Maintenance treatment with the TLR9 agonist lefitolimod in extensive-stage small-cell lung cancer (ES-SCLC): Final results from the randomized phase II IMPULSE study

Abstract

Background: The immune surveillance reactivator lefitolimod (MGN1703), a DNAbased TLR9 agonist, is currently in a comprehensive clinical development program including a phase 3 trial in mCRC. The phase 2 IMPULSE study was designed to evaluate efficacy and safety of lefitolimod in ES‐SCLC, an indication with high unmet medical need and stagnant treatment improvement in the last decades. Methods: IMPULSE is a randomized, international, multicenter, open‐label trial to assess the effect of lefitolimod on overall survival (OS) in ES‐SCLC. 103 patients with objective tumor response following 4 cycles of platinum‐based first‐line induction therapy were randomized 3:2 to receive either lefitolimod maintenance therapy or local standard of care until progression or unacceptable toxicity. Results: From 103 patients, 62 were randomized to lefitolimod, 41 to the control arm. Patient demographics and response patterns to first‐line therapy were balanced. Lefitolimod exhibited a favorable safety profile in this vulnerable population and pharmacodynamic assessment confirmed the mode‐of‐action showing clear activation of monocytes and production of interferon‐gamma‐induced protein 10. While in the ITT population no relevant effect of lefitolimod on OS could be observed, two pre‐defined patient subgroups indicated promising results, favoring lefitolimod with respect to OS: Patients with a low frequency of activated CD86+ B cells (HR 0.53, 95%CI 0.26‐1.08; n=38 of 88 analyzed) and patients with reported chronic obstructive pulmonary disease (COPD) (HR 0.48, 95%CI 0.20‐1.17, n=25 of 103). Notably, a post‐hoc analysis revealed that a strong lefitolimod‐induced immune activation translated into an OS benefit when analysed after 4 weeks of treatment. Two patients from the lefitolimod arm exhibited long‐term disease control. Conclusions: The IMPULSE study showed (1) the expected pharmacodynamic response, (2) positive efficacy signals in two pre‐defined subgroups regarding OS and (3) a favorable safety profile. This data provides significant guidance for defining patient populations most likely to benefit from lefitolimod treatment.