Rituximab monotherapy in CLL

I expect this blog post is going to ruffle some feathers. I can’t wait to see the responses in CLL forum, ACOR and elsewhere.

Patterns of care databases report that during the course of CLL approximately one third of patients will receive mono-therapy with rituximab (ie. rituximab with NO OTHER CHEMOTHERAPY). In fact, it is one of the most commonly utilized therapies in the management of CLL but should almost completely disappear in light of new clinical trial data. Based upon information published within the last 6 months, I think any treatment recommendation for single agent rituximab should he held to some additional scrutiny.

I will admit that I have given this therapy a limited number of times in CLL/SLL before under circumstances where I thought it might be appropriate. In CLL/SLL I think rituximab monotherapy is mostly outdated as of late 2014. Newer drugs such as obinutuzumab and Ibrutinib or new combinations such as idelalisib with rituximab have taken the place of rituximab monotherapy and I have changed my practice patterns as a result.

I recently blogged about rituximab monotherapy in follicular lymphoma and highlighted several key papers published that show how well this immunotherapy drug works. I also blogged about how the addition of lenalidomide may alter the landscape of front line treatment in follicular / indolent lymphoma. Indeed, rituximab monotherapy in indolent NHL (follicular, marginal zone) is a good treatment and definitely appropriate in many circumstances - particularly low tumor burden disease. But what is true for some indolent lymphoma isn’t necessarily true for ALL indolent b-cell disorders.

Small lymphocytic lymphoma and chronic lymphocytic leukemia are often considered two different manifestations of the same disease. Indeed, they are often referred together as CLL/SLL and lumped in with the rest of the indolent lymphomas. But different lymphomas have different behaviors and the response to rituximab is one key difference. Unfortunately, many doctors don’t pay too close attention to this distinction.

Rituximab is often a very easy drug to administer (some uncommon exceptions apply). In most indolent lymphomas and even CLL, you can see things get better and everyone seems happy.  Both doctors and patients can be lulled into a sense that they are getting good therapy when they see things going the right direction – but good can sometimes be the enemy of better and may not be best in long term. 

When rituximab first came out as a new drug it was noted that it had fairly modest activity in the management of chronic lymphocytic leukemia. Response rates were lower than in follicular lymphoma and didn’t last as long. Two key papers were published in the Journal of Clinical Oncology in 2001 authored by John Byrd (linked here) and Susan O’Brien (linked here). Both of them looked at ways to increase the dose of rituximab in order to get a better response in patients with relapsed disease. Dr. Byrd's paper looked at more frequent dosing and Dr O’Brien’s paper looked at giving mega-doses. Despite these efforts the overall response rates were between 35-45% and generally lasted 8-10 months.
 
Two key caveats though should dampen even that modest efficacy. The first is that this was in a population that had largely not been exposed to rituximab previously. Rituximab works better in patients who have never received it before. Nowadays virtually all patients get rituximab added to their first line therapy. When their disease relapses, a sizable population is getting rituximab mono-therapy and it is less likely to work when used a second time. The second caveat is that in 2001 we had different criteria for response assessments and CT scans were not used the same way they are today. Since lots of patients have enlarged lymph nodes hanging out in their chest or abdomen that cannot be detected by physical exam, looking more closely with CT scan would influence the determination of response and progression.

To get a good estimation of how well rituximab or even ofatumumab actually works, I would suggest looking at the control arm of the recently reported studies that led to the approval of idelalisib and Ibrutinib (linked here and here respectively). In these studies patients were randomly assigned to one of the “tried and true” or one of the new drugs but looked at rituxan exposed patients and used CT scans to determine progression. In the rituximab alone arm of the idelalisib study, the lymph node response rate was only 6% and the median progression free survival was under six months. Those response rates are really lousy. In the ofatumumab alone arm of the ibrutinib study, patients didn’t fare much better.

CLL researchers look at the patterns of care data and look at the utilization of rituximab monotherapy with a measure of disdain. While in the past I might have argued back that CLL patients treated in academic centers are fundamentally different from those seen in community practice (an assertion which has good data to support). Indeed, community patients are on average older, have more medical issues, and less good baseline organ function, and several other key differences compared to patients seen in academic medical centers. In the past, I think you could have used that logic to support some utilization of rituximab monotherapy but new data sets strip that away.

