The doctor is out???

I've written several times about the harsh economic environment in which oncology practices are trying to survive.  Many of the people who debate health care reforms and policies have clearly never operated a private practice because the decisions they have made are completely destroying the infrastructure for cancer care in the United States.

This article spells out just how bad things are right now:

Cancer Clinic Closings And Consolidation: Ongoing Cuts To Care And Increasing Treatment Costs

In short:

The COA Impact Report reveals continued negative trending in the nation's cancer care delivery system.  During the past six years 1,338 clinics and practices have been impacted as follows:

• 288 individual clinic sites closed
• 407 practices are struggling financially
• 43 practices sending all patients elsewhere for treatment
• 469 practices have entered into contractual relationship or have been acquired by a hospital
• 131 practices have merged or been acquired by an entity other than a hospital 

This all happened PRIOR to the sequester which accelerating the destruction (see prior post)

If you doc seems more stressed out than usual - or you can't get an appointment - this issue is very real and very important.  Thanks for your support and 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

Generic Cancer Drugs - aka "Biosimilar"

Drugs can have remarkable differences in molecular complexity.  Generally we classify drugs into two categories - either "small molecule" or "large molecule."

Small molecule drugs are often able to be formulated into pills (though many are also given IV) and have relatively simple molecular formulas.  Take a drug like tylenol or ibuprofen - they are comparatively simple.  Most good chemists could whip it together with a few basic chemicals in their lab much like any good chef could pull together a nice meal with whatever you have in the refrigerator.  Some of the new research drugs like ibrutinib, idelalisib, and ABT-199 are in this category.  This doesn't mean the science behind the drugs is simple by any means.  Some of these drugs are based on years of elegant lab research - but the molecule itself is often comparatively simple.

Large molecule drugs on the other hand include antibodies like rituximab, ofatumumab, or brentuximab (the "mab" on the end stands for monoclonal antibody).  These types of drugs are most frequently administered intravenously.  In fact if you were to swallow rituximab your body would digest it in much the same way you would digest a fried egg.  They are both protein structures and neither remain intact following the acid of the stomach or the digestive enzymes of the small intestine.

To put the size difference into proper comparison think of a small molecule as a bicycle.  Using the same analogy, a large molecule drug would be like an aircraft carrier (Scroll to bottom for image). The molecular complexity is truly astounding.  The fact that these drugs can be reproducibly manufactured to be nearly identical (single chemical entity - SCE) from batch to batch is a testimony to the incredible sophistication of chemical engineering.

It probably comes as no surprise then that small molecules have been subjected to "generic drug competition" for quite a while.  Typically once a drug patent expires, generic drugs flood the market and the price drops by 90% in a very short period of time.  The reward for innovation has expired.  When Pfizer's drug lipitor went generic a few years back, it went from something like 7 billion dollars of revenue per year several hundred million with breathtaking speed (I am probably missing the numbers by a fair margin - but you get the point).  There was a reason that the company laid off a ton of their marketing staff around the same time.

Generic "small molecule" drugs are often pretty simple to make.  Furthermore, the FDA standard for what it takes to be an approved generic drug is straight forward enough that many generic drug manufacturers can get their drugs to market quickly.  In everyday cancer practice, small molecule chemotherapy drugs like cyclophosphamide, fludarabine, adriamycin, vincristine, and etoposide are virtually entirely all generic.  Unfortunately the comparatively low cost of these medications has made it hard for many generic drug manufacturers to consider them worth their while and this has resulted in chronic drug shortages for many of the lifesaving drugs we consider standard.

Between the "small molecule" and "large molecule" drugs are a number of "intermediate size drugs."  These may include growth factors like neupogen, neulasta, aranesp, etc.  While these drugs are often considerably more complicated than tylenol, you might think of them as a city bus instead of a bicycle or aircraft carrier.

While these drugs are certainly an order of magnitude more difficult to manufacture than small molecules, it should probably come as not surprise that generic drug makers have decided to tackle this market.  Since single doses of neulasta can cost thousands of dollars, being able to make a generic version of these drugs could definitely be worth the effort.

