New data on an emerging treatment that aims to fight colorectal cancer by stimulating the immune system have been presented at the ESMO 15th World Congress on Gastrointestinal Cancer.

The findings confirm the biological action of the drug called MGN1703 and suggest it may be possible to identify which gastrointestinal cancer patients will benefit most from the treatment, reported Prof Hans-Joachim Schmoll from Martin Luther University, Halle, Germany.

MGN1703 is a small DNA molecule recognised by a receptor --called toll-like receptor 9-- that is expressed in certain immune system cells. The drug is designed to broadly activate all components of the innate immune system to stimulate the destruction of cancer cells.

The new data come from the final analysis of the phase II IMPACT study, which investigated MGN1703 in 59 patients with metastatic colorectal cancer.

The IMPACT study was an international, randomised, double-blind trial that was conducted in patients who had achieved disease control after 4.5 to 6 months of chemotherapy.

Standard chemotherapy for patients with metastatic colorectal cancer who respond to treatment is often completely or partially discontinued until the disease progresses. It was during this ‘maintenance’ phase of treatment that the new drug was administered.

Prof Schmoll and colleagues had intended to test the drug on 129 patients, but difficulties recruiting participants meant the trial was closed after 59 patients had been randomly assigned to either MGN1703 (43 patients) or placebo (16 patients).

“After a median follow-up of 17.3 months, MGN1703 prolonged profession-free survival from the start of induction as well as start of maintenance therapy, including four patients with sustained progression-free survival who are still on treatment,” Prof Schmoll says.

A pre-planned analysis of immune cell populations showed that the activation of a particular subset of immune system cells, called Natural Killer T Cells, appeared to potentially predict which patients might benefit, Prof Schmoll said.

“We saw a significant increase of CD14 CD169 monocytes in all but one of the MGN1703 treated patients but none of the placebo patients, which indicates the drug is having a biological effect,” he said.

“These data, presented at the 15th ESMO World Congress on Gastrointestinal Cancer for the first time, are showing a highly interesting trend which should be followed-up and confirmed in a larger study,” Prof Schmoll said.

Since treatment with immunotherapeutic drugs such as MGN1703 needs time to take effect, patients who have a lower tumour burden and a response to prior chemotherapy might be more likely to have a benefit of the treatment with MGN1703, Prof Schmoll said.

“The evidence we are presenting at the 15th ESMO World Congress on Gastrointestinal Cancer is the first to show an immune cell population that might also help identify patients with greater benefit from MGN1703. There is mounting evidence that patients who achieve a response with immunotherapy seem to have a very prolonged disease control. A large confirmatory trial is needed to confirm these interesting findings.”

Commenting on the findings, ESMO spokesperson Michel Ducreux, Head of the Gastrointestinal Unit at the Institut Gustave Roussy, Villejuif, France, said the new results are supporting the concept for this approach.

“This is a promising drug which represents a new concept of maintenance therapy with immunomodulation,” he said. “The results in terms of progression-free survival and response were consistent, however based on a very small number of patients, and needs follow up and confirmation in a definitive confirmatory trial. ”
 

Source: ESMO

References:

1. Abstracts from the 15th ESMO World Congress on Gastrointestinal Cancer are published in Annals of Oncology, Volume 24 suppls 4 June 2013 (Ann Oncol 2013 Jun; 24(Suppl 4): 5-130) http://annonc.oxfordjournals.org/content/24/suppl_4.toc 
2. Abstract presentation: Friday, 5 July 2013, 09:00 hrs, Session IX: Presentation of selected abstracts IIA

ABSTRACT 0007
Updated results of the phase 2 IMPACT trial: Maintenance with MGN1703 vs placebo in patients with advanced colorectal carcincoma (mCRC)
Hans-Joachim Schmoll 1, Jorge Riera-Knorrenschild 2, Dirk Arnold 3, Hendrik Kröning 4, Frank Mayer 5, Dieter Nitsche 6, Reinhard Ziebermayr 7, Werner Scheithauer 8, Johannes Andel 9, Manuel Schmidt 10, Burghardt Wittig 11

