Current Trial Report. Jonathan W. Goldman, 1 Peipei Shi, 2 Martin Reck, 3 Luis Paz-Ares, 4 Andrew Koustenis, 2 Karla C. Hurt 2

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1 Current Trial Report Treatment Rationale and Study Design for the JUNIPER Study: A Randomized Phase III Study of Abemaciclib With Best Supportive Care Versus Erlotinib With Best Supportive Care in Patients With Stage IV NoneSmall-Cell Lung Cancer With a Detectable KRAS Mutation Whose Disease Has Progressed After Platinum-Based Chemotherapy Jonathan W. Goldman, 1 Peipei Shi, 2 Martin Reck, 3 Luis Paz-Ares, 4 Andrew Koustenis, 2 Karla C. Hurt 2 Abstract This clinical trial summary provides the background and rationale for the JUNIPER study (NCT ). JUNIPER is a randomized study of abemaciclib (200 mg orally every 12 hours) with best supportive care (BSC) versus erlotinib (150 mg orally every 24 hours) with BSC in patients with stage IV nonesmall-cell lung cancer (NSCLC) whose tumors have detectable Kirsten rat sarcoma (KRAS) mutations and whose disease has progressed after platinum-based chemotherapy and 1 other previous therapy, or who are not eligible for further chemotherapy. Approximately 550 patients will be randomized in a 3:2 ratio and stratified according to number of previous chemotherapy regimens (1 vs. 2), Eastern Cooperative Oncology Group performance status (0 vs. 1), sex (male vs. female), and KRAS mutation (G12C vs. others). Erlotinib was chosen as the control arm, because it is the only agent indicated for second- and third-line therapy in advanced NSCLC. Treatment will continue until disease progression or unacceptable toxicity occurs, with assessments every 28 days, followed by short-term and long-term follow-up. The coprimary efficacy objectives of this study are progression-free survival (PFS) and overall survival (OS); secondary objectives are overall response rate, changes in patient-reported pain and disease-related symptoms, changes in health status, resource utilization, safety and tolerability, and pharmacokinetics/pharmacodynamics. This design has 80% power to detect OS hazard ratio (HR) of 0.75 (type I error 0.045) and PFS HR of 0.67 (type I error 0.005). If the coprimary objectives (OS and PFS) are achieved, this study will provide a new alternative third-line treatment option for patients with NSCLC whose tumors have detectable KRAS mutations. Clinical Lung Cancer, Vol. 17, No. 1, 80-4 ª 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( Keywords: Biomarkers, CDK4, CDK6, Cyclin-dependent kinase, LY Clinicaltrials.gov NCT Department of Hematology and Oncology, UCLA Medical Center, Santa Monica, CA 2 Eli Lilly and Company, Indianapolis, IN 3 Department of Thoracic Oncology, Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), Grosshansdorf, Germany 4 Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain Submitted: Jul 22, 2015; Accepted: Aug 11, 2015; Epub: Aug 18, 2015 Address for correspondence: Jonathan W. Goldman, MD, UCLA Hematology and Oncology, 2020 Santa Monica Blvd, Suite 600, Santa Monica, CA Fax: ; contact: jwgoldman@mednet.ucla.edu 80 - Clinical Lung Cancer January /ª 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (

2 Introduction Mutations in the Kirsten rat sarcoma (KRAS) oncogene have been implicated in the development of nonesmall-cell lung cancer (NSCLC). 1 Patients with metastatic NSCLC who have KRAS mutations (15%-25%) 2 have a poor prognosis compared with NSCLC patients with KRAS wild type. 3 Of the KRAS mutations in NSCLC, approximately 97% occur in codons 12 or These mutations lead to persistent activation of rat sarcoma (RAS) signaling, which contributes to unregulated growth and malignant transformation. The activity of cyclin-dependent kinase (CDK)-4 is required for tumor progression in a KRAS-induced lung adenocarcinoma model. RAS and CDK4 coexpression promotes retinoblastoma protein (Rb) phosphorylation, ultimately resulting in human invasive neoplasm. 5 Ablation of CDK4 selectively induces senescence of KRASexpressing cells. 6 Therefore, CDK4 might be an attractive drug candidate for KRAS mutation-positive NSCLC. Abemaciclib (LY ) is a potent and selective small molecule inhibitor of CDK4 and CDK6 7 that has been shown to inhibit cell cycle progression by prevention of phosphorylation and functional inactivation of the Rb tumor suppressor protein. Abemaciclib effectively inhibited growth of cancer cells in cell culture, and when administered orally, demonstrated single-agent efficacy in various xenograft models for human cancer including NSCLC. 7 In a phase I study (I3Y-MC-JPBA; ClinicalTrials.gov Identifier: NCT ), 7 abemaciclib showed acceptable safety and tolerability, and evidence of clinical activity in pretreated patients with multiple tumor types. In one cohort of the study, the KRAS mutation status of tumors from patients with advanced and/or metastatic NSCLC (n ¼ 57) was identified (n ¼ 53). 