Tuesday, July 29, 2014

Ibrutinib in 17P deleted CLL

Yesterday the FDA expanded the "label" (or the set of conditions that the drug is approved for) for ibrutinib.  See the ASCO news release here.

I think the news coverage missed the most important aspect of the change in the label.  Most of the coverage focused on the usefulness of the drug in patients with the dreaded 17P deletion (which I have written about quite a bit). The analysis was based upon the RESONATE trial (summarized here) in which the benefit of ibrutinib over ofatumumab was particularly striking and one other unpublished study in abstract form here.

Since ibrutinib is already approved for patients with "one prior regimen" at first blush, this would not change the group of people eligible for the drug.  I actually like to read the specifics of labeling information so I read the updated "label" (linked here) and was surprised that the language didn't distinguish between those patients who have been previously treated or not.

I was able to verify today that indeed, previously untreated patients with the 17P deletion are considered appropriate for the drug.  That is much bigger news than what I read.

I have a huge blog post I've been working on for some time - hopefully ready to go in next few weeks about utilizing newer molecular diagnostics to select therapy in CLL.  This new information corresponds to trends I have seen emerging where many of my CLL researcher colleagues have started using this drug in this setting.  Keep in mind, quite a few patients have abnormalities in TP53 (on 17P) and may not be aware of it due to insufficiency of current FISH testing. 

Another key trial in this population involves the recently approved idelalisib and rituximab in patients with untreated 17P deleted CLL (linked here).  In addition to those sites listed on clinical trials.gov it is also available at most of the places on this map (linked here)

Although the number of  CLL patients with 17P treated with this combination in the frontline setting is small, the overall response rate is 100% and the European Agencies have recommended frontline status for idelalisib in this setting as well. 

Thanks for reading

Wednesday, July 23, 2014

Idelalisib / Zydelig approved

There is a new kid on the block!

First it was called CAL-101.  It is common for a drug company to use letters from the name of the company.  In this case, it was originally Calistoga Pharmaceuticals.  The 101 part is a little more funny.  I understand one of the early investors in the company was driving in Palo Alto California and turned from University Drive onto the 101 highway and decided to call the drug CAL-101.  True? False?  Not sure. 

Then Gilead bought up the drug from Calistoga.  Next step?  Change the numbers.  CAL-101 became GS-1101.  GS = Gilead Science.  Not sure where the extra "1" came from.  Perhaps it was an effort to differentiate from GA-101 which became obinutuzumab before it became Gazyva.

Next step is to give the letter / number combo an actual name.  In this case it was idelalisib.  As difficult as that seems, it actually makes perfect sense.

Idelalisib (pronounced I-Dela-Lisib)
Dela= delta isoform of PI3K
Lisib = that is the mandatory suffix of drugs that inhibit PI3K enzymes

I have heard this drug mispronounced so many ways that it is almost comical -I-del-isilib, I-dela-mab, etc.  I think I would have chosen Ideltalisib if I were in control of all things as that would make a lot of sense (inhibit-delta-PI3K).

Every drug has two names (brand name vs generic name).  You would be amazed how much effort goes into coming up with a name for a drug.  You would also be amazed how often drug names begin with the letter "Z."  Some sort of market research I don't know about I suppose.  So idelalisib is now called Zydelig.  I think this is a combo of the "z" and the "delta" but not sure I know where the "ig" comes from.

As if we were not already spoiled by approvals of the latest treatments for CLL including the addition of obinutuzumab and ibrutinib within the last 12 months, now we have yet another new agent that is simultaneously remarkably effective, well tolerated, and has proven to prolong survival for patients with CLL and show efficacy in hard to treat low grade lymphoma!

It has been an interesting race for approval between ibrutinib and idelalisib.  These two drugs entered human clinical testing at nearly exactly the same time and in the grand cosmos of time and were approved nearly simultaneously in blinding speed.  Idelalisib was the first to present randomized phase III study showing dramatically improved progression free survival (being alive and without progression) as well as improved overall survival against a control arm in CLL.  I think ibrutinib ended up crossing the finish line first because they got the early papers published more quickly creating a strong buzz in the literature. Idelalisib was sold from Calistoga pharmaceuticals to Gilead pharmaceuticals midway through the development.  This results in enormous changes on the development team that probably caused some regulatory delay while ibrutinib was held onto by Pharmacyclics all the way through development (sparing a joint venture with Jannsen). 

We are lucky in NHL/CLL that we have discovered an entire new PATHWAY in which many of the enzymes make good targets for drugs.  Since this pathway travels several key enzymes like Syk, BTK, PI3K, we will probably have a multitude of new drugs for these diseases.  Indeed, there are several BTK inhibitors, several PI3K inhibitors, several Syk inhibitors all working their way through development.   

What is so special about idelalisb?

I've had the opportunity to work with this drug quite a bit over the last several years all the way from the early phase I combination studies through helping the team at Calistoga write the main phase III protocols in relapsed disease.  I would like to highlight two patients I have treated with the drug because they both illustrate something really remarkable.

The first patient came into my clinic shortly after I started in Eugene.  He had some of the nastiest CLL I've ever seen.  He presented with a white blood cell count of about 140 thousand, enormous lymph nodes, and red blood cells and platelets so low that I had to transfuse him weekly.  Worse yet, all of his cells had the 17P deletion.

I started him on FCR but after two cycles he had made zero progress and indeed his transfusion requirement went up.  I gave him campath and rituximab which at least cleared his marrow enough to stop transfusions but he still had big bulky nodes and was considered ineligible for transplant.  From there we quickly cycled through R-ESHAP, R-Bendamustine, high dose steroids, revlimid and ofatumumab.  Unfortunately that list of drugs took quite a toll on him and he was back to weekly transfusions.   

