LBA29 - CARRIE: A 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

Abstract

Background: High serum IGF-1 levels have been associated with more aggressive pancreatic cancer (PDAC). Pre-clinical data suggest that dual blockade of the IGF-1 and HER3 pathways has superior activity to IGF-1 blockade alone in PDCA. We tested whether istiratumab, an IGF-1R and ErbB3 bi-specific antibody, can enhance the efficacy of standard of care (SOC) chemotherapy in patients with high serum IGF-1 levels. Methods: CARRIE was a randomized, double-blind, placebo-controlled, international Phase 2 study of nab-paclitaxel/gemcitabine alone or in combination with istiratumab in front-line metastatic PDAC. In Part 1, 10 patients were evaluated for PK and safety. In Part 2, patients with high free serum IGF-1 levels were randomized 1:1 to receive either istiratumab (2.8 g. IV Q2W) or placebo plus nab-paclitaxel/gemcitabine at the approved dose schedule. Heregulin (HRG) was tested in pre-treatment tumor samples. The co-primary endpoints were Progression Free Survival (PFS) in patients with high IGF-1 levels and in patients with both high IGF-1 levels and HRG+ tumors. Key secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) by RECIST v1.1, and adverse events (AEs) rate. Results: A total of 317 patients were screened to enroll 88 patients (experimental arm n = 43; control n = 45) in Part 2. In the high IGF-1 cohort, median PFS was 3.6 and 7.3 months in the experimental vs. control arms, respectively (HR = 1.88, p = 0.027). In the combined high IGF-1/HRG+ subgroup (n = 44), median PFS was 4.1 and 7.3 months, respectively (HR = 1.39, p = 0.42). Median OS and ORR for the overall population were similar between two arms (8.9 and 11.7 months, HR = 1.36, p = 0.22 and 39.5 vs. 51.2%, p = 0.33, respectively). 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%) vs. control arm (24.4%). Conclusions: Istiratumab failed to improve the efficacy of SOC chemotherapy in the front-line treatment of patients with metastatic PDAC and high IGF-1. High serum IGF-1 levels did not appear to be an adverse prognostic factor in this setting. Clinical trial identification: NCT02399137. Legal entity responsible for the study: Merrimack Pharmaceuticals, Inc. Funding: Merrimack Pharmaceuticals, Inc. Disclosure: A.H. Ko: Clinical research support for conduct of this study to institution: Merrimack; Clinical research support for conduct of a separate study paid to institution: Celgene; Advisory board (self): Celgene. M. Kundranda: Consulting: Bayer; Speaker bureau: Bayer, Amgen. F. Rivera Herrero: Consulting: Celgene; Research fundings: Amgen, Merck-Serono, Roche, Sanofi, Bayer, Lilly, Celgene; Honoraria: Amgen, Merck-Serono, Roche, Sanofi, Bayer, Lilly, Celgene, Tecnofarma. D. Watkins: Funding to support educational conference attendance: Amgen. W. Downing, B. Wang, G. Kuesters, J.M. Pipas, V. Askoxylakis: Employee and stock share holder: Merrimack. S.L. Santillana: Employee and stock share holder: Merrimack Pharmaceuticals. All other authors have declared no conflicts of interest.