dargistotug (M6223)

P2, N=256, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2025 --> Jul 2026 | Trial primary completion date: Jan 2025 --> Jun 2025

M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530).

We then assess the applicability of this PD-1 model to elucidate the relationship between drug concentration and target engagement for tiragolumab, an anti-TIGIT antibody, across various doses...The approach is then extended to project efficacious doses for M6223, another anti-TIGIT antibody, using the established PD-1 model, by leveraging the M6223 clinical PK and PD data, as well as virtual population analysis. This work provides a case study of a possible framework for refining dose projections via quantitative estimation of drug-target relationship at the site of action by leveraging established drug-target relationships. Through extrapolating information from a well-characterized pathway, we offer a method to inform dose optimization strategies with limited data using model-informed drug development.

P2, N=256, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Recruiting --> Active, not recruiting

P1, N=58, Completed, EMD Serono Research & Development Institute, Inc. | Active, not recruiting --> Completed

Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics.

Conclusions The results demonstrate that innate depletion of TIGIT+ immune subsets by Fc-mediated effector function plays an important role in anti-tumor immunity and suggest that immune pharmacodynamics in clinical trials should be closely monitored at early time points. Currently, M6223 is being evaluated in combination with avelumab as first-line maintenance therapy for advanced urothelial carcinoma in the phase 2 JAVELIN Bladder Medley umbrella trial ( NCT05327530 ).

Conclusions This study confirmed that NK cell cytotoxicity plays an important role in the anti-tumor activity of M6223 and demonstrated the additive effect of avelumab and M6223 in enhancing NK cell activation, especially in CD155+ human leukocyte antigen (HLA) class I-deficient target tumors. Currently, M6223 plus avelumab is being studied as first-line maintenance therapy for advanced UC in the phase 2 JAVELIN Bladder Medley umbrella trial ( NCT05327530 ).

9/24 and 2/17 pts receiving M6223 and M6223 + BA, respectively, achieved clinical benefit (stable disease at first on-Tx assessment); 3/24 and 2/17 patients, respectively, were on Tx for ≥20 weeks. Conclusions M6223 ± BA had an acceptable safety profile with favourable PK and target modulation effect.

The study is currently ongoing in the United States and Canada. Trial Registration NCT04457778