OS Endpoint Not Met in Pivotal Phase III CRC IMPALA Trial

Stefan M. Manth, MD

Stefan M. Manth, MD

Overall survival (OS) was not improved with the use of lefitolimod (MGN1703) as a maintenance therapy compared with local standard-of-care therapy in patients with metastatic colorectal cancer (CRC), according to early findings from the pivotal phase III IMPALA trial. The median OS was 22.0 months with lefitolimod compared with 21.9 months with standard of care (HR, 1.12; 95% CI, 0.91-1.38;P= .2765), which failed to meet the primary endpoint of the trial.

Further data, including progression-free survival and predefined subgroup analyses also did not show a benefit for the use of lefitolimod, topline data released by MOLOGEN, the developer of the TLR9 agonist, demonstrated.

In the press release, the CEO, Stefan M. Manth, MD, mentioned the company’s disappointment with the topline results and that further data from IMPALA will be analyzed in depth to inform the future development of the agent. Detailed findings from the trial will be submitted for presentation at an upcoming scientific meeting.

The company believes that the future for lefitolimod may lie in combination approaches for patients with cancer: “Unfortunately the positive results in our single-agent lefitolimod phase II IMPACT study did not translate into a successful outcome of our phase III IMPALA trial despite the fact that all learnings have been incorporated into the trial design. In contrast to the time when the IMPALA design was conceived, it now appears that for successful anti-cancer immunotherapies a combination approach is of paramount importance. Due to the large body of evidence indicating the potential of TLR9 agonism in this context we remain committed to the further development of our candidates,” said Matthias Baumann, MD, the chief medical officer of MOLOGEN, in the press release.

The randomized, international, multicenter, open-label phase III study investigated the use of lefitolimod as maintenance therapy compared with standard maintenance regimens in patients with metastatic CRC who had achieved tumor reduction with induction therapy (NCT02077868). More than 540 patients were enrolled across 8 European countries.

Patients in the trial had received a standard first-line chemotherapy regimen with or without biological agents and had achieved a complete or partial response to treatment. Lefitolimod was administered subcutaneously at 60 mg twice daily in the investigational arm.

The primary endpoint of the trial was OS and secondary endpoints included progression-free survival, overall response rate, safety, and quality of life.

Findings from the phase II IMPACT trial had demonstrated prolonged progression-free survival (PFS) with lefitolimod monotherapy as a maintenance treatment.²

Fifty-nine patients with mCRC who had received first-line chemotherapy with or without bevacizumab (Avastin) and had disease control were randomized 2:1 to receive lefitolimod or placebo.

By independent review, the hazard ratio for PFS was 0.56 (95% CI, 0.29-1.08;P= .07) from the start of maintenance therapy and was 0.49 (95% CI, 0.26-0.94;P= .03) from the start of induction therapy versus placebo.

Maintenance therapy with lefitolimod was considered to be well tolerated as most adverse events were mild to moderate, mostly limited to injection-site reactions or associated with immune system activation.

References

1. MOLOGEN AG Announces Top Line Data of Pivotal IMPALA Study in Metastatic Colorectal Cancer [press release]. Berlin: MOLOGEN AG; August 5, 2019. https://bwnews.pr/2MFs9MR. Accessed August 8, 2019.
2. Schmoll HJ, Wittig B, Arnold D, et al. Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial.J Cancer Res Clin Oncol. 2014;140(9):1615-1624. doi: 10.1007/s00432-014-1682-7.