VIENNA – Maintenance therapy with the investigational immunomodulator MGN1703 reduced the risk of progression in patients with metastatic colorectal cancer in the phase II/III IMPACT trial.
Median progression-free survival from the start of maintenance therapy was 2.8 months with MGN1703 and 2.6 months with placebo. This was not statistically significant (P = .06) but represented a 47% reduction in the risk of progression (hazard ratio, 0.53).
Patrice Wendling/IMNG Medical Media
Dr. Dirk Arnold
The benefit was even greater in a subgroup of good-risk patients, where the risk of progression was reduced 61% and the median time to progression more than doubled from 2.7 to 5.8 months with MGN1703 (HR, .39; P = .013).
"The findings indicate a potential new approach in the management of metastatic colorectal cancer patients," investigator Dr. Dirk Arnold said at the European Society for Medical Oncology Congress.
MGN1703 is an immunomodulator and toll-like receptor (TLR) 9 agonist that activates all components of the innate and adaptive immune system.
TLR9 agonists have shown activity in clinical trials in renal cell carcinoma, cutaneous T-cell lymphoma, and non-Hodgkin’s lymphoma. In a prior study, a TLR9 agonist combined with first-line taxane-plus-platinum chemotherapy reduced the risk of death from advanced-stage non–small cell lung cancer by 26% (J. Clin. Oncol. 2008;26:3979-86).
Dr. Jean-Yves Douillard, who was invited to discuss the study, agreed that immunomodulation represents a new approach to metastatic colorectal cancer.
"This is an additional set of data showing activity with TLR9 agonists, but this is the first time in metastatic colorectal cancer, which has never been considered a really immunosensitive type of tumor," he said. "The tolerance profile is excellent and this type of approach certainly deserves further evaluation in a larger sample to be convincing."
IMPACT was stopped early after an interim analysis of 55 patients because of slow accrual and observed benefit with MGN1703 in a subgroup of patients with no signs of tumor progression.
The 55 patients had achieved disease control after standard first-line chemotherapy and were randomized in a 2:1 fashion to subcutaneous 60 mg MGN1703 or placebo twice weekly until disease progression.
The good-risk subgroup was composed of 46 patients with two of three previously identified factors: carcinoembryonic antigen less than 30 times the upper limit of normal (ULN); gamma glutamyl transpeptidase less than two times the ULN; or alkaline phosphatase less than two times the ULN.
First-line therapy was: FOLFOX/XELOX or FOLFIRI/XELIRI chemotherapy combined with a standard dose of bevacizumab or FOLFOX/XELOX alone; these regimens were given over an average of 5 months and completed within 2 weeks before treatment with MGN1703.
Complete or partial responses to induction therapy had been observed in 72% of the 40 patients in the MGN1703 arm and 93% of the placebo arm. "This is very unusual and we are dealing here with a very chemo-sensitive population," remarked Dr. Douillard, professor of medical oncology at the University of Nantes and ICO R. Gauducheau, St. Herblain, France.
The secondary end point of progression-free survival from the start of induction reached a median of 9 months in the experimental arm and 8.6 months in the control arm, representing a significant risk reduction of 50% (HR, 0.50; P = .047), reported Dr. Arnold of University Cancer Center Hamburg, Germany.
In all, 33% of patients in both arms reporting a drug-related adverse event. Tolerability was good, with only two patients reporting grade 3 hypertension and two reporting grade 4 ileus, he said.
A further clinical study of MGN1703 is being planning, and the drug is also in development for non–small cell lung cancer.
Based on the data now available, Dr. Douillard said patients can no longer be randomized to placebo and that more effective strategies such as those used in the Treatment Across Multiple Lines (TML) trial could be used as a reference arm to be improved by the immunostimulant.
IMPACT was sponsored by Mologen AG, which is developing MGN1703. Dr. Arnold reported no conflicts, but several of his co-authors reported relationships with Mologen including employment. Dr. Douillard reported serving as a consultant, adviser, or speaker for Roche and Sanofi Aventis, and serving as a consultant, adviser, and data safety monitoring board chair for Bayer.