Tuesday, February 4, 2014

ASH 2013: Dr. Jennifer Brown Discusses the New Data on Obinutuzumab (GA-101 or Gazyva)

At ASH 2013, there was much to celebrate for those us with CLL.

This interview was recorded immediately after Dr. Jennifer Brown of Dana Farber had moderated an exciting CLL press conference in that same noisy press room.

While the small molecules that can be taken orally such as ibrutininb, idelalisib, ABT-199 and even the newer IPI-145 and ONO 4059 may have hogged much of the headlines over the last few year in the CLL world, there was important news about a new and better monoclonal antibody or mAb, namely obinutuzumab.

This one, like rituximab and ofatumumab, is directed against CD20, a surface protein found on all B cells, good and bad.

So like its fellow anti-CD20 mAbs, obinutuzumab knocks out all our B cells, leaving us at an increased risk for new infections and reactivation of old ones such as hepatitis B.

A bit of a background on another mAB first.

I have to say after all the excitement following the the approval of the second generation fully humanized CD20 antibody, ofatumumab, I have been disappointed in the results. Its main advantage seems to be for anyone allergic to rituximab, lovingly called "mouse juice" by the thousands of us who have had it dripped into our arms at infusion centers across the world because of its unholy but magic mix of mouse and human proteins (especially strange to think about if you are vegan like me). Despite high doses of pre-medications with steroids and antihistamines, some of us patients just can't get our bodies to stay calm in the presence of the mouse antigen and let the antibody do its important work. That is where ofatumumab has shined. No mouse proteins, so those who could not tolerate "Vitamin R" had an option. But the impressive improvement in efficacy over rituximab that I and many others were hoping for has not really materialized.

Obinutuzumab tells a different story. People are living longer significantly longer as Dr. Brown will detail on camera. The results are clearly better. The bar with rituximab was already set pretty high. Rituximab might be a lousy CLL drug on its own, but as a dancing partner it makes everyone look like a Fred Astaire (or Ginger Rogers). Its addition to FC forming the "gold standard" of FCR was the first time that any therapy was shown to prolong survival in CLL.

Dr. Brown of Harvard now gives us even better news on obinutuzumab.

But first we review how it was engineered to get these strong results and explains why being the first type 2 anti-CD20 antibody is so important to its efficacy.

And she discusses the management of the higher risk of infusion reactions. Please remember that although these new antibodies have no murine proteins, they can still cause rather severe infusion reactions, precisely because the bind so strongly to our B cells and are such potent killers.

Here is Dr. Jennifer Brown:



Remember too that this drug is already approved for CLL. From the package insert: in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

As I have reviewed in a prior post, this is a very limited indication, and much of its benefit would be expected to come in its use with other more potent combinations than with chlorambucil and for patients who have relapsed or who are refractory to other therapies including other mAbs. I would hope that it appropriate use off label is not rebuffed by the payers.

I expect soon to see a growing number of trials mixing and matching the new TKIs with obinutuzumab to get us that elusive CR. We need more trials. To get to our ultimate goal, a cure, we must first get to and pass CR, and most of the TKIs are leaving stalled on 3rd base with some persistent measurable disease. These new oral wonder drugs still need a teammate to get us home to a cure, and obinutuzumab is a very strong candidate to play that role.

That is the future I want. Rational non-chemo combinations edging us closer to a cure. It can't come soon enough. But we need more creative trials and more brave risk takers to make them happen.

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5 Comments:

Anonymous Anonymous said...

Very helpful. I had wrongly thought ofatumumab was a significant leap over Rituxan and closer to obinituzumab in terms of efficacy. Was I wrong at least based on the info out there so far! Thats one reason why your posts are so great Dr. K... they cut through the pharma-speak and get to what matters. And the mouse proteins stuff... how cool and underground is that?!

February 4, 2014 at 1:08 PM  
Anonymous Anonymous said...

Very exciting information!

February 4, 2014 at 4:39 PM  
Anonymous Fred said...

I do have to speak up in defense of Ofatumumab. Not only does it seem to be less toxic (due to having its proteins having been humanized - no more "mouse juice" like Rituximab), but the CD20 molecules are also attacked more vigorously (closer to the cell surface) than with Rituximab.

On a personal level, I have to be grateful for the use of Ofatumumab (in combination with HDMP and Campath) for proving me with a CR over a year ago. This was the magic provided by a Dana-Farber clinical trial, designed especially for 17p-deleted CLL-ers, of which Dr. Jennifer Brown is the Principal Investigator, that I have been participating in at D-F. So, Ofatumumab is OK in my book...

Thank you for the continuing series of informative video interviews, Dr. Koffman. (Just one constructive suggestion to offer - perhaps closer miking during videoing, especially in noisy environments, might make the background noise less obtrusive, improving the overall audio signal-to-noise ratio.) :-)

[Fred]

February 5, 2014 at 8:59 AM  
Blogger Adam Irgon said...

This is a helpful segment, but I think it's wrong to say infusion reaction is the only concern associated with Obinutuzumab. If this antibody behaves like Rituximab and Ofatumumab, delayed-onset neutropenia could occur in many patients, and more seriously the antibody could cause (re)activation of Hepatitis. Ofatumumab now carries a black box warning about Hepatitis after occurrences of virus activation. Will Obinutuzumab carry a similar warning?

This is my first exposure to Dr. Brown, who seems to be a terrific person and an asset to the CLL community.

February 7, 2014 at 10:01 AM  
Anonymous p53 antibody said...

Thank you for your article, it was very informative.

February 24, 2014 at 10:54 PM  

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