So what are the key new data sets?

In previously untreated CLL, obinutuzumab is better than rituximab. These are both CD20 antibodies but obinutuzumab has a number of key modifications that make it more effective than rituximab. In a paper published late last year (linked here), the German group performed a three arm study comparing chlorambucil to chlorambucil in combination with either rituximab OR obinutuzumab. From progression free survival perspective these came in at 11, 16, and 26 months respectively with obinutuzumab the clear winner. If you only compared the chlorambucil arm to the obinutuzumab arm, you even saw an overall survival benefit (second paper to ever show this in CLL). I have heard some people argue that the better performance of obinutuzumab was just based on differences in dosing in the study.  I believe that is an argument made by people who are unfamiliar with obinutuzumab (gazyva).  Clinically, it is a very different drug and the differences in dosing are pretty minimal.

This study was in CLL patients that are more typical for the disease (average age 71). Of course chlorambucil is somewhat of a pariah in the US and many have asked whether it is even a necessary part of the regimen. I was recently at the International Myeloma, Lymphoma, and Leukemia conference in NY where this topic was the subject of a one hour debate (hot Friday nights in the CLL research world). Hard to debate the topic given the lack of published data in this space but our group led a large study of obinutuzumab monotherapy that was presented at ASCO (link here) and will hopefully be published soon. My take on the data: you get a little more bang for the buck when you add the chlorambucil but not clear it is worth the cost, particularly with the agents available now in the relapsed setting.

Two years of average benefit in this disease can be meaningful. It will even be more meaningful if we can apply molecular data to pull out the patients less likely to benefit as well. There is new data from two studies that suggest the presence of NOTCH1 mutations makes CD20 antibody therapy considerably less effective (FC vs FCR and Chlorambucil vs chlorambucil-ofatumumab). Not sure if it applies yet to obinutuzumab yet, but hopefully that data will come out soon. You can test for NOTCH mutations here.

The second key data set (linked here) led to the approval of idelalisib. In this study, patients received either rituximab alone or in combination with idelalisib – a twice daily, non-chemotherapy pill. The difference was striking. Instead of a nodal response rate of 4% it was 96% and the difference in progression free survival was improved by 82%. In fact the difference was so striking the study had to be terminated for ethical reasons because the difference in overall survival started becoming too obvious to ignore (which we were not expecting to be different for technical reasons attributable to cross-over study design). This was the third study ever reported to show that there could be a survival difference in CLL with a new regimen.

I fundamentally believe that there is a significantly sized population of CLL patients who are not appropriate for an aggressive chemotherapy regimen. Let’s face it, the average age at first treatment in CLL is between 71-74 years old. Many are much older. Tack on heart and lung disease or multiple other medications, arthritis, etc which is entirely common in the population and things like FCR are absolutely prohibitive and even bendamustine-rituximab can be a stretch. If a CLL patient TODAY received the recommendation for rituximab therapy alone, I think it would be hard to justify why idelalisib isn’t included (note, I do not put rituximab or ofatumumab in combination with ibrutinib outside of a clinical trial as there is some suggestion that the ibrutinib may make the antibody work less well).

The third data set (linked here) compared Ibrutinib pills to ofatumumab infusions. Here too, the differences were so striking the study had to be terminated before it was planned to do so. In clinical research you set out to conduct studies when there is a sense of “equipoise.” That means there is an honest uncertainty about the difference between two therapies that you need to prove. The difference between ofatumumab and Ibrutinib in this particular study shatters the possibility of equipoise – the differences are too overwhelming.  Response rates, progression free survival, and overall survival for patients treated with ibrutinib absolutely trounced ofatumumab.

So between these three papers the justification for rituximab monotherapy in either front line or relapsed CLL disappears. In front line, obinutuzumab is better than rituximab and in relapsed disease either adding idelalisib or swapping the two for Ibrutinib improve outcomes enough to fundamentally change the paradigm.

