Long-Term Maintenance Therapy with the TLR-9 Agonist MGN1703 in a Subgroup of Metastatic Colorectal Cancer Patients from the Impact Study

Abstract

ABSTRACT Background The IMPACT trial assessed the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent TLR9 agonist, as switch maintenance after first line induction therapy in mCRC patients at the dose of 60 mg subcutaneously twice weekly. We report here the updated follow-up of 4 patients who completed the study without disease progression. Methods Patients with mCRC and disease control after induction 1st-line chemotherapy +/- bevacizumab were included in the IMPACT placebo-controlled phase 2 study. The trial was closed after randomization of 59 patients and the final analysis showed a superior effect of MGN1703 compared to placebo: the hazard ratio for the primary endpoint PFS on maintenance was 0.55 (p = 0.041) by local investigator assessment and 0.56 (p = 0.070) by independent radiological review. During the study 3 responses were observed in the MGN1703 arm, two of them appearing as late as 9 months after the start of treatment. Overall 4 patients (the 3 responders to MGN1703 and 1 patient in CR after induction chemotherapy) were still free of progression at time of the study closure and were allowed to continue MGN1703 treatment in compassionate use programs. Results As of April 2014, only 1 patient stopped treatment with MGN1703 due to disease progression after 17 months. Three patients are still not progressing and continue to receive MGN1703 monotherapy in excess of 32, 36, and 40 months. No relevant toxicity or SAE was reported during the extended follow-up and treatment. Patients with normalized CEA and objective response at the end of induction chemotherapy appear to benefit the most from maintenance with MGN1703. Notably, the presence of activated NKT-cells (CD3+/CD56+/CD69+) also appears to predict a benefit, possibly linked to the activation status of the immune system before receiving MGN1703. Conclusions Very prolonged responses with the TLR9 agonists were achieved in a subgroup of mCRC patients, without evidence of relevant toxicity. IMPALA, a large international phase 3 study, aims to confirm the role of MGN1703 as first line switch maintenance in mCRC patients with an objective response to standard induction therapy. Disclosure A. Zurlo: Mologen AG employee and owner of stocks and stock options. All other authors have declared no conflicts of interest.