Lefitolimod vs standard of care (SOC) for patients with metastatic colorectal cancer (mCRC) responding to first-line standard treatment: Results from the randomized phase III IMPALA trial

Abstract

Background: The TLR9 agonist lefitolimod broadly activates the innate and adaptive immune system. Based on encouraging data from the randomized phase II IMPACT trial, lefitolimod was evaluated in this phase III trial as switch maintenance treatment in patients with mCRC who have responded to first‐line therapy. Methods: The international, multicenter, open‐label phase III IMPALA trial was conducted including the AIO, TTD and GERCOR cooperative groups and recruited 549 patients across 8 European countries. Patients who had an objective response to any standard first‐line induction therapy (5FU/FA or CAPE, plus OX or IRI, alone or plus antiVEGF or antiEGFR) were randomized to receive either lefitolimod monotherapy (experimental arm) or local standard of care (control arm). After first progression, patients started re‐induction therapy, with those in the experimental arm continuing lefitolimod on top. Results: Demographics and baseline characteristics were well balanced between the study arms. Median duration of follow up was 35 months. The primary endpoint overall survival (OS) was not met: median OS was 22.0 and 21.9 months in the lefitolimod and control group, respectively (p=0.2765; HR=1.12; 95% CI 0.91 ‐ 1.38). Progression free survival, event‐free rates, pre‐defined sub‐group analyses including molecular and immunological parameters for OS did also not indicate a benefit. In comparison with the control arm treatment with lefitolimod was generally well tolerated. Rates of grade 3, 4 and 5 toxicities were 6.3, 1.9 and 0%, respectively and no new safety signals or autoimmune events were identified while immune activation was confirmed in peripheral blood. Conclusions: Lefitolimod did not show superiority to standard of care as a single agent maintenance treatment in patients with mCRC. Limited add‐on toxicity confirmed the favorable safety and tolerability profile of lefitolimod. Hence, and given its mode of action, lefitolimod will be evaluated in combination with other anti‐cancer immunotherapies.