P-307 - Immunomodulatory switch maintenance therapy to improve overall survival in metastatic colorectal carcinoma: The phase 3 IMPALA study

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Cancer Immunology and Immunotherapy
Rectal Cancer
Presenter D. Arnold
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors D. Arnold1, A. Sobrero2, D. Cunningham1, M. Ducreux3, E. Van Cutsem4, T. Waddell1, W. Scheithauer5, R. Salazar6, A. Zurlo7, A. Stein8, C. Tournigand9
  • 1Tumor Biology Center, Freiburg/DE
  • 2IRCCS AOU San Martino IST, Genoa/IT
  • 3Gustave Roussy Cancer Campus Grand Paris, Villejuif/FR
  • 4University Hospitals Leuven, Leuven/BE
  • 5Medizinische Universität Wien, Vienna/AT
  • 6Institut Català d'Oncologia, L'Hospitalet de Llobregat/ES
  • 7Mologen AG, Berlin/DE
  • 8University Medical Center Hamburg, Hamburg/DE
  • 9Hôpital Henri Mondor, Créteil/FR

Abstract

Introduction

The potent immunomodulator MGN1703, a DNA-based Toll-like receptor 9 (TLR-9) agonist, was compared to placebo in metastatic CRC (mCRC) patients with disease control after standard induction chemotherapy +/- bevacizumab in the double-blind randomized phase 2 IMPACT study. The drug was given as switch maintenance in 59 patients not progressing after 4.5 to 6 months of first line induction, since the mode of action of MGN1703 postulates the need of free circulating tumor-associated antigens for optimal activation of the innate and adaptive immune system. MGN1703 showed a superior effect over placebo, with a hazard ratio (HR) for the primary endpoint “PFS on maintenance” of 0.55 (p = 0.041) by local assessment and 0.56 (p = 0.070) by independent radiological review. Exploratory PFS analyses of pretreatment characteristics identified patients with objective RECIST response, normalized CEA and presence of activated NKT cells at the end of induction treatment to benefit the most with MGN1703 maintenance. This was confirmed by overall survival (OS) evaluation, with the subgroup of patients with RECIST response after induction therapy reporting a HR of 0.40 (median 24.5 vs. 15.1 months). Furthermore, at time of IMPACT study closure, 4 MGN1703 patients were still without progressive disease and continued treatment in compassionate use settings. As of September 2014, 3 patients were still receiving MGN1703 treatment in excess of three years (37-45 months), with 2 objective responses ongoing over 36 months. The phase 3 IMPALA study was designed to confirm this encouraging preliminary evidence.

Results

The IMPALA study is a randomized, international, multicenter, open-label phase 3 trial with participation of the AIO, TTD, and GERCOR cooperative groups. In IMPALA mCRC patients having achieved an objective tumor response following any type of first line induction therapy with or without biological agents are randomized to receive MGN1703 switch maintenance monotherapy in the experimental arm or local standard of care in the control arm. In case of relapse on maintenance, patients will reintroduce the initial induction treatment whenever feasible, with those in the experimental arm continuing to receive MGN1703 therapy in the weeks without infusional chemotherapy. The primary endpoint of the study will be OS, considered as the most appropriate and clinically meaningful endpoint to assess an immunomodulatory treatment in the maintenance setting, based on the evidence of large phase 3 studies that recently failed to show an improvement in OS when comparing different maintenance strategies with 5FU and/or bevacizumab. Secondary endpoints include PFS, response rates, safety, and QoL in selected centers. Type of induction treatment, CEA and activated NKT at baseline are stratification factors for the study and will be prospectively assessed. All randomized patients will take part in a comprehensive immune monitoring plan evaluating cytokines and chemokines in serum and the activation status of various immune cell populations. Additional translational research programs are under evaluation. Recruitment started in September 2014 and the study is expected to recruit 540 patients within 24 months in 8 European countries.