With increased molecular complexity comes a lot more difficulty in reproducibly manufacturing a copy cat drug.  While you can probably go out to your garage and put a bicycle together, making a city bus is probably out of your league - and unless you are a modern day Noah - an aircraft carrier is simply out of the question.

The problem is that very small differences can result in enormous biologic consequences.  In some cases "generic" erythropoeitin have been associated with extremely dangerous allergic reactions, or in other cases caused the immune system to shut down all red blood cell production (a huge problem for a drug that is supposed to treat anemia).  Despite these well publicized failures generic drugs have moved much more quickly in India (where different market forces, regulations and intellectual property rights have allowed earlier utilization of generic drugs) and even in much of Europe.

You can probably guess where this post is going next.

Generic "aircraft carriers" or large molecule drugs are next.  There are something like 8-10 companies getting ready to move forward with a generic version of rituximab as soon as the patent expires.  This is part of the reason Roche has worked so hard to make a better version of the drug and looks for obinituzumab to be rituximab 2.0.

Due to the incredible complexity of producing drugs on this scale, the FDA has taken quite a while putting out the rules for what it takes to become a generic large molecule drug.  Most of these drugs will require a clinical trial in which the standard drug is compared to the generic drug.  The generic manufacturer wants the results in both arms of the study to be equivalent - not better.  If the results are better it is probably not the same drug after all.

You can imagine how this can turn clinical trials on upside down.  Instead of trying to get on a study for access to the next best drug, now you are just trying to get a drug that is exactly the same as the innovator molecule.  A lot of patients may find that less than compelling.  Perhaps there would be a financial incentive?  You have to be extremely careful if that is the case that it is not coercion or that there is a financial interest for the doc recommending the study.

These studies will be showing up in the next 12-24 months.  They pose a bunch of challenging questions.  I am not sure I can predict how they will go, but I am eager to see how the process unfolds.

Thanks for reading.

Ibrutinib for CLL and MCL in New England Journal of Medicine

It is with considerable pride that I get to report our ibrutinib study was published today in the most prestigious medical journal out there.

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

Time magazine says:

New Drug May Be Best Treatment for Leukemia Yet

I've written extensively on my blog about ibrutinib because I have been working with it and other similar drugs since 2005.  I got to treat the first two CLL patients in the world with ibrutinib and also one of the very first mantle cell lymphoma patients.  It is fun to see the world waking up to the significance of these therapies.

It was a cool experience treating the first two CLL patients because it was immediately clear that the drug was doing something significant (though in the first few days it wasn't clear if it was good or bad).  The patient had a white blood cell count of 50k and the next day she came back feeling great with nodes that had shrunk tremendously and her WBC had risen to about 150K.

I remember discussing it with the medical monitor and we hastily got a scan to make sure we were not making the patient worse.  I had thought this might happen because of our prior experience with fostamatinib but the monitor at the time was uncertain of what it meant.  After a few months we became aware of just how special this drug might be - the rest they say is history (recorded here)

There is also an article about ibrutinib in mantle cell lymphoma in the same journal and a fantastic editorial about why these drugs work.  For patients with mantle cell lymphoma over age 65 there is a critically important new study to be aware of - linked here.

There is never a good time to get CLL, but if you had to pick one, now would be the time to get it!  Lots of cool change coming. 

Engineered T Cells

Engineered T cells are an exciting new development for patients with B cell cancers.  This will take a while to become "prime time."  Once some huge logistic details are worked out - this could potentially apply to most types of lymphoma and CLL.

The science is early but encouraging.  I've written an analysis of the technology previously (how it works / dangers / etc) but came upon this video at a Lymphoma and Leukemia Society volunteers event.

If this doesn't get you excited and bring a tear to your eye at the same time - check your pulse.    I've watched it four times and welled up with a tear every time.  It is less than four minutes - I highly encourage you to watch it!



Fire With Fire | Ross Kauffman from Focus Forward Films on Vimeo.

Cure for CLL & NHL?.... or just better control?

Newsflash: Magic Johnson has HIV!