The remaining setting where CD20 antibody therapy such as rituximab or ofatumumab is used in CLL is as a “maintenance therapy” following some other chemotherapy. There have been several recent updates in this space and I think you could make a rational argument in support of maintenance though I’m not sure this is widely adopted in CLL treatment. I have provided a few links (here and here) but will leave this discussion for another time.

To summarize:

In previously untreated CLL, I think obinutuzumab has demonstrated sufficient clinical superiority over rituximab (either monotherapy or in combination with chlorambucil) to justify the swap in most cases - there is some debate about this point but I think the argument is settled.  To date, there is not enough published data to routinely combine obinutuzumab with drugs like bendamustine or fludarabine outside of a clinical trial.  

In patients with relapsed CLL, adding idelalisib to rituximab makes it work a whole lot better and Ibrutinib monotherapy trounces ofatumumab. Neither rituximab nor ofatumumab look nearly as good as single agents as we had believed in the past.

I anticipate the next several years of research will be about swapping out the various parts and putting them together again. Newer antibodies will be combined with newer pills and newer pills will be used earlier and earlier in the disease. It is a new era and we are quite fortunate to be in a time period where many of the “rules” are being re-written. Patients will live longer than our standard “prognosis” dictums and maybe we will even begin see a disease once considered incurable to be curable. Throw in BCL-2 inhibitors, CAR-T cells, bi-specific antibodies, and immune checkpoint inhibitors and I hope all patients will look to join in research studies so we can move the needle more quickly.

Thanks for reading

Immunotherapy for Indolent (low grade) Lymphoma

An academic mentor once told me, “scientific advances are a lot like a game of baseball.”  Curious, I asked him what he meant.  He shared with me, “most advances are like getting a base hit.  Doubles happen but are not terribly common, triples are rare, home runs don’t happen all that often and genuine grand slams change the field all together.” 

As I shared with him my idea of turning off B cell receptor signaling using pills, he told me, “Jeff, it sounds like you are swinging for the fences, and for our Stanford fellows, we are happy if you just crowd the plate and get hit by a pitch…”  Oh well, I suppose everything worked out fine, and I still don't really care much for baseball.  I wanted to compile the history of home-runs in the field to highlight just where we are and point out where I think we are going.

If you look back over the last 60 years of advances cancer medicine, there are only a handful of clinical breakthroughs in low grade lymphoma (indolent) that fundamentally re-oriented our treatment strategies in the disease and upended the status quo of the time.  It hasn’t necessarily been a story of slow and steady progress.  Instead there are discrete episodes that shred through the treatment landscape and when the dust settles, the field has evolved into something new. 

Cancer is a complex beast and many discoveries have only served to show us just how little we actually know.  While the progress is now exponential, so too is the amount we realize we don’t know.  Every so often something comes along that genuinely moves the needle and patients have longer and better lives.  I am very excited about an emerging story in indolent NHL and I wanted to help put in context a story that I think we are going to hear about very soon.

Here is my short list – for the interested reader, I highly recommend the book The Emperor of All Maladies.  It was written by one of my residency training classmates at MGH and has received the Pulitzer Prize.   It is a fantastic read. 

1)  Way back in the 1940's local radiation therapy was the only treatment available.  This really didn't work well in a disease that is typically "systemic."  Since we didn't know much about radiation dosing, patients were burned and burned again until their disease became "radiation resistant" and they died of massive lymph node enlargement or complications from radiation.

 2)  In 1946 we had the introduction of "chemotherapy" which actually spun out of chemical warfare research during WWII.  (The remarkable story of America’s “Second Pearl Harbor” and the birth of chemotherapy is one of the most amazing little known stories in medicine). Patients with lymphoma were the very first to be treated with modified versions of mustard gas.  Responses were short-lived but merely 15 years after the introduction of penicillin the idea that “medicine” could treat cancer was born.

