Abstract B61: Exploratory analyses of the randomized phase 2 IMPACT study: Patients with response to prior induction chemotherapy have improved outcome when treated with the TLR-9 agonist MGN1703
Authors: Scheithauer Werner , Riera-Knorrenschild Jorge , Kopp Hans-Georg , Mayer Frank , Kroening Hendrik , Nitsche Dieter , Kuhlmann Jan , Ziebermayr Reinhard , Andel Johannes , Arnold Dirk , Zurlo Alfredo , Wittig Burghardt , Schmoll Hans-Joachim 
Published: October 2015

Abstract
Background: The international randomized (2:1) double-blind placebo-controlled phase 2 IMPACT trial recruited patients with metastatic colorectal cancer (mCRC) and disease control after induction with 1st-line chemotherapy +/- bevacizumab. The trial aimed to assess the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent Toll-Like Receptor 9 (TLR9) agonist, given at the dose of 60 mg subcutaneously twice weekly as switch maintenance after 4.5 to 6 months of induction therapy.
Methods: After randomization of 59 patients (43 MGN1703, 16 placebo) the trial was prematurely closed. The final analysis showed superiority of MGN1703 over placebo with hazard ratios (HR) for the primary endpoint PFS on maintenance of 0.55 (p=0.041) and 0.56 (p=0.070) by local investigator assessment or independent radiological review, respectively. Some delayed and long term responses were observed, 3 still ongoing in excess of 36 months. Exploratory PFS analyses of pretreatment characteristics identified patients with objective response (HR=0.39, p=0.0051), normalized CEA (HR=0.07, p&lt;0.0001), and the presence of activated NKT-cells (CD3+/CD56+/CD69+) (HR=0.26, p=0.0017) at the end of induction chemotherapy to benefit the most from maintenance with MGN1703. Since PFS is not considered the best endpoint to assess the benefit of immunotherapies, we analyzed the impact of these factors on the secondary endpoint overall survival (OS).
Results: Despite a median follow up of 17.7 months at the time of final study analysis, the OS data were not mature with only 35% and 50% of patients in the MGN1703 arm and placebo arm with an event, respectively. The power of the following OS analyses is therefore limited and will require confirmation when a large majority of events has been observed. The HR for the whole study ITT population was 0.63 (median 22.6 vs. 15.1 months for MGN1703 vs. placebo; p=NS). The subgroup of patients who were randomized into the study after achieving a RECIST response to prior induction therapy had HR of 0.40 (median 24.5 vs. 15.1 months; p=NS). Patients randomized in the study with stable disease had instead no benefit (HR 1.57; p=NS). The HR for OS of patients with presence of activated NKT cells and normalized CEA level after induction therapy was 0.43 and 0.69, respectively. Overall these results appear in line with the evidence from PFS subgroup analyses suggesting that responders may benefit the most from switch maintenance treatment with MGN1703. Recent literature provides a rationale for such finding, as a large series showed that presence of high density of lymphocyte infiltration in CRC metastases strongly predicts responses to chemotherapy (Halama et al, Cancer Res 2011; 71:5670-5677). A good response to chemotherapy may thus be a surrogate marker for increased immunogenicity of the tumor and allow identifying patients with an immune system that may be able to control tumor progression when broadly activated by MGN1703. Based on this hypothesis, the phase 3 IMPALA study has recently started recruitment in several European countries. Patients who achieved an objective response to their 1st-line induction therapy for mCRC are randomized to either continue local standard treatment or start switch maintenance with MGN1703. CEA and activated NKT values at baseline are stratification factors and will be also assessed prospectively.
Conclusions: The exploratory PFS and OS subgroup data from the IMPACT study support the hypothesis that is possible to identify patients more likely to benefit from an immunomodulatory treatment following active induction chemotherapy. This information has been used to design the phase 3 IMPALA study currently recruiting patients.
Citation Format: Werner Scheithauer, Jorge Riera-Knorrenschild, Hans-Georg Kopp, Frank Mayer, Hendrik Kroening, Dieter Nitsche, Jan Kuhlmann, Reinhard Ziebermayr, Johannes Andel, Dirk Arnold, Alfredo Zurlo, Burghardt Wittig, Hans-Joachim Schmoll. Exploratory analyses of the randomized phase 2 IMPACT study: Patients with response to prior induction chemotherapy have improved outcome when treated with the TLR-9 agonist MGN1703. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B61.