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MM-141) Plus Nab-Paclitaxel and Gemcitabine Versus Nab-Paclitaxel and Gemcitabine in Front-Line Metastatic Pancreatic Cancer (CARRIE)

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MM-141) Plus Nab-Paclitaxel and Gemcitabine Versus Nab-Paclitaxel and Gemcitabine in Front-Line Metastatic Pancreatic Cancer (CARRIE) ORIGINAL ARTICLE Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE) M. Kundranda1, A. C. Gracian2,3, S. F. Zafar4, E. Meiri5, J. Bendell6, H. Algül7, F. Rivera8, E. R. Ahn9, D. Watkins10, U. Pelzer11, V. Charu12, A. Zalutskaya13, G. Kuesters13, J. M. Pipas13, S. Santillana13, V. Askoxylakis13 &A.H.Ko14* 1Medical Oncology, Banner MD Anderson Cancer Center, Gilbert, USA; 2Medical Oncology, Centro Integral Oncologico Clara Campal and 3Departamento de Ciencias Médicas Clínicas, Universidad CEU San Pablo, Madrid, Spain; 4Hematology and Oncology, Florida Cancer Specialists, Fort Myers; 5Medical Oncology, Comprehensive Care and Research Center, Atlanta; 6GI Oncology, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA; 7TUM School of Medicine, Klinikum rechts der Isar, Medizinische Klinik II, Technical University of Munich, Munich, Germany; 8Medical Oncology, Hospital Universitario Marques de Valdecilla, Santander, Spain; 9Medical Oncology, Cancer Treatment Centers of America Chicago, Zion, USA; 10Department of Medicine, Royal Marsden Hospital, Sutton, UK; 11Charité e Universitätsmedizin Berlin, Germany; 12Hematology/Oncology, Pacific Cancer Medical Center, Anaheim; 13Clinical Development, Merrimack Pharmaceuticals, Inc., Cambridge; 14Hematology/Oncology, University of California San Francisco Cancer Center, San Francisco, USA Background: Preclinical data suggest that dual blockade of the insulin-like growth factor-1 receptor (IGF-1R) and HER3 pathways has superior activity to IGF-1R blockade alone in pancreatic ductal adenocarcinoma (PDAC). We tested whether istiratumab, an IGF-1R- and ErbB3-bispecific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with metastatic PDAC selected for high IGF-1 serum levels. Patients and methods: CARRIE was an international, randomized, double-blind, placebo-controlled phase II study for patients with previously untreated metastatic PDAC. In part 1, 10 patients were evaluated for pharmacokinetics and safety. In part 2, patients with high free serum IGF-1 levels were randomized 1 : 1 to receive either istiratumab [2.8 g intravenously (i.v.) every 2 weeks] or placebo combined with gemcitabine/nab- paclitaxel at approved dose schedule. The co-primary endpoints were progression-free survival (PFS) in patients with high IGF-1 levels and PFS in patients with both high serum IGF-1 levels and heregulin (HRG)þ tumors. Key secondary endpoints were overall survival (OS), objective response rate (ORR) by RECIST v.1.1, and adverse events (AEs) rate. Results: A total of 317 patients were screened, with 88 patients randomized in part 2 (experimental arm n ¼ 43; control n ¼ 45). In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental versus control arms, respectively [hazard ratio (HR) ¼ 1.88, P ¼ 0.027]. In the high IGF-1/HRGþ subgroup (n ¼ 44), median PFS was 4.1 and 7.3 months, respectively (HR ¼ 1.39, P ¼ 0.42). Median OS and ORR for the overall population were similar between two arms. No significant difference in serious or grade 3 AEs was observed, although low-grade AEs leading to early discontinuation were higher in the experimental (39.5%) versus control arm (24.4%). Conclusions: Istiratumab failed to improve the efficacy of SOC chemotherapy in this patient setting. High serum IGF-1 levels did not appear to be an adverse prognostic factor when compared with non-biomarker-selected historic controls. Clinical Trial Registration numbers: ClinicalTrials.gov: NCT02399137; EUDRA CT: 2014-004572-34. Key words: CARRIE, heregulin, insulin-like growth factor 1, istiratumab, metastatic pancreatic cancer, MM-141 INTRODUCTION within the decade.1,2 In patients with metastatic disease, two fl Pancreatic ductal adenocarcinoma represents one of the most chemotherapy options, FOLFIRINOX ( uorouracil, leucovorin, aggressive malignancies and is expected to become the sec- irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel, ond leading cause of cancer-related death in the United States have emerged as front-line standards of care based on data demonstrating a significant survival benefit for each of these regimens compared with single-agent gemcitabine. However, *Correspondence to: Dr Andrew H. Ko, Hematology/Oncology, University of in each of these pivotal studies the median survival of patients California San Francisco, PO Box 0981, University of California, San Francisco, þ remained less than 1 year, highlighting the ongoing need to San Francisco, CA 94143-0981, USA. Tel: 1-415-353-9888 3,4 E-mail: [email protected] (A. H. Ko). develop