Sunday, May 17, 2015

Take your pills - ibrutinib dosing matters!

When we are investigating new drugs that have never been tested before, we start with what's called a phase 1 study.  Historically, the goal of a phase 1 study was to define the "maximum tolerated dose." In the era of traditional cytotoxic chemotherapy, you knew you had arrived at that dose when patients simply couldn't handle any more - it was just to much. Perhaps they had too much nausea or vomiting, or the liver couldn't handle it anymore, kidneys failed, or some other toxicity made it clear that you had reached the limits of human tolerance.  As researchers, we just hoped we could get the drug levels high enough without causing too much damage.  If we achieved blood levels that we expected to kill the cancer cells without irreparably harming the patient in the process - that was victory.

Many of the new drugs challenge that paradigm.  When treatments effectively target the specific molecular abnormality with a cancer cell we can see considerably more efficacy while at the same time reducing toxicity.  This has led to the concept of "optimal biologic dose."  Instead of pushing the dose to the max, you only increase the dose as far as you need to - often with substantially less side effects than the traditional therapies.

Unfortunately, "optimal biologic dose" is much harder to define than "maximum tolerated dose."  It presumes that we have effective and accurate means of actually measuring what were trying to do.  While it may come as a surprise to many patients, the unfortunate reality is that there is an enormous amount of human judgment as well as a paucity of clear data involved in early clinical trials. Things are not as scientifically certain in early trials compared to the level of data we have later in a drugs like cycle.  Furthermore, we often need to generalize to the larger population from a very small subset of patients that are appropriate for a phase I study.

There is new data regarding the dosing of Ibrutinib that I think is really important to consider.

Most drugs inhibit enzymes in what we call a "reversible" fashion.  This means that the particular target is turned off only when you have high enough levels of the drug in the blood.  Ibrutinib is a little bit different, it is what we call a "covalent" inhibitor.  When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body.  Within just a few hours of taking a pill there is virtually no free drug in the blood.  Instead, it is all bound to the BTK protein - completely shutting down that signaling pathway until the cell makes more BTK.  This is very different than most oral drugs where we are trying to make sure the levels are still high enough right before you take your next dose.

When you had a sore throat as a kid, the doctor always said to be sure to take all your pills so that the bacteria didn't become resistant.  It is virtually a scientific paradigm that exposing bacteria to inadequate antibiotic dosing creates resistance.  The same is probably true in leukemia and lymphoma with some of the new drugs.  A CLL cell that has its B-cell receptor signaling pathway completely inhibited has a hard time escaping that inhibition.  If that same pathway is only partially inhibited however, it will try to find ways to escape.   This is why the discovery of mutations in the BTK protein that confer resistance to Ibrutinib or so important. These can only arise in cells that have survived the BTK inhibitor long enough to figure out how to thrive under the suppressive influences of Ibrutinib.

Dose intensity can be measured in two key ways.  The first is how many days you take it out of how many days you are supposed to take it.  We already know in other chronic leukemias like CML, adherence to Gleevec (imatinib) is the biggest predictor of treatment success.  Heck, it is even true in breast cancer with hormonal agents.  Now it looks like the same is true in CLL.  Sometimes side effects force you to hold therapy - but prolonged drug holds are undesirable.  Patients who had drug holds in excess of 8 days were almost three times more likely to experience a disease progression (link to ASCO 2015 abstract here).  

The second way dose intensity is measured reflects what dose you take daily compared to the "optimal biologic dose."  There was a very compelling presentation at AACR a few months ago  (I am still trying to figure out how to link to the actual poster, but here is link to the session).  The study title was "Population Pharmacokinetic-Pharmacodynamic (PKPD) Modeling of Ibrutinib in Subjects With B-Cell Malignancies" by Poggesi et al. (prize to the first person who figures out how to find the actual poster).  I need to get a little technical for a minute - stick with me.

As I wrote above, ibrutinib has a cool property that is unique compared to most drugs.  Since it covalently (or irreversibly) binds to BTK, we can do a blood draw, isolate the CLL cells, purify the BTK protein, and look to see how many molecules of the BTK protein are "bound" to a molecule of ibrutinib.  This is what we call, "receptor occupancy."  The higher the occupancy, the more drug is bound to the protein, and the more the pathway is shut off.

You can then ask how many people have how much of their BTK protein "occupied" or inhibited by ibrutinib at different doses.  If we set the bar pretty low at 75% occupancy, any dose above 280mg (two pills) is pretty effective.  96% of patients achieve that level of occupancy at any of those doses.  that may seem good but unfortunately, that low bar means that the pathway is only 75% "turned off."  It is more like a dimmer switch on the lights instead of an on/off.  75% occupied means that there is a lot of room for cells to try to discover ways to become resistant.  If you set the bar much higher at 90% occupancy, the standard CLL dose of 420mg (three pills) can accomplish that in 86% of patients but only 75% of patients who take two pills and 53% of patients taking on pill.  In short - dose matters.  You get more complete pathway inhibition with higher doses of ibrutinib.

What we don't really know what level of pathway inhibition is optimal for CLL treatment.  It is tempting to think that 100% occupancy in 100% of subjects might be much better at preventing eventual resistance - but honestly, we do not know if that might mean higher levels of side effects. How could we get there?  Well, perhaps we didn't actually define the "optimal biologic dose" correctly in the original phase I study.  We pretty much stopped escalating dose because it seemed to be doing what we wanted it to do in the relatively small population of patients we were studying.