3)  In the 1950's the drug Adriamycin was isolated from a soil sample of a 13th century Italian Castle and subsequently was shown to be effective in lymphoma.  This drug became a "backbone" of many treatment strategies in lymphoma and is still commonly used today.  It is the “big red” drug that makes many lymphoma patients lose their hair but is also commonly used in breast cancer, gastric cancer, sarcoma’s and other diseases.

4)  For the next several decades, progress was built in many small steps.  New drugs were found, developed, and tested one at a time. Vincristine was isolated from the Madagascar Periwinkle, Etoposide was isolated from the “mayapple” and so forth.  Multiagent drug cocktails were assembled and tested.  When you put as many drugs together as you possibly could, you got crazy names such as M-Bacod (6 drugs), Pro-Mace-Cytabomb (8 drugs), and CODOX-M-IVAC (7 drugs).  While some of these were for more aggressive lymphomas, each had their loyal adherents and debates raged without much comparative data. That all ended however in 1993 CHOP (4 drugs) was declared the winner over several more "intensive" regimens.

5)  In 1997 we saw the introduction of rituximab in lymphoma.  This was the first time we used a therapeutic antibody (like the ones your body makes to fight the flu) to treat cancer.  Rituximab administered alone has impressive single agent activity and has become increasingly utilized as monotherapy.  It was also quickly added to CHOP to make the R-CHOP regimen.  This was the first "chemo-immuno-therapy" regimen and led to substantial improvements in long term outcome of patients with both low grade and DLBCL.  Until 2007, patterns of care data indicate that if you were going to get chemo for follicular lymphoma, 50% got R-CHOP, and another 25% got the same regimen without the Adriamycin which adds quite a punch in terms of side effects (R-CVP), and about 15% received rituximab alone.

6)  In 2008, there was a US based study of a drug that had been floating around East Germany during the entire cold war yet remained unknown to western cancer doctors.  This was the first that most US docs had heard of Bendamustine. The data was quite impressive for how effective the drug was compared to standard alternatives.   In 2009, the German lymphoma study group initially presented data at ASH comparing bendamustine-rituximab to R-CHOP in follicular lymphoma.  It was actually only published in Lancet last year.  This showed improved efficacy with bendamustine, and far reduced side effects which led to the sweeping changes in patterns of care.  Bendamustine with rituximab has upended practice patterns.  In the last two years, US patterns of care data reveals approximately 1/3 of previously untreated follicular lymphoma patients needing treatment receive Bendamustine-Ritxuximab, 1/3 receive rituximab alone, and only about 1/5 receive R-CHOP in front line treatment and virtually nobody receives it following relapse.  Fludarabine utilization is virtually gone (see attached slide presentation at the bottom of this post and my post on "How I treat follicular lymphoma). 

7)  As ASCO 2007, our lab at Stanford presented the first “pre-clinical” data showing that inhibition of B-Cell receptor signaling enzymes could have therapeutic effect in B cell malignancies.  This  theory was subsequently confirmed in a plenary session presention at ASH in 2008 utilizing the drug fostamatinib.  The discussant at the time felt that the data met the criteria for “game-changing” and put it on his list of NHL history makers.  While fostamatinib is no longer being actively developed, the proof of concept directly preceded / led to the exploration of ibrutinib and idelalisib in similar diseases.  In heavily pretreated patients, both of these drugs have approximately 50% overall response rate (size criteria for response determination, many more actually shrink and benefit – just not enough to be considered “partial response”) and average a year of benefit for responding patients.  Idelalisib was recently FDA approved in follicular lymphoma and we await data on ibrutinib in this population.  While the impact in follicular lymphoma remains an evolving story, the impact in chronic lymphocytic leukemia and small lymphocytic lymphoma is nothing short of transformative. 

8)  I believe story 8 in indolent lymphoma will be “immunotherapy."  Rarely a day goes by where I am not asked by a patient, “is there anything I can do to boost my immune system.”  While my answer has always been, “not really” a number of very important new therapies are showing that harnessing the power of the immune system to attack cancer can be extremely powerful.  Drugs have been either approved or are soon to be approved in melanoma, lung cancer, kidney cancer, and bladder cancer that help the immune system identify and destroy the cancer cells – without using chemotherapy.  Some of these are antibodies that interfere with the “on/off” switches of the immune system.  Others “re-program” T-cells using engineered viruses that can go absolutely crazy on B cells (see amazing video here).  The most accessible and perhaps most exciting of these for patients with indolent lymphoma may very well be the combination of revlimid with rituximab.  There are several very important studies that are poised to position this combination at the center of treatment pathways for patients with follicular lymphoma.