1 Martin Luther University Halle-Wittenberg, Halle, Germany, 2 Universitätsklinikum Giessen und Marburg, Marburg, Germany, 3 Tumor Biology Center, Freiburg, Germany, 4 Schwerpunktpraxis für Hämatologie und Onkologie, Magdeburg, Germany, 5 Universitätsklinik, Medizinische Klinik, Tübingen, Baden-Württemberg, 6 Barmherziger Schwestern Linz, Linz, Austria, 7 Academic Teaching Hospital Elisabethinen, Linz, Austria, 8 Medizinische Universität Wien, Vienna, Vienna , 9 Landeskrankenhaus Steyr, Steyr, Austria, 10 Mologen AG, Berlin, Germany, 11 Foundation Institute Molecular Biology and Bioinformatics, Berlin, Germany

Background: Since standard induction chemotherapy for mCRC is often completely or partially discontinued until first progression in patients responding to 1st-line treatment, maintenance phase opens a window of opportunity to investigate the potential contribution of new drugs. MGN1703 is a synthetic DNA-based immunomodulator acting as TLR-9 agonist which has shown preclinical activity in mCRC and a good safety profile in patients with metastatic solid tumors in a Phase 1 trial. The IMPACT trial was conducted to assess clinical efficacy, safety, and immunological effects of MGN1703 as maintenance therapy vs. placebo.

Methods: IMPACT was an international, multicenter, randomized (2:1) double-blind placebo-controlled phase 2 trial in patients with mCRC, who achieved disease control (CR, PR, SD) after 4.5 to 6 months of 1st-line induction chemotherapy with FOLFOX/XELOX or FOLFIRI /- bevacizumab. Due to recruitment problems the trial was prematurely closed in May 2012 after randomization of 59 out of 129 planned patients (43 received MGN1703, 16 placebo). We report here the results of the final analysis of the trial.

Results: After a median follow-up of 17.3 months (CI 95% 13.8-21.6) the HR for the primary endpoint PFS on maintenance was 0.56 in favor of MGN1703 (CI 95% 0.29-1.08; p=0.070). The secondary endpoint PFS calculated from beginning of induction chemotherapy had HR of 0.49 (CI 95%: 0.26-0.94, p=0.030). Cox regression analysis identified patients with clinical CR or PR to prior induction chemotherapy or with normal CEA values as more likely to benefit with MGN1703 treatment. While on maintenance, three objective responses were observed in the MGN1703 arm and one in the placebo arm. Overall 4 patients are still disease free and receiving MGN1703 (treatment range 11 to 25 months). Survival data are still immature as only 35% of the MGN1703 treated patients died (50% of placebo). The preliminary HR for OS is 0.6 (CI 95%: 0.3-1.5 p=0.29). Treatment was well tolerated: 32.6% vs. 18.8% of patients (MGN1703 vs. placebo) had any drug-related adverse events (AE) and only 1 patient per arm had a grade 3 drug-related AE (MGN1703: sensory polyneuropathy, placebo: papular exanthema). A pre-planned analysis of immune cell populations by flow cytometry showed a possible predictive effect of activated NKT (CD3 /CD56 /CD69 ) cells on treatment with MGN1703 (HR 0.34; CI 95%: 0.14-0.82, p=0.008). As a sign of biological activity, a significant increase of CD14 CD169 monocytes was observed in all but one of MGN1703 treated patients while absent in all placebo patients.

Conclusions: MGN1703 compared to placebo showed a prolongation of PFS from start of induction as well as start of maintenance therapy, including 4 patients with sustained PFS still on treatment. Pre-treatment characteristics and immunological biomarkers may prove useful to identify patients who might benefit most from MGN1703 maintenance therapy.