8 Among patients with KRAS mutant tumors (n ¼ 29), 16 patients had a Response Evaluation Criteria in Solid Tumors (RECIST) response of stable disease (SD) or better (disease control rate [DCR], 55.2%). For patients with KRAS wild type tumors (n ¼ 24), 9 had a response of SD or better (DCR, 37.5%). These findings led to the current study design, in which the combination of abemaciclib with best supportive care (BSC) versus erlotinib with BSC will be evaluated in pretreated patients with advanced stage NSCLC whose tumors have a detectable KRAS mutation. Patients and Methods Study Objectives The coprimary objectives of this study are to compare progression-free survival (PFS) and overall survival (OS) in the 2 study arms. Secondary objectives include the following: to compare overall response rate (complete response þ partial response); to investigate the safety and tolerability, and resource utilization (for example, analgesic type, hospitalizations, transfusions); to evaluate changes in health status via European Quality of Lifee5 Dimensions-5 Level, and changes in patient-reported pain and disease-related symptoms collected via the MD Anderson Symptom Inventory; and to characterize the pharmacokinetics and pharmacodynamics properties of abemaciclib. The exploratory objectives of the study are to explore biomarkers relevant to abemaciclib and the disease state and to correlate these markers with clinical outcome and to abemaciclib. Study Design and Treatment This multicenter, randomized, open-label, parallel, comparatorcontrolled trial consists of eligible patients randomized in a 3:2 ratio to 1 of 2 treatment arms. Patients in the abemaciclib arm will receive 200 mg orally every 12 hours with BSC on days 1 to 28 of a 28-day cycle. Patients in the erlotinib arm will receive 150 mg orally every 24 hours plus BSC on days 1 to 28 of a 28-day cycle. Randomization will be stratified according to differences in factors thought to be associated with clinical outcomes to further reduce the potential for bias and improve the power of the analyses. The study design is shown in Figure 1. Palliative and supportive care for other disease-related symptoms and for toxicity associated with treatment will be offered to all patients on this trial and will be reported in case report forms. Figure 1 Study Design Stage IV NSCLC that has previously progressed during platinum-based therapy KRAS Mutant (n = 550) Randomization Stratified by Number of previous chemotherapy regiments (1 vs. 2) ECOG PS (0 vs. 1) Sex (male vs. female) KRAS mutation (G12C vs. all others) 32 3:2 Abemaciclib 200 mg PO/Q12H Days 1-28 plus best supportive care until PD (n = 330) 28-Day Cycle Erlotinib 150 mg PO/Q24H Days 1-28 plus best supportive care until PD (n = 220) Abbreviations: ECOG ¼ Eastern Cooperative Oncology Group; KRAS ¼ Kirsten rat sarcoma; NSCLC ¼ nonesmall-cell lung cancer; PO ¼ orally; PS ¼ performance status; Q12H ¼ every 12 hours; Q24H ¼ every 24 hours. Clinical Lung Cancer January

3 Treatment Rationale and Study Design for the JUNIPER Study Rationale for the Erlotinib plus BSC Control Arm Erlotinib is indicated for the first-line treatment of metastatic NSCLC patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. Erlotinib is also approved for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 previous chemotherapy regimen. 9 The use of erlotinib for secondand third-line treatment has no limitation with regard to EGFR or KRAS mutation status. There has been some concern regarding the activity of erlotinib in the treatment of NSCLC with KRAS mutations because of results from 3 studies First, in the BR-21 study, a subgroup evaluation of 30 patients with KRAS mutant tumors randomized between placebo and erlotinib showed a nonsignificant better survival outcome in the placebo group. 10 In TITAN (Tarceva In Treatment of Advanced NSCLC), a second-line study of erlotinib versus chemotherapy, in patients with KRAS mutant tumors (n ¼ 35) there was some evidence of a greater risk of death in the erlotinib group (P ¼.057). 11 Last, a meta-analysis of response rate showed a numerically inferior response rate in patients with KRAS mutant tumors treated with EGFR tyrosine kinase inhibitors (such as erlotinib and gefitinib). 12 However, the small number of patients in the KRAS mutation subgroups precluded definitive conclusions in these trials. In the TAILOR (Tarceva Italian Lung Optimization Trial) study, in a comparison of docetaxel and erlotinib as second-line therapy in advanced NSCLC, there was not a significant treatment interaction based on KRAS status. 13 In the SATURN (Sequential Tarceva in Unresectable NSCLC) study of erlotinib maintenance therapy, improved PFS was preserved in a subset of 90 patients with KRAS mutant tumors (hazard ratio [HR], 0.77). 14 The DELTA (Docetaxel and Erlotinib Lung Cancer Trial) study evaluated docetaxel and erlotinib as second- or third-line therapy in patients unselected for EGFR status with advanced NSCLC and found no significant difference in PFS between the 2 treatments. 15 However, in a subgroup analysis it was found that PFS and response rates were significantly better with docetaxel in patients with EGFR wild type tumors, and erlotinib resulted in longer PFS and OS in patients with EGFR mutant tumors. 