Those expecting a load of new information on Ofatumumab (O) from ASH are likely to be disappointed. Only three papers have been accepted and only one of these is clinically relevant.
A multi centre trial looked at two doses of O (500mg and 1000mg) used in combination with FC in previously untreated patients with CLL. Only 61 patients were involved, so nothing much can be made of the study statistically. The overall response rate was 70% and 73% respectively, but there were more CRs with the higher dose (50% v 32%) but the difference was not statistically significant. The overall response rates were less than historical controls with FCR, but the make up of cases could account for that. For example 20% of those receiving the higher dose had del 17p. I think all that can be said of this study is that O can be given safely with FC and that responses are in the same ball-park as with FCR. There were no unexpected toxicities.
The other two studies were more technical. One looked at the pharmacokinetics (PK) of O. It demonstrated that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. In other words the more disease there is to soak up the antibody, the lower the serum concentration and the higher the serum concentration, the better the response. Not exactly counter-intuitive, is it.
It is known for NHL (but not for CLL) that a polymorphism on the FC receptor affects response to rituximab. The third paper assessed FcgRIIIa affinity and potency to induce ADCC by purified NK cells for ofatumumab and rituximab in a blinded study. Expected differences in affinity for the 158V and 158F allotypes of FcgRIIIa were observed for both ofatumumab and rituximab. These differences correlated with a stronger ADCC by FcgRIIIa 158V/V compared to 158F/F expressing NK cells. Significantly, ofatumumab was able to induce ADCC more potently than rituximab for both Fc receptor allotypes. Ofatumumab binds CD20 stably and at a distinct membrane-proximal epitope compared to rituximab. Our data suggest that these binding characteristics may positively impact ofatumumab’s ability to direct killing of tumor cells via ADCC. Most of this information was already available from experiments in our lab by Martin Glennie.
Certainly it is far to soon to draw meaningful conclusions about how well ofatumumab will ultimately compare to rituximab, but it is fair to say that the "bang" that many of us were hoping for seems to be more of a "pop."
ReplyDeleteI suppose that over time we will see the true value (or lack thereof) of ofatumuab's "human" derivation (hopefully less hypersensitivity &/or resistence from antibodies directed at it) and it's apparent greater ability to produce ADCC as compared with rituximab. The ability of ofatumumab to "hold on" to the B cell through use of a different CD 20 epitope may also give it theoretical advantages over rituximab.
Thus far, the most impressive results were in the 2 studies utilizing it in patients refractory to F&A or those with LNs > 5 cm. Were such groups ever studied using rituximab alone?
Perhaps it will prove to be a dosing issue (perhaps 1500 mg/m2 is required) or, perhaps, like many "me too" drugs in other areas it just doesn't work any better that the original flavor.
Time will tell.
DWCLL