I grew up in Southern California during the Lakers and Celtics rivalry.  At the time, Magic Johnson was a living legend.  The way he elevated the play of all his teammates was truly extraordinary.  So when he announced his diagnosis with HIV the sports world collectively gasped.  My hero had been given a death sentence that we had all seen many times before.  He was certain to die a horrible wasting death.  Purple skin lesions, muscle wasting, and infections would transform the sports legend into a pathetic state and we would see it slowly chronicled by our tabloid press.

Newsflash:  That was 22 years ago and Magic Johnson is doing great.

What changed?  Dedicated scientists learned the biology of HIV, figured out where it was most vulnerable, designed rational, smart, effective, less toxic drugs.  They figured out how to put them together into powerful combinations.  They figured out how to monitor for mutations that conferred resistance, how and when to change therapy.  They figured out how to go from 70 pills per day to two pills per day and patient compliance went up – resistance went down.  Side effects of treatment became much less.  When the global research community galvanizes against a task – huge changes are soon to follow.

The lessons from HIV serve as the foundation for where we are now in CLL and in some types of NHL.  While we may be starting to hit our stride twenty years after HIV, the pace of change has exploded so we will catch up soon – and maybe even do better?  The main question many patients rightfully ask is whether this progress will lead to prolonged disease control or actual cures.  When HIV was changed by the explosion of new drugs 20 years ago, it took a number of years to figure out how to put all the progress together to achieve the prolonged disease control we can observe today (such as Magic Johnson) but patients are still taking their medications and we do not think that a cure has been achieved.  Will the same be true in CLL/NHL? I’m not sure yet….

I had the pleasure of hearing a lecture at ASCO this weekend by Charlie Sawyers.  For individuals like myself who think in bizarre protein names, listening to someone as brilliant as Dr. Sawyers describe the multitude of discoveries his team has been a part of and to put it into one story is beyond compelling.  I need to take a detour into prostate cancer in order to talk about CLL.

After working out a lot of the science of resistance to Gleevec in CML and helping create the “second generation” of CML drugs that are incredibly effective, Dr. Sawyers decided to leave CML, move across the country,and turn his sights on prostate cancer.

Prostate cancer is almost singularly driven by testosterone.  In the past, our management of prostate cancer included removal of the testicles in an effort to deplete the body of testosterone.  That didn’t "sit well" with many men and we were all relieved when scientists figured out how to suppress testicular production of testosterone using injectable hormones to “castrate levels" (medical terminology at its finest).  Unfortunately, the body was still able to produce a trace amount of testosterone from the adrenal glands and the prostate cancer would find a way to survive by either producing its own testosterone or adapting to the very low testosterone environment.  Unfortunately, the cancer would start to grow again and we had to give chemotherapy for “testosterone independent prostate cancer.”

So we got smarter.  Prostate cancer is one of the diseases that have been revolutionized inthe past three years.  We have a ton of new rational drugs and Dr. Sawyers is taking all of us to school by figuring out how prostate cancer is adapting to the new drugs.

Several of the new drugs actually bind directly to the “testosterone receptor” and prevent its function.  These are incredibly potent and focused drugs (think extremely effective antibiotic for strep throat) that interfere with testosterone’s interaction with the prostate cancer cells.  They prolong survival in men whose prostate cancer has figured out how to survive the injectable hormone drugs that reduce the testosterone to “castrate levels.”

One thing both cancer and HIV have taught us is that single drugs do not control the emergence of resistance.  Give a patient with HIV a single drug, and the disease control is fairly brief.  Give a man a single drug for prostate cancer and it too will eventually figure out a way around the drug.  In this case, the prostate cancer can either activate another receptor that acts like a surrogate for the testosterone receptor (the glucocorticoid receptor) or just get a mutation in the testosterone receptor that makes the drug useless or in some evil cases can even make the drug act like it is turning the testosterone back on.  What is cool though is that you can test for that mutation and in some cases it may suggest an alternative drug could work.

This is the same story we saw in chronic myelogenous leukemia.  The BCR-Abl protein causes CML.  Give it Gleevec and some number of cases can become resistant.  Other drugs can sometimes recapture disease control.  Sometimes “compound mutations” can render the second drug ineffective.  Sequential single agent therapy creates sequential mechanisms of resistance.

