Abstract 109P
Background
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).
Methods
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.
Results
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. Table: 109P
Efficacy by ADA status
| 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) |
* One patient in the efficacy population had non-neutralizing ADA
Conclusions
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.
Clinical trial identification
NCT03363373.
Legal entity responsible for the study
Y-mabs Therapeutics.
Funding
Y-mabs Therapeutics.
Disclosure
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.