PD-0009 - A subgroup of metastatic colorectal cancer patients with very prolonged disease control under maintenance therapy with the TLR-9 agonist MGN1703
|Date||27 June 2014|
|Event||World GI 2014|
|Session||Poster discussion session II – Tumor burden and biomarkers|
|Topics|| Colon Cancer
Cancer Immunology and Immunotherapy
|Citation||Annals of Oncology (2014) 25 (suppl_2): ii5-ii13. 10.1093/annonc/mdu164|
J. Riera-Knorrenschild1, H.G. Kopp2, F. Mayer3, D. Nitsche4, J. Kuhlmann5, R. Ziebermayr6, J. Andel7, M. Schmidt8
The IMPACT trial was conducted to assess clinical efficacy, safety, and immunological effects of the immunomodulator MGN1703, acting as a potent TLR-9 agonist. MGN1703, which has previously shown good safety profile in patients with metastatic solid tumors and activation of the innate and adaptive immune system, was evaluated at the dose of 60 mg subcutaneously twice weekly as maintenance therapy in mCRC.
Patients with mCRC and disease control after induction with standard 1st-line chemotherapy +/- bevacizumab were included in the double-blind placebo-controlled phase 2 IMPACT trial. The trial was prematurely closed after randomization of 59 (43 MGN1703, 16 placebo) out of 129 planned patients due to slow recruitment. In the final analysis reported in 2013 a superior effect of MGN1703 compared to placebo was shown; the hazard ratio (HR) 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, showing a pattern similar to other immune active agents currently under investigation. At time of study closure 4 patients (3 responders to MGN1703 and one patient randomized with a CR after induction chemotherapy) were still free of progression and opted to continue MGN1703 monotherapy treatment in compassionate use programs. Thus the patients were trained to administer their subcutaneous injection autonomously at home. We retrieved recent information from these patients.
As of January 2014 3 patients are still receiving MGN1703 monotherapy being on treatment for 29, 33, and 37 months. One of the patients with a response to MGN1703 eventually progressed after 17 months on treatment. No SAE were reported during the compassionate use programs.
Evaluation of possible predictive parameters for a benefit of MGN1703 by Cox regression and ROC analyses identified potential predictive factors at baseline. Patients with normal CEA (HR of 0.07; p < 0.0001) and objective response (HR of 0.39; p = 0.005) after induction chemotherapy appear to benefit the most from maintenance with MGN1703. Additionally, a pre-treatment parameter related to the activation status of the immune system appeared potentially predictive for a benefit as well: the presence of activated NKT-cells (CD3 + /CD56 + /CD69+) at baseline yielded a HR of 0.26 (p = 0.002).
This long-term update of mCRC patients who completed the IMPACT trial without evidence of progression provides preliminary evidence that in some patients very prolonged disease control can be obtained with the immunomodulator MGN1703. Analysis of pre-treatment characteristics suggests that patients with smaller tumor burden and with a good response to chemotherapy may be the best candidates to receive immunotherapy; similar evidence is growingly being reported for other immunotherapeutic approaches. On this basis IMPALA, a large international phase 3 study, has been designed to confirm the role of first line maintenance treatment with MGN1703 in mCRC patients with an objective response to induction chemotherapy.