I recently wrote about ibrutinib resistance in CLL.  I went to the poster session on last Sunday where Joe Buggy presented his team’s findings (shout out to Joe for having had the ride of a lifetime sticking with ibrutinib from the very beginning - couldn't have happened to a nicer guy).  While it is only a few cases right now, there have been at least four cases where the binding site for ibrutinib on the BTK molecule gets altered and the drug stops working.  There was one other case where the mutation was in a different protein but the same chain of enzymes downstream of the B cell receptor.  This highlights a very important theme that cancer can outsmart effective drugs if given the opportunity to do so.  We just need to be smarter and take away that opportunity.

Interestingly those two different types of ibrutinib resistance would be predicted to be sensitive to idelalisib.

In HIV and even some of the lymphomas, combining drugs was key to progress.  Think R-CHOP for DLBCL or FCR in CLL.  What would happen if patients were on BOTH ibrutinib and idelalisib? (this has NEVER been studied and is not recommended outside of a clinical trial!)  Why would a patient develop a BTK mutation if it didn’t let them escape the idelalisib?  I wager that once the tidal wave of coming drugs in CLL gets approved you will see a dramatic increase in the number of studies where targeted biologic drugs are combined.  Indeed, some of those studies are taking shape now (link and link).

While patients are not particularly excited about taking a bunch of pills, I dare say that that is a problem we can only hope to have at this point.  It sure beats taking multiple different chemotherapies with all of the attendant side effects.

Another lesson of HIV was that the more disease that is present, the faster you will see resistance.  If you have a trillion little viruses all working out their mutations, one is more likely to get it right than if you only have ten thousand viruses.  We see this in CML too.  CML is “staged” differently than the normal stage I-IV.  In CML someone with very advanced disease may have what is called “accelerated phase” or even “blast crisis.”  Gleevec doesn’t really work so well there.  If you get disease control, it is often brief.  With a ton of cancer cells, they will find a way around any selective pressure.  On the other hand, if you get to a level where we cannot detect your CML, chances are you are set for life provided you stay on your drug (although trials are starting to show that SOME patients may be able to stop therapy).

I think we will see the same thing with CLL – and it makes me wonder how long it will take before we revisit the appropriate timing oftreatment in the disease.  Nobody does watch and wait in CML.  For the time being though, the reasons for starting therapy are pretty well set.  Provided those conditions are met, we would be wise to figure out combinations that get rid of as much CLL as quickly as possible. 

By now, most patients are aware that in CLL, taking ibrutinib or idelalisib causes the white blood cells to go up and then slowly drift back down.  Meanwhile the lymph nodes rapidly shrink and stay down.  This is because the cells are merely getting shuffled around from a place where they are happy (lymph nodes and bone marrow) to the blood (where they are unhappy).  Starting these drugs do not really eradicate a ton of cells right away though over time the cancer cells die off (death by neglect – a topic for another time).

We have already seen results where these drugs are combined with rituximab, ofatumumab, or several chemotherapy regimens.  I am very optimistic about what we are seeing in these studies.  I’ve had patients ask me though why we need to add the chemo on top of the non chemo drugs.  For some, it probably feels like as doctors we can’t give up a bad habit.  I might take the opposite angle and speculate that by removing a bunch of cancer cells we may allow the ibrutinib or idelalisib to be exposed to fewer CLL cells seeking to become resistant.

Most patients I’ve talked to are hoping that we will be able to combine these drugs with other “targeted” agents instead of chemo.  For a variety of reasons, that is unlikely until some of the drugs get approved by the FDA – but it isn’t that far away. 

Some of the new drugs work extremely quickly.  In the long run, we will figure out how to do these combinations but we must be extremely careful.  Sometimes when you put drugs together you get unexpected side effects – we have seen that quite a few times in recent clinical trials – even with “targeted agents.” 

Another lesson from HIV is that no patient can take 70 pills per day – even when they are purposefully trying to be good patients and take all of their drugs.  Some have to be taken with food, some have to have an empty stomach.  Some make you tired, and some get you all amped up.  The problem is that treatment adherence drops the more complicated our regimens become.  When adherence drops, resistance emerges.  Patients with HIV can now take a single pill that combines several medications.  One in the morning and one at night is all some patients require (Thank Gilead for that!). 

