Background: Patients with mCRC and disease control after induction with first-line chemotherapy +/- bevacizumab were included in the double-blind placebo-controlled phase II IMPACT trial, aiming to assess the clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, a potent TLR9 agonist, given at the dose of 60 mg subcutaneously twice weekly as switch maintenance after first line induction therapy in mCRC. Methods: The trial was prematurely closed after randomization of 59 patients. The final analysis showed a superior effect of MGN1703 compared to 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. Exploratory PFS analyses of pretreatment characteristics identified patients with normalized CEA, objective response, and the presence of activated NKT cells at the end of induction chemotherapy to benefit the most from maintenance with MGN1703. We analysed the impact of these factors on the secondary endpoint overall survival (OS). Results: At time of final study analysis, OS data were not mature. Only 35% of MGN1703 patients had an event, as opposed to 50% of placebo patients. The HR for OS of whole study population was 0.63 (median 22.6 vs. 15.1 months, p=NS). The subgroup of patients randomized into the study with confirmed RECIST response had a HR of 0.40 (median 24.5 vs. 15.1 months, p=NS), suggesting this may be the population with greater benefit. HR for patients with normalized CEA or with activated NKT cells were 0.69 and 0.43, respectively. Based on this evidence, in the phase III IMPALA study patients with objective response after standard induction therapy are randomized to standard treatment or switch maintenance with MGN1703. CEA and activated NKT cells are stratification factors for the study and will be prospectively assessed. Conclusions: The pretreatment characteristics predictive of a PFS benefit in the IMPACT study seem to retain their value also in exploratory analyses for OS. This information has been used to design the phase III IMPALA study, currently recruiting patients. Clinical trial information: NCT01208194