I would be curious to go back and do a "dose optimization" study to see if we could modify either the dosing schedule or the actual dose taken to see if we could make ibrutinib work better than it already does.  I also worked on another BTK inhibitor that is no longer in development called CC-292.  We never really got it to behave as well as ibrutinib until we started giving it to patients twice daily. Other BTK programs are looking at this as well.  Another way of potentially addressing such drug limitations is by adding a second drug that acts through different mechanisms.  This should ONLY be done in the context of a research study.  We have three such studies within the US Oncology network of sites (and here as well) including the addition of ublituximab (an updated version of rituximab), the combination of a BTK and PI3K inhibitor, or even BTK in combination with one of the new immune checkpoint inhibitors - pembrolizumab. 

Doctors tend to reduce doses when there are problems.  It is how we think about so many different clinical problems, that we tend to assume it is smart decision making.  In my own patients, I am concerned that dose reductions or prolonged dose interruptions may be causing ibrutinib to be less effective than if we can maintain the dose intensity.

To leave a comment, click on the title of this blog post.  It will open up the blog post in a separate window with a comment field at the bottom.  All comments are reviewed by myself before being allowed to be posted - be patient, I'm a busy guy.

Thanks for reading.

Thursday, May 14, 2015

ASCO 2015 - NHL

OK, so yesterday I put up my choices for the best of CLL abstracts at ASCO.  Here is my list for NHL.  I have to say, it seems like a pretty thin selection.  I looked at all 320 abstracts with lymphoma in the title and this is the best I could do.  Only one big NHL phase three study that is really about getting Gazyva approved in indolent NHL - and we can't even see the data just yet.

I am deeply passionate about management of DLBCL in patients above age 70 and hope to see more pharma moving in this direction.  Seems stunningly foolish to me that fully HALF of all DLBCL cases are virtually ignored in terms of age appropriate therapy trials.

Anyhow, here is my list.  Feel free to use the comment section if you think I am missing something really important.

CAR-T therapy in NHL - yet another entity out there that could be called a "game changer" Durability of responses in DLBCL to be key determinant of value

Novel endpoints in FL studies - technical paper about defining a variable you can actually measure in real time to figure out if you are on right track with new approach

R2-CHOP in DLBCL - trial in progress, but I have hopes this will be legitimate change to standard of care.  No data yet.  Fingers crossed.  Going to be a while before this reads out…. like several years.  Watch for R-CHOP vs G-CHOP to be first phase III DLBCL study to challenge status quo.

Impact of weight an obesity on rituximab dosing - American love for cheeseburgers killing us with lymphoma

Molecular changes in BCR correlate with ABC vs GCB in DLBCL - nerdy article, but I like it

DLBCL in the elderly - the greatest unmet medical need in lymphoid cancers

More on elderly DLBCL - median age 70, yet such patients rarely on prospective trials

Yet more on elderly DLBCL - any drug company with NHL drug is foolish to ignore the opportunity here

Bendamustine +/- Gazyva in rituximab refractory - big phase III study.  May prompt FDA.  Curious to see the data.  We have a press release linked here.  Keep in mind, trials to get approval can be very different than trials to change the way we practice.

Idelalisib in Waldenstroms - didn't make the FDA label, but still active.

Clearing the junk in amyloid - ok not normally a NHL disease symptom, but this is just too cool

Wednesday, May 13, 2015

ASCO 2015 - CLL

The new ASCO abstracts are out.  After going to this meeting regularly for over 10 years, I only now feel like I know how to approach it.  I am also struck more and more by the sheer volume of data that comes out at ASH and the comparatively small quantity of CLL/NHL data at ASCO.  Of course now we have SOHO (Society of Hematologic Oncology) and the new ASH September meeting to directly compete with SOHO.  Don't forget about IWCLL (in Sydney this year) and ICML (Lugano) and EHA (European Hematology Association).  If I went to all these meetings, I think my colleagues would fire me from my practice because I couldn't hardly see patients.

I thought I would highlight the CLL / NHL abstracts that I think are the most compelling and offer a sentence about each one.  I will get the CLL ones out tonight and then work on NHL in next few days.

Duvelisib in untreated CLL - Small number of patients, but decent activity.  Not a ton of LFT discontinuations

Use of molecular prognostic testing in clinical practice - Shameful how little people use FISH

ROR1 small molecule inhibitors - could be wrong, but I suspect this could prove to be a big deal

TGR-1202 in CLL/NHL - No LFT abnormalities with PI3K inhibitor?  Curious

Ofatumumab +/- Idelalisib - Another strong phase 3 result.  Might anticipate another FDA indication

Bleeding rates on Idelalisib - Attacking one of ibrutinib's few weak spots

CLL prognostic index - first the IPI, then the FLIPI and MIPI, now the CLL-IPI

Ibrutinib dose intensity and outcome - Importance of not skipping doses.

Bendamustine / Rituximab +/- Ibrutinib in relapsed CLL - late breaking.  No data, but there is a press release - linked here

Relatively few practice changing data sets out there.  FDA will probably act on the two phase 3 studies here and expand labeled indications, but I don't really think many patients with relapsed CLL are going to be affected by the BR +/- ibrutinib study because everyone wants to take ibrutinib as a single agent.  The Ofa +/- idela might have some traction, but the more ofa data I see, the more I think it is just another rituximab - and we've already had positive phase 3 results and FDA approval.