Sometimes adherence is not about swallowing all of your pills at the right time, sometimes it is about not being able to afford the medications.  I’ve recently written on this topic and heard insightful analysis of how much the health system can afford these drugs.  It is bad enough when they are given individually but few have begun to even consider the cost of putting them all together.  If each one is 100k / year and a patient is taking two or three at a time – yikes.

In CLL there are two VITAL pathways – those are the B cell receptor pathway (with several key targets including Syk, BTK, and PI3K) and the BCL-2 cell survival protein.  I’ve written much more about the former than the later but both can now be targeted with incredibly potent research drugs.  Furthermore we have figured out how to recruit the immune system through very effective antibodies (rituximab, ofatumumab, obinituzumab) as well as several others working through the system.  There is also lenalidomide which can “re-boot” the immune system to target CLL (not approved for that purpose but being actively studied).  We have four totally different ways to hit key aspects of CLL cell survival – that can be independently targeted – without ANY chemotherapy.

Dr. Sawyers challenged the cancer research community with several lessons in his lecture 1) sequential monotherapy generates sequential mechanisms of resistance 2) combination therapies reduce risk of resistance by eliminating the total amount of disease faster so that fewer cells or viruses can experiment to find escape mechanisms AND making it harder for a single mutation to escape multiple drugs given at the same time 3) regimens do not work if the patient does not take them.

In the past, when you have been able to combine several effective treatments at the same time, that has been when you started to see cures – will we get there in CLL?  It will take a handful of years to figure out the safest, most effective way to put these together but there is more reason for optimism than ever before.

In CML a small number of highly selected patients have been able to stop their medications (under extremely controlled clinical trial conditions) and their disease has not come back after a few years of observation.  The longer they go that way, the more everyone is starting to believe they have been cured.  I believe some of our new CLL drugs are in the same league as gleevec but instead of only one target we have many (syk, btk, pi3k, CD20, CD37, BCL-2, cereblon).  So will we have a cure or prolonged control?  Let’s just say, I’m glad I know how to treat a bunch of different types of cancer…  I would hate to be out of a job.

Thanks for reading,

Jeff

Lenalidomide approved in relapsed Mantle Cell Lymphoma

The following is copied text related to a newly approved therapy in NHL:

 "On June 5, 2013, the U. S. Food and Drug Administration approved lenalidomide capsules (REVLIMID®, Celgene Corporation), for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 

The approval was based a single-arm, multicenter clinical trial enrolling 134 patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. All 134 patients received prior treatment with bortezomib and 60% were documented to have disease refractory to bortezomib therapy. Patients received a median of 4 prior therapies for MCL. The median age was 67 years, 81% were male, 96% were Caucasian, and 61% had MCL for at least 3 years

The efficacy endpoints were overall response rate (ORR) and duration of response (DOR). The ORR was defined as the proportion of patients whose best response was complete response (CR), complete response unconfirmed (CRu), or partial response (PR). In the 133 patients who were evaluable for efficacy, the ORR was 26% (95% CI: 18.4, 33.9). CR or CRu was achieved by 9 patients (7%) and 25 patients (19%) achieved a PR. The median DOR for the 34 patients who achieved a CR, CRu, or PR was 16.6 months (95% CI: 7.7, 26.7).

Safety data was evaluated in 134 patients who received at least one dose of lenalidomide. The median duration of therapy was 95 days (range 1-1002) and 78 (58%) of patients received 3 or more cycles of therapy. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events.

The most common (greater than or equal to 15%) grade 1-4 adverse reactions included neutropenia, thrombocytopenia, fatigue, anemia, diarrhea, nausea, cough, pyrexia, rash, dyspnea, pruritis, constipation, peripheral edema and leukopenia. The most common (greater than or equal to 5%) grade 3-4 adverse reactions were neutropenia, thrombocytopenia, anemia, pneumonia, leukopenia, fatigue, febrile neutropenia, dyspnea and diarrhea.

The recommended dose and schedule for lenalidomide is 25 mg orally once daily on days 1-21 of repeated 28-day cycles. Lenalidomide should be taken at about the same time each day, either with or without food. This supplemental application also included the approval of a new 20 mg capsule strength.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021880s034lbl.pdf