Nathan Fowler’s data from MD Anderson – link here (expecting updates at publication)

Nearly completed study in frontline follicular lymphoma Rev-Rituximab vs R-Chemo – link here

Open study of Rev-Ritux in relapsed follicular lymphoma – link here

I think of the combination of revlimid-rituximab (also called R2) as a road trip with a pot of coffee and a map.  Rituximab helps orient the immune system to go after the cancerous b cells by coating the outside of them and serving as an alarm for the T cells (like a road map).  Revlimid (lenalidomide) helps overcome what has been called T-Cell “pseudo-exhaustion” and get them to reactivate (ready for the road).  B cell cancers have a remarkable ability to “put the t cells to sleep.”  Whether though secretion of hormones, or actually manipulating the on/off switches of T cells, the cancerous B cells literally put the other half of the immune system into a post thanksgiving meal food coma.  Revlimid acts like a cold splash of water to the face for the sleepy T cells.  Not bad for a drug that really isn’t chemotherapy but is considered an “imid” for – immunomodulatory drug.

The combination has been explored in CLL.  It can be so active at times that there can be problems with tumor lysis syndrome.  The combination is not approved by the FDA in this setting and should be utilized very carefully due to the associated risks.

The combination has also been explored in follicular lymphoma with some pretty spectacular results… and that will be the subject of an upcoming post!

Thanks for reading

(Patterns of care data and a nice view of the Sisters volcanic range in Oregon from Mt Bachelor Ski area)

Treatment patterns in indolent nhl from Jeff Sharman

Rituximab monotherapy in follicular lymphoma

When patients are diagnosed with follicular lymphoma, the treating doc often uses the “eye ball” test on the CT scans, blood work, and physical exam to figure out whether or not a patient has “a lot” or “a little” follicular lymphoma.

While the “eyeball test” is an approximation that requires individual physician judgment (ie. subject to considerable error), such measurements have been codified by what we call the “GELF criteria” which is a French acronym for “groupe d’Etude des lymphomes folliculaires” (ie. French study group of follicular lymphoma).

You are considered “low tumor burden” provided you lack any node > 7cm, have less than three nodes areas > 3cm each, no B symptoms (night sweats, fever, weight loss), spleen below the belly button, circulating follicular lymphoma, or bone marrow dysfunction from involvement (and a few others).

The distinction between “low tumor burden” and “high tumor burden” is relevant because clinical trials often distinguish between such patients in terms of the appropriateness of certain therapies (see: how I treat follicular lymphoma part 1 and part 2).  Patients with “low tumor burden” follicular lymphoma have been studied in studies such as “rituximab vs watch and wait” or the Resort trial (how much rituxan alone do you need), or even the SAKK study (some rituxan vs some plus more rituxan) whereas patients with high tumor burden are more likely to be studied in chemotherapy type studies such as bendamustine-rituximab vs R-CHOP type studies or perhaps other new study designs.

I wanted to focus on the “low tumor burden” population because I was preparing a talk and thought there were a number of important statistics that such patients should be aware of.  I want to simply list them here for your consideration.  They are drawn from three main studies linked here:

Rituximab vs Watch and Wait

Resort Trial (Induction and Maintenance vs Induction and Retreatment when needed)

SAKK Trial (Four doses in one month vs eight doses in nine months)

From the study of “rituximab vs watch and wait”

Approximately 20% of patients with asymptomatic advanced stage disease can be followed for over 10 years without requiring treatment

Thus far NO study has shown that starting treatment EARLIER (ie immediately at diagnosis vs when needed) improves overall survival (very few studies have ever tried to prove this point

Patients who undergo watchful waiting may experience spontaneous regression in 12% of patients by two year mark evenly split between ones that completely disappear from CT scans and ones that partially disappear (in no case do we think the body has “cured” it, we just can’t detect it on scan

40% of patients with low tumor burden follicular lymphoma on watchful waiting will have growth of their lymphoma by two year mark.

