Conferences | Pharma Strategy Blog

Tumor Lysis Syndrome – what is it and why is it important in cancer research?

By MaverickNY on February 18, 2013

After the hullabaloo on Friday regarding AbbVie’s suspension of the ABT-199 trials following not one, but two, unexpected deaths from tumor lysis syndrome (TLS), a few people asked what is this condition and what causes it?

In simple terms, lysis is a medical word used to describe the break up or breakdown of cells – whether through decomposition, destruction, or dissolving. Thus, we have hemolysis, which is the destruction of red blood cells with the release of hemoglobin.

Tumor lysis, however, is a medical emergency whereby the sudden production of massive amounts of potassium, phosphate, and nucleic acids into the systemic circulation overwhelms the body’s garbage disposal units, the liver and kidneys. Urgent hospital treatment is usually required, often diuretics can be helpful to flush out and dilute the excess potassium (too much can slow or stop the heart beating), but sometimes kidney dialysis is also needed to speedily remove the excess production of the potassium. Death can unfortunately (but not always) result.

TLS is most common in aggressive, fast growing (high grade) lymphomas and acute leukemias (e.g. ALL), but is less common in indolent disease such as chronic lymphocytic leukemia (CLL).

Given that AbbVie were testing their Bcl2 inhibitor in CLL, where TLS is rarer, some might think two deaths from TLS a surprise, especially given the positive results reported at the recent American Society of Hematology (ASH) meeting in December (more about the ABT-199 data).

This is not the first time TLS has been reported in leukemias though. Carl June (U Penn) presented the data on their chimeric antigen receptor therapy (CART), a collaboration with Novartis, in CLL and also childhood acute lymphoblastic leukemia (ALL) at ASH. Their lead therapy, CTL019 (formerly CART19), also leads to TLS in both ALL, where it is more common, and CLL patients, although he did state in the Ernest Beutler lecture that the patients received urgent renal dialysis and recovered.

Interestingly, Dr June described the TLS as occurring not immediately, but delayed until 20-50 days post infusion. Given what we know about autologous cellular immunotherapy, a delayed response is not a surprise, but in line with our scientific knowledge to date, since it takes a while post apheresis to activate the T-cells.

You can see from Dr June’s slide that the serum levels of creatinine and uric acid spiked around day 20, but the patient was hospitalized for TLS a few days later:

It is possible that the TLS occurs in CLL as a result of rapid efficacy and on target effects – in other words, the treatment is doing it’s job of killing the cancer cells, perhaps a little too well.

Final thoughts…

We will have to wait and see what happens with the larger randomized phase 3 trials for both ABT-199 and CTL019:

We don’t yet know whether the effect in ABT-199 is a dose-schedule issue or a compound structure issue (especially given the reformulation from the original navitoclax molecule).
If TLS is a persistent toxicity issue and efficacy is durable, then it may well limit both potential treatments to Academic centers with experience and resources to quickly monitor and treat such sudden events in future.
These are exciting molecules but care is clearly needed in managing the toxicities.

Contrast these approaches with ibrutinib, a tyrosine kinase inhibitor that targets Bruton Kinase, where the effects appear to be slow but steady inhibition of a key target driving CLL proliferation. TKI therapies are very Community oncology friendly in comparison, particularly for indolent diseases. Although the Bcl2 and CART therapies look very promising, they may need a more careful and judicious approach to reduce the risk of sudden deaths from TLS.

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Making a difference in Advanced Prostate Cancer – an interview with Bertrand Tombal

Since 2010, we have seen several technological advances in therapies for metastatic castration resistant prostate cancer (CRPC), leading Professor Bertrand Tombal (an Academic urologist in Brussels, Belgium) to describe 2011 as a Grand Cru year for CRPC at the European Society of Medical Oncology. One of the most promising therapies in this category was enzalutamide (Xtandi) from Medivation.

Enzalutamide is an anti-androgen receptor antagonist similar to bicalutamide, but differs in that it is a more potent inhibitor and has no agonist properties. Initially, it was approved by the FDA post chemotherapy but trials are currently ongoing in the pre-chemotherapy setting.

In patients with advanced prostate cancer with hormonally-sensitive disease, the treatment choices can be fairly stark – active surveillance (for low risk patients), surgery (for resectable disease), radiation (risk of long term side effects) and/or androgen deprivation therapy (ADT) for high risk patients with rising PSA. When ADT fails and PSA rises dramatically again, then men may receive an androgen receptor antagonist such as bicalutamide. An advantage of bicalutamide is that it avoids medical castration and has been shown to have a favourable safety profile compared to ADT.

ADT is useful for controlling PSA levels in high risk patients, but it is not without complications, as Prof Tombal discusses below and explains why there is a need for an alternative approach:

In US, however, ADT is more commonly used in high risk patients than bicalutamide.

The most obvious question though, is how might enzalutamide compare with bicalutamide in the advanced prostate cancer setting? To find out about progress here, I interviewed Prof Tombal about his poster being presented at the ASCO Genitourinary meeting yesterday.

PSB: How would you describe the rationale behind your study?

