfizer, OSI Pharmaceuticals, and Roche. Silvia Novello states no conflicts of interest.
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