Between 80-90% of patients with low tumor burden follicular lymphoma who receive rituximab will experience a response when evaluated several months post treatment

Between 10-30% of patients suitable for watch and wait yet receive rituximab will experience progression within 24 months (partially depends on how much rituximab is given)

Despite responses seen following rituximab, after following patients on average four years after randomization there is no apparent difference in overall survival or rates of histologic transformation between patients assigned to watch and wait versus rituximab (perhaps will change when data more mature?)

The average time a between diagnosis and disease progression when following watch and wait is approximately two years.

The patients who have most emotionally stable reaction to their lymphoma are patients who start rituximab and then continue on maintenance compared to those who take four doses and stop or those on watch and wait.

From the RESORT study (Rituxan followed by rituxan maintenance versus four doses or rituxan and rituxan re-use when needed)

In the average patient with low tumor burden indolent lymphoma who starts rituximab (whether with maintenance or reuse) it will work for about four years before something new is needed.

Patients who stay on maintenance rituxan are less likely to have disease progression, but those patients who “reuse” rituxan are often able to keep the disease under control for about same amount of time and use less rituxan (about 75% less rituxan)

From the SAKK study (which compared four doses of rituximab over one month versus eight doses over nine months in both previously treated and untreated follicular lymphoma)

If you don’t respond initially to rituxan, continuing it for four more doses doesn’t help

In previously untreated follicular lymphoma patients who respond to rituxan and get total of eight doses, almost half have not experienced any progression by 8 years compared to about a quarter of patients who only get four doses

There is a trend that does not reach the level of “statistical proof” that any patient with follicular lymphoma who gets eight doses compared to four might have better overall survival.  Caution here – not clear if this is real or statistical chance just making it look better

Long story short, you can slice and dice this info to do just about anything you want it to mean.  In my own practice, I generally start with rituximab once per week for four weeks then give one dose every other month for four more doses if I am starting rituximab alone in previously untreated patients.  I would not strenuously argue with others if they did it differently.  Here are a few key slides that come from the representative papers as well as a beautiful view of Mt. Washington in the Cascades east of Eugene

Rituximab Therapy in Follicular Lymphoma from Jeff Sharman

More on Gazyva (Obinutuzumab)

Genentech / Roche put out a press release this morning about the German CLL11 study that we have talked about several times previously.  American Society of Hematology meets in December and the abstracts were just released - hence the multiple press releases you will see in the news.

The drug was approved last week for the front line treatment of "typical patients" with CLL (they tended to be older and sicker than the FCR crowd).  Our center has had the opportunity to study the drug extensively and in the surrounding news coverage, one of my patients was featured in local news.  I think it is a nice story about a person taking the drug.  I encourage you to watch it (note this was different study design than CLL11, there was no chlorambucil in this study).

The reason for the press release today is the big news that we had been expecting / waiting for to show that GA-101 (obinutuzumab, gazyva) looks like it did quite a bit better than rituximab.  If you recall, at ASCO, they did a presentation where they compared chlorambucil (C) alone to C-Rituximab and a second comparison of C alone to C-Obinutuzumab.  They did not release the comparison that everyone wanted to see which was the C-Rituximab versus C-Obinutuzumab.  That is what is in the press release and will be presented in the plenary session at ASH in December.

The "progression free survival"  is actually two separate criteria: 1) alive AND 2) no relapse of CLL.  In the C-R arm the rate was 15 months and in the C-G arm it was 26 months - a full year better.  The rest of the data will need to wait for the presentation - can't wait to see it.

Thanks for reading

GA-101 aka. obinutuzumab in CLL

I love it when a drug comes out of nowhere to suddenly become the hottest thing around...  The latest recipient of that distinction is obinutuzumab.

