Gazyva (obinutuzumab) approved

It is really satisfying to work on a drug before it gets approved.  I have had the opportunity to treat quite a few patients with both DLBCL and CLL with a drug that was approved earlier today called Gazyva (AKA: obinutuzumab or even GA-101).  Some people just call it "G."

I was aware this day was coming for a little while as Genentech did a video series on several of my patients who had been treated with the drug so that they could use the video in news / media once the drug was approved.

Drug companies have to be EXTREMELY CAREFUL what they say publicly about their drug.  Virtually every word they put out in advertisements gets carefully reviewed by the "commercial team" because if they make claims that are "off label" they can get into pretty deep trouble: see here.

I do not work for Genentech.  I have not received any direct payment from them (they do provide research funding to my organization - US Oncology for studies we have performed).  I have declined offers to be on a "speakers board" where I would receive compensation for speaking about their drug.  In short, I am not bound by the same restrictions they are - so I thought I might share my thoughts.

I really think that this drug is a big deal in CLL - and they can't say it.  In NHL the answer is still up in the air.

"Minimal residual disease" is a term we apply to a sensitive type of test (flow cytometry) where we can look for very small amounts of CLL in either the blood or the marrow.  Patients can be categorized as MRD negative, MRD positive, or MRD intermediate.  Not surprisingly, the less CLL you find, the longer the response lasts.  I desperately need to do another post about MRD because I think it is how we are going to be comparing the efficacy of new drugs in the future.

If you look at data from the german CLL8 study in which FC was compared to FCR, the rate of achieving minimal residual disease negativity in the FCR arm was about 50%.  If you look at the patients in the CLL11 study (that served as the basis for approval for this drug) the rate of MRD negativity in the GA101 / chlorambucil arm was about 30%.  Since the MRD negativity to chlorambucil alone arm was a big fat zero, you can attribute most of the MRD activity to the GA-101.

What is remarkable to me is that you can get rates of MRD negativity of 30% with an antibody.  I can tell you that ofatumumab, rituximab, and alemtuzumab can't touch that.  Indeed, MRD negativity to the rituximab plus chlorambucil arm was only 8%.  The FDA granted approval on the basis of the improvement of GA-101 plus chlorambucil over chlorambucil alone.  There is no mention in the approval of the difference between the GA-101 plus chlorambucil versus the rituximab plus chlorambucil.  Indeed, if you look at the graphs of how patients do, it is pretty apparent that GA-101 (obinutuzumab) is better than the rituximab arm - but since that is not what the data that supported approval, they cannot make that statement.

Rituximab is pretty much the only drug so far in CLL to improve overall survival.  I am convinced that obinutuzumab is a much better drug in this disease.  Median progression free survival for R-Chlorambucil was 15 months while it was 23 months for G-Chlorambucil.   I have written a prior post about what makes GA-101 different.  Until the FDA is able to review that arm of the study (which simply takes longer to evaluate because the data isn't yet "mature") - Genentech can't say that.

So how will the drug be used?  Insurance will be the police making sure it is used according to the label.  Every insurance company will have its own policies so some may allow off label use, some won't.  The drug is approved in combination with chlorambucil for front line therapy of patients with CLL.  Genentech is making much use of the word, "typical patients."  That is because the average age of the patients in the study was 73 years old.  Since that fits the exact age for average age for first therapy in CLL they like the word "typical."  Others have used the term "elderly."  I guess I sort of agree with their word.  Keep in mind the average age in the FCR front line study was 62 years old.  Those 11 years are enormously important.

Chlorambucil is hardly ever used in North America (although common in much of Europe and Australia).  In the US, I am guessing that many patients will use the drug alone (without chlorambucil). Chlorambucil really has a reputation that is pretty unfair.  It is a good drug, but there are many that are better.  In the right patient though, chlorambucil can be really helpful.  There have been studies that have combined GA-101 with bendamustine or even FC.  That data has not really seen the light of day so I would be nervous to use it in combination with those drugs just yet.

The main downside to GA-101 is the infusion reactions.  I have compared rituxan to rolling thunder and GA-101 to lightning.  On the first dose of either drug it is common in CLL for a patient to have either shortness of breath, low blood pressure, hives, etc.  With rituximab, it seems like those can come and go.  Every time you turn up the rate of the infusion the symptoms can start again.  You resolve the problem by slowing down, giving more tylenol, benadryl, steroids and starting again.  It can feel like the rolling thunder that goes on for minutes in a good east coast storm.  With gazyva the reactions happen very early in the infusion and feel a little more severe.  Once they are done though it seems they really don't come back - more like lightning.  With either drug it is considerably less frequent to experience these reactions on the second or subsequent dose.  My fantastic infusion nurses seemed to figure out that if you stop the infusion at the first sign of trouble, the reactions were very manageable in the patients we treated.

What I found shocking working with the drug was that when the infusion reactions had settled down, if you rechecked the blood counts they had almost normalized - even just a few milligrams into therapy and after only thirty minutes.  My research nurses and lab manager asked me several times, "what did you do to that patient?"  It defied our experience to see blood counts change so quickly.

I am pleased to see this drug get approved.  It was always a dark horse in the race.  Everyone has been focused on ibrutinib and idelalisib but I had my bets placed on this drug crossing the finish line first.  I think it is a significant new option for docs who treat the disease - but more importantly, combining it with other new drugs will give us the option to achieve very successful results without chemotherapy.  Keep in mind that Genentech is co-developing ABT-199 (GDC-0199) with Abvie.  That will be their obvious drug to combine it with.  Now that obinutuzumab has been approved though, any company can begin to combine their drugs with it.  Pharmacyclics, Gilead, and Jannsen would be smart to start combining their BCR signal inhibitors with obinutuzumab.  I bet MRD rates will be VERY impressive with such combinations!

Thanks for reading.

FDA speed!?

When you have a disease that can take your life away - it can be an awful experience knowing there is a "wonder drug" out there that hasn't been approved yet.  Many patients with CLL are living in that world right now with the coming tidal wave of CLL therapies.

Patients are already asking for "expanded access" protocols for drugs like ibrutinib, idelalisib, and obinituzumab.  In some cases those will be available but in other cases we will need to wait until the drugs are actually approved.

Back in the 80's when HIV was out of control, the outcry for faster action from the FDA was enormous.  Fortunately, they responded.  Now there are several mechanisms that can enable a more rapid approval of effective drugs (fast track, orphan indication, breakthrough therapy).

In our hyperlinked, social media world, new effective drugs can be broadcast by trial participants to chat forums and patients can know about the "next best thing" in near real time.  That undoubtedly makes the FDA feel glacial - but I do believe they are moving considerably more quickly than in the past (post explaining why it takes so long).  Many have asked why drugs cost so much.  I have a post describing that here.

I came across this article and I thought it was a great read.
The FDA's Cancer Czar Says He Can't Approve New Drugs Fast Enough

This article in Forbes (link here) talks about Richard Pazdur and how he has brought speed and efficiency to a government organization (yes it can happen).  While he has his critics, I think we are fortunate in the oncology community to have someone like Dr. Pazdur working to bring drugs forward.    Keep in mind, there are billions of dollars on the line with many FDA decisions.  If you don't think some people are going to be disappointed or complain - perhaps you've never lost several billion dollars.

As an aside - If you read the comments section - you will find out why I have disabled the comment section on my blog - you cannot control some of the nonsense people will write (internet graffiti).  Anyhow, I thought it was a good article.  It actually has some of the ibrutinib history included.

Thanks for reading!
Jeff