Investigating the Novel Combination of the Innate Cell Engager (ICE®) Acimtamig with Off-the-Shelf Allogeneic Natural Killer Cells AlloNK® in Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL): Initial Results of the Phase 2 Luminice-203 Stu

Introduction: Patients (pts) with R/R cHL are in need of new treatment options, especially after failure of standard treatments including brentuximab vedotin (BV) and PD-1 inhibitors. Acimtamig (AFM13), a first in class tetravalent, bispecific innate cell engager, binds to CD30 on lymphoma cells and selectively to CD16A on NK cells and macrophages, thereby augmenting the innate immune response against CD30+ lymphoma cells. Acimtamig has demonstrated pronounced efficacy in combination with fresh cord blood derived allogeneic NK cells in R/R cHL in a previous study (NCT04074746). The LuminICE-203 study(NCT05883449) evaluates the efficacy and safety of acimtamig in combination with cryopreserved off-the-shelf-cord blood derived NK cells (AlloNK®: AB-101) in patients with R/R cHL. Methods: This Phase 2, open-label, multi-center, multi-cohort study, has an initial dose finding part with four cohorts investigating two doses of acimtamig (200mg or 300mg) and two doses of AlloNK (3x2 billion and 4, 2, 2 billion), followed by expansion cohorts. After a standard lymphodepletion treatment regimen with fludarabine/cyclophosphamide (Days -5 to -3) pts receive AlloN- and acimtamig coadministered on days 1,8,15 followed by acimtamig only on days 22,29 and 36 of a 48-day cycle for up to 3 cycles. Disease assessments by positron emission tomography-computed tomography (PET-CT) are performed at screening and on day 43 of each cycle. Eligible pts must have R/R cHL following standard systemic therapy that must include combination chemotherapy, BV and PD-1 inhibitors. The primary endpoint of this trial is to determine the objective response rate (ORR) assessed by Independent Radiology Committee (IRC) based on PET-CT per Lugano classification criteria. Secondary endpoints include safety, tolerability, immunogenicity, complete response rate, duration of response, progression free survival and overall survival. Results: As of 24 July 2024, 10 pts were treated with acimtamig and AlloNK in the first two treatment cohorts and assessed by the IRC for metabolic response. The median (range) age was 42.5 (23-80) years; 8 males and 2 females; ECOG status at baseline being 1 for 8 pts (80.0%) and 0 for 2 pts (20.0%). All patients were heavily pretreated with a median (range) of 4 (2-11) prior therapy lines that included chemotherapy, PD(L)1 inhibition, and BV. Five patients (50.0%) also had received previous autologous stem cell transplant. Overall, no unexpected safety signals were identified, with all 10 patients (100%) experiencing treatment emergent adverse events (TEAEs). The most frequent treatment related adverse event was infusion related reactions (IRR) in 6 (60.0%) patients, all were mild to moderate (G1 and G2, no ≥ grade 3). Mostly the IRRs occurred only in the beginning of the therapy, but in 2 patients repetitive IRRs were reported. Cytokine Release Syndrome (CRS) was reported in 3 (30.0%) patients, which was mostly mild, with 1 short lasting Grade 3 CRS event in a patient who was also diagnosed with acute CMV infection. All IRR and CRS events resolved quickly under standard of care treatment (SOC). There were no treatment discontinuations due to adverse events considered related to acimtamig or AlloNK. Furthermore, no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were reported. Best responses of the 10 evaluable pts included 6 Complete Responses ([CR] 60.0%) and 3 Partial Responses ([PR] 30.0%), resulting in an ORR of 90.0% by IRC based on PET-CT per Lugano classification criteria. The study is actively enrolling and updated safety and efficacy data, including preliminary pharmacokinetic and pharmacodynamic results will be presented. Conclusion: This is the first study that evaluates the coadministration of a specific CD16A targeting ICE® with cryopreserved, off-the-shelf allogeneic NK cells. These early results are in line with previous data from study NCT04074746 which used fresh allogeneic NK cells thereby validating the co-administration approach of acimtamig with an off-the-shelf, allogeneic, cryopreserved NK cell product (AlloNK) in R/R cHL. This treatment has the potential to address a high unmet need in R/R cHL pts who have otherwise no SOC option.