Prof Tombal: The first thing that is important is what is the philosophy of the clinical trial? There has been a lot of activity in medical treatment for prostate cancer with new drugs like abiraterone, Jevtana, new chemotherapies, a vaccine, but what they all have in common that they are used in patients who are failing hormonal treatment. Today, hormonal treatment worldwide is basically medical castration, meaning that you suppress the testosterone in the whole body to get an effect on the prostate and the metastases.

The idea was to test enzalutamide, not the way it is used and prescribed now in patients who fail androgen therapy, but in patients who have never received androgen deprivation therapy. There was always the hypothesis that it might not work for unknown reasons. So we took patients who needed hormone therapy, some of them were already quite advanced, and we gave enzalutamide alone.

PSB: What kind of results did you see?

We were extremely impressed by the amplitude of response of these men. If we look at the PSA decrease, when we did that hypothesis that if 80% of the men would have a good PSA response, we would potentially have a drug with some future in that setting. But it’s not 80%, it’s much more than that. Almost all the men responded extremely profoundly to the drug with a sharp decrease in PSA, and with a toxicity that apparently is less pronounced than with androgen deprivation therapy.

The hypothesis that we might have a drug that could eventually replace androgen deprivation therapy, we now we know that the idea seems to be working and we are now saying OK, now we might have a compound simply to replace androgen deprivation therapy in all these men who need it and suffer from side effects.

Now it is creating a new paradigm because now we have to think about how we are going to develop this in the next 4 to 5 years. What is striking with the result is that actually enzalutamide is the only drug you can use as an alternative. If you think, for instance, about Zytiga/abiraterone, it needs to be used with hormone therapy, it will never replace hormone therapy. Here it is a short series (of treatment) but you have to understand we went totally blind in that patient population.

What we can say about the results is that it is far beyond any expectations we made when we planned the trial.

PSB: How would these results compare with what you would expect with bicalutamide?

Prof Tombal: In Europe, bicalutamide is registered and we still use it. If I take for instance, my personal patients, I would say 10-15% of the patients are treated with bicalutamide monotherapy.

The problem with bicalutamide is that we know that the PSA drop is never what we see with LHRH agonists; we know it is a good drug, but the trial I have indicated, that it was a chemo-equivalent only for patient with minimal disease.

Although we have no direct comparison, but we have historical comparison in Europe because we use bicalutamide a lot. If we just look at the PSA drop for instance [with enzalutamide], it is apparently much more profound than [we normally see] with bicalutamide. That is clear.

From the patients in the trial, we have observed objective tumor shrinkage, and sometimes very impressive one, something we have not seen very well with bicalutamide. We have no direct comparison, but it is clear from my perspective that it compares well with bicalutamide in terms of side effect profile because there is no castration syndrome, there is a little bit of gynecomastia, little bit of fatigue, things that are extremely well tolerated by the patient in comparison to LHRH agonists.

But the tumor response, seems – and I do insist – much better than with bicalutamide.

PSB: So will you be planning any other head to head trials with bicalutamide or the LHRH agonists?

Prof Tombal: The problem of drug development is that actually the leading dancers are the regulatory authorities. If you go to EMA, European Medicines Agency, because bicalutamide is accepted we could easily plan a trial head to head bicalutamide versus enzalutamide. The problem is that FDA never registered bicalutamide, so we have to see how they are going to behave. There are plans to conduct a trial, but the exact design of the trial, and we can’t do nothing about this, will be decided by FDA. We don’t even know right know whether it is going to be one global trial, or trial made for Europe and the US.

Interestingly also, in contrast to all the agents that have been developed in castration resistant prostate cancer, nobody has ever gone to FDA with a modern plan saying these are the problems, these are the compounds. We don’t know how they will react.

Clearly if I had all the money and all the patients, the ideal trial would be a three arm trial comparing standard hormonal treatment to enzalutamide to bicalutamide. Because, if we do that then we could really have the answer both in term of survival and in term of quality of life.

I am a urologist by training, so most of the patients I see, I would say even 85%, they won’t die from the disease. Those who have aggressive disease are seen mostly by medical oncologists. The medical oncologist concern is primarily to increase overall survival. Where my concern as a urologist is to get a similar overall survival, to keep the good result we have right now, but lower the toxicity. If I want to answer both questions at the same time, the ideal would be a three arm trial to get all the information on the quality of life and overall survival.

PSB: I think the three arm trial would be most optimal and give the definitive answer

Prof Tombal: That would be the more elegant and would be the one that would be the most scientifically satisfying.

PSB: Are there any other combination trials with enzalutamide in that setting that have piqued your interest?

Prof Tombal: If you give me $1 million dollars and ask we what is the best combination, I would say it is enzalutamide and radium-223. Because, we know something in prostate cancer, it is that there is something magical that is happening when you combine radiation therapy and hormonal treatment. That is where androgen deprivation therapy has been shown to increase overall survival. All the trials done by SWOG, EORTC and early work back in the 70’s showing that if you hit the cell with some form of DNA breaking mechanism like radiotherapy plus hormone therapy you have got something magical.