The annual mega-conference ASCO (american society of clinical oncology) starts up in the last few days of this month.  There are a few big papers for CLL/NHL patients.  I hope to capture the highlights over the next few weeks as I put out updates.

One thing to be VERY careful about is the misuse of the term, "significant."  There is a huge difference between something that is "statistically significant" (ie. a comparison in which the results are unlikely to have occurred by chance) and "clinically significant" (ie. this makes a genuine difference for patients with the disease).  Read my prior post about how things get mischaracterized as "significant."

So what are the big updates this year?

Ibrutinib is in a data lull between the mature reports of the early studies and the ongoing registration studies that have not yet reported.  There is a fantastic piece about ibrutinib resistance that I put up a few days ago.  Idelalisib is still reporting out the mature results of early studies.  Phase III trials are ongoing.  I've been after them to get their phase I studies published but they have been quite slow getting those out the door.

GA-101 (also named obinutuzumab) has a very important presentation.  Rituxan comes off patent pretty soon - hopefully that would lower drug costs (although in this case - maybe not so much).  While the regulators and industry are all tied up in knots over how to make a generic antibody - Roche has set out to make a better version of the drug - see my post on building a better CD20 antibody.

Our first peak into the "efficacy" of GA-101 came last year at ASH where it was compared straight up head to head with rituxan in relapsed indolent non-hodgkin's lymphoma.  Patients got a dose of either drug once per week then once every two months for two years.

There was a suggestion that patients in the GA-101 arm had a higher response rate compared to rituxan.  Unfortunately when you figured out how long the responses lasted it was pretty equal for both groups.  It was interesting to watch the response.  I think the sponsors were excited to see the increased response rate but a lot of investigators sort of yawned.... yup, just another CD20 antibody - not much to see here.

That is why this ASCO presentation of GA-101 in patients with CLL is so exciting - there is something really different here!

GA-101 was studied in the German CLL 11 study.  This was a three arm study in which chlorambucil was compared to chlorambucil in combination with either rituximab or GA-101.  The study included elderly (average age 73) individuals with decreased kidney function (necessary for fludarabine elimination from the body), or a bunch of other medical problems as defined by the Cumulative Illness Rating Scale (CIRS). 

Addition of either rituxan or GA-101 thumped chlorambucil doubling the overall response rate from 30 to 60-70%.  Complete response rate with chlorambucil came in with a whopping 0%, adding rituxan took it to 8%, and GA-101 got it to 22%.  While the increased response rate was encouraging you could say that was the same in the other study listed above that wasn't quite as exciting.

The key to this being something really new was that the progression free survival went from 10 months with chlorambucil to 15 months with rituxan and 23 months with GA-101.  To me that indicates that GA-101 is really doing something new / better than the stalwart rituximab.  Infusion reactions were a bit more significant with GA-101.

For a variety of statistical considerations they did not directly compare the rituxan group to the GA-101 but looking at the raw numbers things look good for GA-101.  In fact Genentech looks pretty happy with the data and sounds like the drug has been labeled "breakthrough drug" with the FDA indicating a fast track for approval in near future!

GA-101 has been circling around under the radar for a little while.  While the stories of patients on the new B Cell receptor inhibitors have been very exciting, I don't think there was quite the buzz out there for this drug.  I love it when we get a nice surprise!

Building a better CD20 antibody?

Rituxan was an unbelievable breakthrough drug in the treatment of all sorts of B cell lymphoid cancers (CLL / NHL) as well as a lot of autoimmune conditions to boot.  At the time it was put into the patients, the idea of using therapeutic antibodies to treat cancer had not really been done.  Skeptics abounded.  As soon as it was tried, it was immediately obvious that there had been a breakthrough.  One theme I continually revist is that the immune system can be a very powerful cancer fighter when properly directed.  Rituxan was one of the first ways to focus this aspect of the immune system to fight off lymphoma.

You make antibodies to fight off the flu, e. coli, etc.  Instead of the naturally occuring variety of antibodies, rituxan is a synthesized antibody designed to fight off B-Cells (ie. the cells that give rise to lymphoma and CLL).  Rituxan binds onto the outside of the cancer cell (on a marker known as CD20) and has about 4-5 ways to kill the cell. 

