One more Weapon in Our Arsenal: Obinutuzumab is Approved for Treatment Naive Patients

That was pretty fast.

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

For Immediate Release: Nov. 1, 2013
Media Inquiries: Tara Goodin, 240-402-3157, tara.goodin@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA 

FDA approves Gazyva for chronic lymphocytic leukemia

Drug is first with breakthrough therapy designation to receive FDA approval

The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

CLL is a blood and bone marrow disease that usually gets worse slowly. According to the National Cancer Institute, 15,680 Americans will be diagnosed and 4,580 will die from the disease this year.

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 is the first drug with breakthrough therapy designation to receive FDA approval. This designation was requested by the sponsor and granted soon after the biologic license application to support marketing approval was submitted to the FDA. The FDA can designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.

The FDA also granted Gazyva priority review because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. And the FDA granted Gazyva orphan product designation because it is intended to treat a rare disease.

“Today’s approval represents an important new addition to the treatments for patients with CLL,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval reflects the promise of the Breakthrough Therapy Designation program, allowing us to work collaboratively with companies to expedite the development, review and availability of important new drugs.”

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.

The most common side effects observed in participants receiving Gazyva in combination with chlorambucil were infusion-related reactions, a decrease in infection-fighting white blood cells (neutropenia), a low level of platelets in the blood (thrombocytopenia), low red blood cells (anemia), pain in the muscles and bones (musculoskeletal pain), and fever (pyrexia). 

Gazyva is being approved with a boxed warning regarding Hepatitis B virus reactivation and a rare disorder that damages the material that covers and protects nerves in the white matter of the brain (progressive multifocal leukoencephalopathy). These are known risks with other monoclonal antibodies in this class and rare cases were identified in participants on other trials of Gazyva. Patients should be advised of these risks and assessed for Hepatitis B virus and reactivation risk. 

Gazyva is marketed by Genentech, a member of the Roche Group, based in South San Francisco, Calif.

For more information:

• FDA: Office of Hematology and Oncology Products
• FDA: Breakthrough Therapies
• FDA: Drug Innovation
• FDA: Approved Drugs: Questions and Answers
• NCI: Chronic Lymphocytic Leukemia

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.