Monoclonal antibody (mAb) immunogenicity manifests as ADA generation that may impact mAb efficacy and safety. Naxitamab (NAX) is a humanized GD2-binding mAb. We explored ADA formation to NAX in the ongoing phase II clinical trial 201 (NCT03363373).
NAX was administered with granulocyte-macrophage colony-stimulating factor (GM-CSF) on 4-week cycles. ADA positivity and neutralizing potential were assessed at baseline and post-baseline (Cycle 1 Day 12; pre NAX infusion for subsequent cycles) by validated assay following a multitiered approach, and effect on efficacy and safety was evaluated.
At data cutoff (Dec 31, 2021) of planned interim analysis 74 patients (pts, safety population) contributed ADA data; 29 ps (39%) had positive ADA titers at any time during trial, 33% had neutralizing ADA post-baseline. In efficacy population (N=52) 17 pts had neutralizing ADA: 4 pts achieved complete response (CR), 3 pts had minor response, 6 had neutralizing ADA at time of response, 1 had non-neutralizing ADA, later became neutralizing with ongoing response. In all CR pts (n=4) the neutralizing ADA became undetectable after continued NAX treatment. The highest titers were found in patients with CR. Progressive disease was confirmed in 5 pts at first response assessment (study days 38-45) coinciding with first detection of neutralizing ADA (study day 29-57). All subjects with neutralizing ADA reported CTCAE Grade ≥2 pain AEs and pain as per Wong Baker/FLACC scales, indicating that NAX may bind to GD2 in the presence of neutralizing ADA. The NAX safety profile was similar between pts with or without neutralizing ADA. Notably, 4 SAEs of anaphylactic reaction occurred in 3 ADA-negative pts. Efficacy by ADA status * One patient in the efficacy population had non-neutralizing ADA
Response ≥ one positive neutralizing ADA titer (n=17*) No ADA positive titers (n=34) ORR, % (number of responders) (95% CI) 24 % (4) (6.8 – 49.9) 65% (22) (46.5 – 80.3) CR, % (number of responders) (95% CI) 24% (4) (6.8 – 49.9) 47% (16) (29.8 -64.9)
The presence of ADA during NAX+GM-CSF treatment did not impact the NAX safety profile. Presence of neutralizing ADA in CR patients warrants further exploration to better understand the impact of ADA on efficacy.
NCT03363373.
Y-mabs Therapeutics.
Y-mabs Therapeutics.
D.A. Morgenstern: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Clarity Pharmaceuticals, EUSA Pharma, Roche, Y-mAbs Therapeutics, Oncoheros Biosciences. K. Nysom: Financial Interests, Personal, Advisory Board: Y-mAbs, EUSA Pharma; Financial Interests, Personal, Invited Speaker: Y-mAbs, Bayer; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Other, Data Monitoring Committee: Lilly. J. Faber: Financial Interests, Institutional, Invited Speaker: Y-mAbs Therapeutics Inc.; Non-Financial Interests, Personal, Principal Investigator: Y-mAbs Therapeutics Inc.; Non-Financial Interests, Institutional, Other, Participation in compassionate use program: Y-mAbs Therapeutics Inc. M. Bear: Financial Interests, Personal, Advisory Role: Y-mAbs. K. Tornøe: Financial Interests, Personal, Full or part-time Employment: Y-mAbs; Financial Interests, Personal, Stocks/Shares: Y-mAbs. P.S. Sørensen: Financial Interests, Personal, Full or part-time Employment: Y-mAbs; Financial Interests, Personal, Stocks/Shares: Y-mAbs. J. Mora: Financial Interests, Personal, Advisory Role: Y-mAbs. All other authors have declared no conflicts of interest.