better therapies for this disease. Lack of effective 0923-7534/© 2019 European Society for Medical Oncology. Published by targeted agents and a paucity of validated predictive Elsevier Ltd. All rights reserved. Volume 31 - Issue 1 - 2020 https://doi.org/10.1016/j.annonc.2019.09.004 79 Annals of Oncology M. Kundranda et al. biomarkers that can guide therapeutic decision making randomized in a 1 : 1 fashion to the experimental arm represent major limitations in the treatment of pancreatic (istiratumab plus gemcitabine and nab-paclitaxel, at afore- cancer. said doses and schedule) or to the control arm (placebo i.v. Insulin-like growth factor (IGF) signaling plays an impor- every 2 weeks plus nab-paclitaxel and gemcitabine). tant role in regulating growth and development in normal Assignment was stratified by region (United States or human tissues.5 The IGF axis comprises insulin and two Europe). Treatment started within 7 days following related ligands, IGF-1 and IGF-2, that regulate cellular pro- randomization and continued until investigator-determined cesses by interacting with specific cell-surface receptors. progressive disease (PD) based on RECIST v.1.1 or unac- The IGF-1 receptor (IGF-1R) is a heterotetrameric tyrosine ceptable toxicity. The primary endpoint was progression- kinase receptor with two extracellular ligand-binding alpha free survival (PFS), defined as the time from randomiza- subunits and two transmembrane beta subunits containing tion to the first documented radiographical progression of the kinase domain.6 Increased expression of IGF-1R and/or disease using RECIST, or death from any cause, whichever circulating levels of IGF ligands have been observed in came first. Two patient populations were used for co- various cancers, including pancreatic cancer, Ewing sar- primary PFS analysis: (i) those with high levels of free IGF- coma, breast cancer, prostate cancer, and melanoma.7 In 1 (the entire study cohort), and (ii) those with both high addition to its presence being essential for malignant levels of free IGF-1 and whose tumors showed high level of transformation, overexpression is associated with faster heregulin expression (HRGþ), as measured retrospectively disease progression and poorer prognosis.7 Furthermore, in pretreatment tumor samples by an HRG RNA-in situ hy- increased levels of IGF-1 are associated with greater risk of bridization assay (Advanced Cell Diagnostics reagents cancer development and resistance to chemotherapies.8 [Newark, California], tested and scored at Merrimack). Istiratumab (MM-141) is a fully human tetravalent bispe- HRGþ was defined as at least 10% of tumor cells showing cific antibody that binds to and co-inhibits IGF-1R and the positive staining. Secondary efficacy endpoints included epidermal growth factor family of receptor tyrosine kinases disease control rate (DCR), defined as complete response, B3 (ErbB3). Structurally, it is a homodimer containing two partial response, or stable disease lasting at least 16 weeks; sets of identical polypeptide chains: a heavy chain of an overall survival (OS); investigator-assessed objective immunoglobulin-type G1 antibody targeting IGF-1R that is response rate (ORR); duration of response, and safety engineered to present a single-chain Fv antibody fragment profile. targeting ErbB3 at the C terminus; and a light chain targeting 8 IGF-1R. The dual activity of this agent is intended to over- Patient eligibility come the limitations of monospecific anti-IGF-1R antibodies, Primary eligibility criteria included age 18 years; including inhibiting the compensatory ErbB3 signaling that confirmed metastatic adenocarcinoma of the pancreas; no occurs upon IGF-1R blockade. This multicenter, double-blind, prior surgery, chemotherapy, or investigational therapy for placebo-controlled randomized phase II trial evaluated metastatic disease; high serum levels of free IGF-1 (defined chemotherapy in combination with either istiratumab or as 0.235 ng/ml using an enzyme-linked immunosorbent placebo in patients with untreated metastatic pancreatic assay validated at a single USA-based Clinical Laboratory cancer selected for elevated free serum IGF-1 levels. Improvement Amendments-certified central laboratory); an Eastern Cooperative Oncology Group (ECOG) performance PATIENTS AND METHODS status of 0 or 1; adequate organ and bone marrow function; and measurable disease based on National Cancer Institute CARRIE was a randomized, double-blind, placebo-controlled, RECIST v.1.1.9 Free IGF-1 serum samples were shipped international, phase II study of istiratumab in combination frozen and results provided within 5 business days of with nab-paclitaxel and gemcitabine versus nab-paclitaxel receipt at the central laboratory. An archived formalin-fixed and gemcitabine alone as front-line therapy for metastatic
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