We got him enrolled onto an idelalisib study and it was magic.  His white blood cells shot up immediately (typical for these drugs), and his nodes shrank.  His marrow began to "wake up" and we got him off of his transfusions again.  Indeed, he went two and a half years almost completely normal taking only his idelalisib before his disease became problematic again.  It was amazing to see him take advantage of the time this drug gave him - his life was completely changed by idelalisib in a way that was profoundly meaningful.

The second patient is an older gentleman with mantle cell lymphoma.  He had a few lines of therapy before his MCL became a problem and we got him enrolled into the first ever clinical study of ibrutinib.  He had several years of fantastic disease control on ibrutinib before he began having problems.  He developed a cough and was short of breath.  We found that one of his lungs had filled up with fluid from his lymphoma.  We sent the sample for analysis and found that he had the BTK Cys481Ser mutation that inactivates ibrutinib.  We were able to get him enrolled on an idelalisib study and that was over a year ago.  His lungs cleared up, cough improved, fluid was dramatically reduced, etc.

Zydelig is approved in combination with rituximab for patients with relapsed CLL AND as a single agent (no rituximab) for patients with follicular lymphoma / small lymphocytic lymphoma who have become refractory to rituximab AND alkalating agents (bendamustine, chlorambucil, Cytoxan).  Ongoing studies are likely to expand the circumstances where it is approved.

These are good times indeed!

Thanks for reading.

Sunday, July 13, 2014

ASCO Ibrutinib Update 2014

So I am a little late again.  I started writing this blog post on my way back from ASCO (6 weeks ago) but upon landing in the whirlwind I call life this was put on hold.  Take yourself back in time (at least 6 weeks) and this may seem like news that is "hot off the press."

As I make my way back from ASCO, it is hard to digest the pace with which CLL is changing.  In three years we have gone from the FCR supremacy to a coming tidal wave of well tolerated pills that are a lot easier to take and are seeking to both displace chemotherapy entirely and change the rules of the game.

Ibrutinib had a lot of important data and I thought I would just update a few things we learned.  Susan O'Brien presented the long term data from the original phase II ibrutinib study.  There were a few take home points:

1) In patients who have had 4 different rounds of chemotherapy on average who then went on this study, ibrutinib has probably saved many of their lives.  They were a really beaten up group of patients and many of them are still doing incredibly well after 3+ years on the drug.

2) Patients with 17P deletion really have the worst disease still.  Over half such patients who have been treated with ibrutinib have progressed.  While ibrutinib is likely better than anything else they could have gotten, this population will still likely need new agents.  Patients with 11Q deletion are also experiencing progression

3) There has occasionally been concern about risk of infections in patients treated with ibrutinib.  It looks like the longer you are on the drug, the better the immune system works because the rate of infections seems to go down over time.

4) The patients treated with ibrutinib in the front line have really done quite well.  While a handful of patients stop the drug early, those patients who are able to stay on the drug are doing remarkably well.  It remains to be seen if ibrutinib is better than chemotherapy in the frontline setting but with each new update of the data it gets more and more impressive.

Dr. Jennifer Woyach from Ohio State presented a poster that was simultaneously published in the New England Journal of Medicine about ibrutinib resistance.  It fits well with the data I've blogged about once previously.  Several things are worth noting:

1)  In "evolutionary biology" we think that any strong "selective pressure" likely has influence over the nature of resistance.  Ibrutinib binds to the BTK protein at a very specific location called "Cysteine 481."  The bond is very specific, so the way to get around that is for the cancer cell to change it's BTK at position 481 from cysteine to serine.  Ibrutinib has a much harder time binding to the protein and shutting it down.  Genentech has a drug they are developing that is supposed to "get around" this mutation and still inhibit BTK.

2) An alternative route to resistance is to activate an enzyme in the "signaling cascade" downstream of BTK.  PLC-gamma is just such a protein and can be artificially "turned on" by the cancer cell.  It is like the electrical circuit has a short and is locked in the on position below the level of BTK so ibrutinib still binds but doesn't stop the electricity.

3)  Neither of these are terribly common.  In the Ohio State experience, they have treated something like 250 patients and only 15% have stopped the drug because it wasn't working.

Dr. John Byrd presented the results of the Resonate trial in which patients with relapsed CLL were randomized to either ibrutinib OR ofatumumab.  Patients who progressed on ofatumumab could then receive ibrutinib (cross over).

1) Thank goodness for randomized data.  There were rumors about ibrutinib causing Richter's transformation and kidney problems.  When you don't have a similar group of patients observed under similar circumstances, you don't necessarily know the rate at which things actually happen.  Turns out that changes in kidney function while on ibrutinib are no different than kidney changes for patients receiving ofatumumab

2)  Ibrutinib beats the socks off ofatumumab.  The overall response rates (10x higher), progression free survival (80% better), and even overall survival (60% better) all favored ibrutinib.

3)  There did seem to be a slightly higher rate of atrial fibrillation (irregular heart rate) and possibly bruising / bleeding on ibrutinib which may be something to watch over time.  Sometimes it is hard to strike the right balance between blood clotting and bleeding.

4)  Multi-center data is NEVER as good as single center data.  I was surprised to see how high the number of patients that had stopped ibrutinib by the one year mark.  While it is still a relative minority of patients, it leaves a window for other drugs to be developed.  In some cases this was due to progression or in other cases patient / clinician choice.

We are hoping to have approval of idelalisib quite soon - another drug that makes a dramatic impact for patients with relapsed CLL.  It will be very interesting to see how we decide to use these two remarkable breakthroughs - perhaps a topic for an upcoming blog post

Thanks for reading.