15 Absence of significance in that study was attributed to the small sample size. Overall, the data remain conflicting after extensive review of the literature. Because of the differences in toxicity profiles for available treatments and the limited treatment options for patients, erlotinib was considered an acceptable control arm, because it is the only drug approved by the US Food and Drug Administration as both second- and third-line treatment of NSCLC, and may show some preference for EGFR mutant tumors. Eligibility Criteria The protocol was approved by each participating institutional ethics review board. The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki, and Council for International Organizations of Medical Sciences International Ethical Guidelines and good clinical practice. All patients will sign written informed consent before treatment. Inclusion criteria include age 18 years of age, confirmed diagnosis of stage IV NSCLC, and a mutation in codon 12 or 13 of the KRAS oncogene. Patients must have disease progression after platinum-based chemotherapy and must have received 1 other previous chemotherapy for advanced and/or metastatic disease or be judged by the physician as ineligible for further standard second-line chemotherapy. Patients will be excluded from the study if they have a personal history of clinically relevant cardiovascular disease, presence of unstable central nervous system metastasis, or history of any other significant cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix) unless in complete remission with no therapy for a minimum of 3 years. See Table 1 for a full list of patient selection criteria. Statistical Design The study will enroll approximately 550 patients (330 patients in the abemaciclib arm and 220 patients in the erlotinib arm). One interim futility analysis will be performed by an independent data monitoring committee (DMC). The analysis will occur after 100 PFS events have been observed, and will be based on PFS. The DMC will be instructed to recommend the study be stopped for futility if the observed HR for PFS is > The second analyses will be based on PFS and OS end points to evaluate efficacy. This is the primary PFS analysis, which will be performed after 338 PFS events have occurred. The final OS analysis will occur when approximately 407 OS events have been observed. Safety interim analyses will be performed approximately every 6 months until the final OS analysis. Efficacy analyses will be done on the intention to treat patient population. All safety summaries and analyses will be based on the safety population, defined as all enrolled patients who receive at least 1 dose of any study drug. The studywise a level of 0.05 will be split between the coprimary end points: for PFS and for OS. A fallback procedure will be used. The test on PFS will occur first; if the test on PFS is significant, the a used for this test will be added to the originally allocated to OS for a total of This fallback procedure will maintain a studywise a level of Because OS data are not anticipated to be mature at the time of the PFS analysis, of the a allocated to OS will be spent at the time of the PFS analysis. Assuming a PFS HR of 0.67, this sample size will yield approximately 80% statistical power to detect superiority of the abemaciclib arm over the erlotinib arm with the use of a 2-sided log rank test and a type I error of If the true median PFS for the erlotinib arm is 2 months, then a HR of 0.67 amounts to an approximate 1-month improvement in median PFS for the abemaciclib arm. Assuming an OS HR of 0.75, this sample size will yield approximately 80% statistical power to detect superiority of the abemaciclib arm over the erlotinib arm with the use of a 2-sided log-rank test and a type I error of If the true median OS for the erlotinib arm is 6.5 months, then the HR of 0.75 amounts to an approximate 2.2-month improvement in median OS for the abemaciclib arm. Conclusion If the coprimary objectives are achieved, the JUNIPER (A Randomized Phase 3 Study of Abemaciclib (LY ) plus Best Supportive Care vs. Erlotinib plus Best Supportive Care in Patients with Stage IV NSCLC with a Detectable KRAS Mutation Who Have Progressed After Platinum-Based Chemotherapy) study will provide a new alternative third-line treatment option for patients with advanced metastatic NSCLC whose tumors have detectable KRAS mutations Clinical Lung Cancer January 2016

4 Table 1 Patient Selection Criteria Clinical Lung Cancer January Inclusion Criteria Confirmed diagnosis of stage IV NSCLC according to the American Joint Committee on Cancer Staging Handbook Adequate FFPE tumor-derived material (tumor blocks or slides) from a biopsy, surgery, or fine-needle aspirate for analysis of KRAS mutation status Detectable mutations in codons 12 or 13 of the KRAS oncogene Disease progression after platinum-based chemotherapy (with or without maintenance therapy) and have received 1 other previous chemotherapy for advanced and/or metastatic disease or is judged by the physician as ineligible for further standard second-line chemotherapy Measureable disease defined according to RECIST Performance status of 0 to 1 on the ECOG scale Discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents before receiving study drug Recovered from the acute effects of therapy (treatment-related toxicity resolved to baseline) except for residual alopecia Adequate organ function Men and women aged 18 years Male and female patients with reproductive potential must use an approved reliable contraceptive method Women with child-bearing potential must have a negative serum pregnancy test at the time of enrollment Estimated life expectancy of 12 weeks Reliable and willing to follow study procedures Signed informed consent and/or assent document Exclusion Criteria Currently enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively Previously completed or withdrawn from this study or any other study investigating abemaciclib Personal history of any of the following conditions: presyncope or syncope of either unexplained or cardiovascular etiology, ventricular arrhythmia, or sudden cardiac arrest Presence of unstable CNS metastasis. History of CNS metastasis or stable CNS metastases are allowed. Patients with a history of CNS metastases must have a brain scan within 28 days of randomization to document stability, even if there have been no changes in symptoms History of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission with no therapy for that disease for a minimum of 3 years Serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study Women who are pregnant or lactating Active bacterial, fungal, and/or known viral infection Abbreviations: CNS ¼ central nervous system; ECOG ¼ Eastern Cooperative Oncology Group; FFPE ¼ formalin-fixed, paraffin-embedded; KRAS ¼ Kirsten rat sarcoma; NSCLC ¼ nonesmall-cell lung cancer; RECIST ¼ Response Evaluation Criteria in Solid Tumors. Jonathan W. Goldman et al

5 Treatment Rationale and Study Design for the JUNIPER Study Acknowledgments This work is sponsored and funded by Eli Lilly and Company, Indianapolis, IN, and/or any of its subsidiaries. Eli Lilly and Company is responsible for the study design, and for the collection, analysis and interpretation of data, and the decision to submit the report for publication. Eli Lilly and Company contracted inventiv Health Clinical, LLC, for writing and editorial services. We thank in advance the patients, their families, and the study personnel across all sites who will participate in this study. The authors thank Jody Arsenault, PhD, and Noelle Gasco of inventiv Health Clinical for writing and editorial assistance. Disclosure Karla C. Hurt, Andrew Koustenis, and Peipei Shi are employees of Eli Lilly and Company; and have stock ownership in Eli Lilly and Company. Jonathan W. Goldman reports research funding from Eli Lilly and Company, Bristol-Myers Squibb, Synta Pharmaceuticals, ArQule, Astex Pharmaceuticals, Threshold Pharmaceuticals, and Clovis Oncology. Martin Reck reports having a consulting/advisory role and/or participating in speaker s bureaus for Hoffman-La Roche AG, Eli Lilly and Company, MSD Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Astra- Zeneca, Pfizer and Novartis. Luis Paz-Ares reports receiving honoraria and participating in a speaker s bureauforelilillyand Company. References 1. Porta M, Crous-Bou M, Wark PA, et al. Cigarette smoking and K-ras mutations in pancreas, lung and colorectal adenocarcinomas: etiopathogenic similarities, differences and paradoxes. Mutat Res 2009; 682: Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008; 14: Guan JL, Zhong WZ, An SJ, et al. KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol 2013; 20: Riely GJ, Marks J, Pao W. KRAS mutations in nonesmall-cell lung cancer. Proc Am Thorac Soc 2009; 6: Lazarov M, Kubo Y, Cai T, et al. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 2002; 8: Puyol M, Martin A, Dubus P, et al. A synthetic lethal interaction between K-Ras oncogenes and CDK4 unveils a therapeutic strategy for nonesmall-cell lung carcinoma. Cancer Cell 2010; 18: Shapiro G, Rosen LS, Tolcher AW, et al. A first-in-human phase 1 study of the CDK4/6 inhibitor, LY , for patients with advanced cancer (abstract 2500). J Clin Oncol 2013; 31(suppl). 8. Goldman JW, Gandhi L, Patnaik A, et al. Clinical activity of LY , a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with nonesmall-cell lung cancer. Presented at the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, Tarceva (erlotinib) tablets [prescribing information]. Northbrook, IL: OSI Pharmaceuticals, LLC; Zhu CQ, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008; 26: Ciuleanu T, Stelmakh L, Cicenas S, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, nonesmall-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol 2012; 13: Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-ras mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced nonesmall-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008; 9: Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced nonesmall-cell lung cancer and wild-type EGFR tumours(tailor):arandomisedcontrolledtrial.lancet Oncol 2013; 14: Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced nonesmall-cell lung cancer. JClinOncol 2011; 29: Kawaguchi T, Ando M, Asami K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced nonesmall-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol 2014; 32: Clinical Lung Cancer January 2016