Maintenance with the TLR-9 agonist MGN1703 versus placebo in patients with advanced colorectal carcincoma (mCRC): a randomized phase II trial (IMPACT)

Background: Standard induction chemotherapy for mCRC is often discontinued in patients responding to the treatment. MGN1703, a synthetic DNA‐based immunomodulator, acts as TLR‐9 agonist. This trial has been conducted to assess clinical efficacy, safety, and immunogenicity of MGN1703 as maintenance therapy vs placebo. Methods: The IMPACT trial is an international, multicenter, randomized (2:1) double‐blind placebo‐controlled phase 2 trial in mCRC patients with disease control (CR, PR, SD) after 4.5 to 6 months of 1st‐line induction chemotherapy with FOLFOX/XELOX or FOLFIRI +/‐ bevacizumab. Results: 59 patients have been randomized (43 MGN1703, 16 placebo). Median PFS from start of maintenance was not different with 2.8 vs 2.7 months, however the HR was 0.56 (CI 95%: 0.29‐1.08; p=0.069) in favor of MGN1703, due to a small favorable subgroup with long‐term PFS (20% vs 0% at 9 months; p=0.006). Total PFS from beginning of induction chemotherapy including maintenance was significantly improved: HR 0.49 (CI 95%: 0.25‐0.94), p=0.029. After a median follow‐up of 13 months 66% of patients are still alive (67% vs 62%), therefore survival data are still preliminary (HR 0.79; CI 95%: 0.3‐2.1) and will be mature at the meeting. Activation of cellular immune function as indicated by significant increase of CD14+CD169+monocytes was observed in all but one of the MGN1703 treated patients, while absent in all placebo patients. Treatment was well tolerated: 46.5% vs 31.3% of patients (MGN1703 vs placebo) had any drug‐related adverse events (AE) and 20.9% vs 18.8% had AE with grade 3 or 4 (including hypertension, ileus, sepsis, sensory polyneuropathy, nausea/vomiting for MGN1703 and pain, popular exanthema for placebo). Conclusions: MGN1703 maintenance seems to prolong PFS in a subgroup of patients with disease control after induction chemotherapy vs placebo, and is associated with relative mild toxicity. This in an early signal in a selected and very limited patient population which supports further investigation. Predictive biomarkers are under evaluation to identify a potential subgroup which might have benefit from this TLR‐9 MGN1703 maintenance.