One more Weapon in Our Arsenal: Obinutuzumab is Approved for Treatment Naive Patients
Obinutuzumab is a third generation monoclonal antibody (mAb) directed against a marker (CD20) sitting on the surface of B cells, including our cancerous CLL cells. Rituximab was the first generation, and it has proven to be a great boon to all of us with CLL. I believe that obinutuzumab will prove to be even more of a friend. It is a type of immunotherapy that has shown its value when added to a chemo backbone to treat CLL. Think of the huge improvement FCR was over FC. The addition of that antibody demonstrated for the first time that we finally had a therapy that could prolong our lives.
A couple of thing to note about the FDA new release that follows.
The approval was based on comparison to chlorambucil alone or chlorambucil with obinutuzumab. That seems like a bit of a fixed race. Single agent chlorambucil is a commonly chosen competitor as it one that is easily beaten. Other drugs such as bendamustine have won approval using a similar trial design. It is rarely used in the USA, especially as a single agent, but might be a good choice for some more fragile elderly patients.
Second, obinutuzumab was approved for frontline therapy in combination with chlorambucil in treatment naive patients. That was the way it was studied, and that's what was okayed. Period.
The much bigger issue is that if this is only way its use will be covered by insurance plans, then we are leaving the real power of this potent medication in many other life saving setting sorely neglected. That would be a real disservice to us patients. It remains to be seen how this will play out, but I am dismayed about the limited indication granted by the FDA and frankly worried about how that bodes for ibrutinib and idelalisib. Will their indications also be as tightly focused?
The reality is that many cancer drugs are widely or even mostly used off label, and if there is evidence, usually in the form of published research, then insurance can often be arm wrestled into paying. Once a drug is approved, the options for patients should greatly expand beyond the narrow boundaries of the inclusion/exclusion criteria set forth in a clinical trial. But they are no guarantees.
Does this make pharmaceutical companies rethink how they design trials if the indications approved by the FDA will only reflect the exact manner in which the drug was studied? Those more expert than me in knowing how these processes unfold will need to answer that thorny question. I suspect we will have some more approval news soon on ibrutinib that should give us a clearer indication of how the FDA is handling these issues.
Finally, a reminder that at least to the the FDA's eyes, the concerns with hepatitis B reactivation and the very rare but devastating brain infection, progressive multifocal leukoencephalopathy, are risks for all the CD20 monoclonal antibodies (mAb) such as rituximab and ofatumumab. I am not sure that those unusual complications were even seen in the trials with obinutuzumab, but the black box warning is there nevertheless. I am OK with that. Logically it makes sense, and it is better to err on the side of safety, though I doubt this is an error.
Still is very good news to have this new and more potent option. There are many reasons to believe that this third generation monoclonal antibody obinutuzumab will prove to be a much better CLL killer than rituximab. It got 30% of the patients to MRD (minimal residual disease, that is an important surrogate marker for length and depth of remission) negativity in combination with chlorambucil in the trial that got it approved. And you can bet it did the heavy lifting, because in the arm with chlorambucil alone, the MRD rate was zero.No surprise there. Image what magic it will wrought when matched with an equally potent fighter such as ibrutinib or idelalisib. And now that it is approved, setting up such trials will be much easier. it is already being studied with ABT-199, a trial that I have recommended for many to consider.
Side effects were generally pretty minimal. Except for the nasty infusion reactions common with many mAbs, most of those listed below in the news release were more likely from the effects of chlorambucil on the bone marrow than from the obinutuzumab.
Here is my prayer: That this powerful and important new mAb will be available to all those who might benefit and that means many more than those specified in the narrow indication.
I plan to be at ASH 2013 to hear the details of the phase 3 trial data and will share it all here.
Here's the FDA news release:
FDA NEWS RELEASE
FDA approves Gazyva for chronic lymphocytic leukemia
Gazyva works by helping certain cells in the immune system attack cancer cells. Gazyva is intended to be used with chlorambucil, another drug used to treat patients with CLL.
Gazyva’s approval for CLL is based on a study of 356 participants in a randomized open-label multicenter trial comparing Gazyva in combination with chlorambucil to chlorambucil alone in participants with previously untreated CLL. Participants receiving Gazyva in combination with chlorambucil demonstrated a significant improvement in progression free survival: an average of 23 months compared with 11.1 months with chlorambucil alone.