15 years later, hundreds of thousands of patients have been treated.  As a single agent nearly 70% of patients with untreated follicular lymphoma will respond and in many cases the responses can be very durable.  In most situations where giving chemotherapy for CLL/NHL is good, giving it together with rituxan is better.  Not bad for a drug that has few of the side effects of traditional chemotherapy!

Not long after Rituxan demonstrated its value, lots of science went toward understanding why rituxan does or doesn't work.  With the accumulated knowledge, different companies have sought to make a better version of the drug.

Ofatumumab was the next CD20 antibody to be approved.  The main improvements in ofatumumab was more sturdy binding to CD20, binding at a different location on CD20, and a better job "fixing complement."  Complement is a set of "executioner proteins" that get recruited from the circulation when there is enough antibody bound to the outside of a cell.  "Fixing complement" just means it does a better job attracting those proteins to bind to the outside of the cell and punch holes through the membrane.

GA-101 is an ant-CD20 antibody currently in clinical trials in both CLL/NHL.  GA-101 (aka obinutuzumab) does several things new.  It binds to CD20 in a different orientation.  Imagine an antibody like the letter "Y"  The top of the "Y" is the little "grabber" part that identifies its target while the bottom part of the "Y" sticks out and alerts the immune system.  GA-101 binds more vertically which sticks the action end out there better for the rest of the immune system to see.  Rituxan binds more flat to the cell and the action end sort of gets burried on the surface of the cell.  GA-101 also has a more flexible "hinge region" (where the "Y" splits) which is supposed to help bring together the different proteins better.  GA-101 also "engineers out" the complement activity and instead "engineers in" better ADCC.  ADCC (antibody dependent cellular cytotoxicity) is the term that describes when a "killer cell" attackes a target cell because it is coated with antibody.  Finally there is a somewhat poorly characterized process by which antibodies can cause direct cell killing.  This is supposedly enhanced by antibodies known as "Type 2" antibodies (not really worth explaining this one, except that Rituxan / Ofatumumab are Type 1)

So far, there are not a lot of studies that clinically compare the different anti CD20 antibodies head to head.  Ofatumumab initially tried to get an FDA approval in follicular lymphoma patients considered refractory to Rituximab.  Results didn't really impress all that much.   Based upon FDA approval strategies, it also tried to gain approval in CLL patients were refractory to fludarabine AND campath (or bulky fludarabine refractory where campath doesn't work well).  This worked better and led to the approval of ofatumumab in CLL.  The drug has not yet gained a high utilization in CLL. 

GA-101 is owned by Genentech and with Rituxan likely to go off patent in the future, they are working hard to make GA-101 the standard-bearer.  At ASH 2011 there were a lot of clinical papers with GA-101 but the most notable was a head to head comparison of GA-101 to Rituxan in patients with relapsed follicular lymphoma.  GA-101 had twice the response rate though the duration of response was not a lot different.   Hard to say if that is a glass half full or half empty - trying to extrapolate to different NHL / CLL situations it may depend on the context.  Increasing a response rate in DLBCL might be very important whereas PFS prolongation may be more important in follicular lymphoma.  Furthermore, we should probably consider that the activity of one antibody may be better in CLL while a different set of characteristics may make a different antibody better in follicular lymphoma.

Perhaps the cleanest way to figure if a drug is active is in the previously untreated patients.  Ofatumumab was studied in this setting and reported at ASH.  GA-101 has been evaluated in front line CLL and I found this news story anecdote to be pretty exciting though you must be very careful with anecdotes and no formal reports are available.  Rituximab was evaluated in relapsed patients way back in the early 2000s with pretty modest single agent activity, though improved with higher dosing of the drug or greater frequency (another way of increasing the dose). 

You can bet you will hear a lot about "better versions of rituxan."  Look for head to head comparisons or results that are substantially different from prior series.  Rituxan was definitely a pioneer, but I fully expect we will be able to build a better treatment.  Here is a review published in ASH that goes over a lot of the information above and describes some of the other strategies to improve upon rituxan.