To me, the association of a very effective anti-androgen and radiation therapy is something I want to see. One of the advantage on top of that is that these two drugs do not require corticoids and are extremely well tolerated. So this is really an association i don’t fear. Radium-223 is well tolerated. In all these men we identify now with oligo-metastatic disease, combining these two drugs, give me the drug, give me the money, I would be extremely interested.

PSB: Is that trial planned at all?

Prof Tombal: I think both Bayer and Medivation are speaking to each other, so I am quite sure it is going to be planned sometime.

Additional notes…

Although I spoke to Prof Tombal prior to the meeting, I was quite unprepared for the sheer impressiveness of the waterfall plot, which showed a PSA response (i.e. a reduction > 80%) at 25 weeks of 92.5% with a fairly narrow CI (86.2-98.8%).

In a previous interview, Charles Sawyers, the co-inventor of enzalutamide discussed its potential development, including the translational opportunities beyond CRPC in earlier disease.

It looks likely, with these latest results, that enzalutamide has clear activity in advanced (hormonally-sensitive) prostate cancer and a three arm trial, as suggested by Prof Tombal, would actually answer the key question of which therapy would be the optimal solution in this setting. Hopefully, we will see more advances in this area emerge over the next couple of years. If successful, this would be a large potential market opportunity for enzalutamide, potentially much bigger than the CRPC setting before or after chemotherapy.

Making a difference in pancreatic cancer – an interview with Dr Hedy Lee Kindler

Pancreatic cancer is one of those conditions I never hope to get. Why? Well, for starters, it’s one of the most difficult to treat tumour types, largely because so many patients are detected late, that is with stage IV metastatic disease. The annual incidence and prevalence are pretty much equal, suggesting that the for many with advanced disease, the lifespan is approximately one year or less. In fact, to put things even more succinctly, despite surgical resection, radiation and chemotherapy, more than 90% of people with pancreatic cancer do not survive beyond 5 years.

Over the last few decades we’ve seen a few incremental improvements from the original trials comparing 5FU (fluorouracil) and gemcitabine (GEM) to various gemcitabine based doublets and triplets such as oxaliplatin (GEM-Ox), docetaxel (GTX) and erlotinib. Things improved a little in 2010 though, with the landmark trial for FOLFIRINOX (5FU, leucovorin, irinotecan and oxaliplatin) being presented at ASCO, although the nasty toxicities involved tend to limit this regimen to fit patients with an excellent performance status being treated in Academia rather than the Community setting.

In between these two events, we saw multiple promising GEM-based doublets fail repeatedly after initial promising phase I/II data. It was a dismal period for pancreatic cancer researchers and clinicians.

With the advent of new data being presented at the recent ASCO Gastrointestinal meeting in San Francisco, I chatted with Dr Hedy Kindler (Associate Professor of Medicine, University of Chicago) who is well regarded as a pancreatic cancer expert and sees a large number of patients for this disease each year, about the advances in advanced pancreatic adenocarcinoma.

PSB: Very few of the doublets in combination with gemcitabine have succeeded, I think erlotinib was the only combination that got approved. So the first question to you is, what are you excited about now, what are the new things that are interesting in this disease?

Dr Kindler: The last time we spoke was in 2005 or 2006 – a lot has changed since then and Margaret Tempero summarized this very well today in her discussion about the changes over that period of time.

What did Dr Kindler like about the FOLFIRINOX data? Listen to the audio clip below to find out more:

Dr Kindler: Initially, the trial flew under the radar, many of us were not expecting that this was going to be such a positive trial. When we looked at the combination of these four drugs, it looked quite scarily toxic. For many of us, we chose our first few patients very gingerly. For me, my very first patient I used was a radiation oncology nurse in my center who I knew could be compliant, was performance status 0 and was incredibly healthy, and who I could monitor like a hawk.

Over time, I have learned that I can give this, not only to the perfect PS0 but to the PS1’s. I know that I can say with confidence to most patients, you can respond to this and we will gain disease control. We never had that with gemcitabine. You would expect after a few months that the disease would progress and they would feel minimally better. But now, we are seeing dramatic responses. We are extending this not only from metastatic, locally advanced, to many of those borderline resectable patients who are being transformed into resectable patients.

What is exciting with today’s meeting is that we are seeing that FOLFIRINOX Is not the only kid on the block and that the GEM/Abraxane data also shows activity. Certainly the Phase1/2 of GEM/Abraxane looked very exciting, but we’ve, all of us have learned that phase 2 results don’t always pan out to phase 3. It is very nice to see another regimen that shows activity. There is a caveat, 8.5 months is not 11.0 months. There is a difference between the two regimens, there is also a difference in the patient populations.

We can’t broadly say GEM/Abraxane is definitely inferior or definitely less toxic than FOLFIRINOX. As I look as how I am going to use the regimens, for the most part, the data today don’t change the fact that for most of my patients I am going to use FOLFIRNOX, because that is the regimen that has the higher response rate and that has the longer median survival, for most of my good performance status patients.

Will there be patients in whom I use GEM/Abraxane? I am eager to use it, l am eager to learn more about it, but I think it represents a new choice and not merely a new standard. Now I think what we are also going to learn over the future is that there will be certain patients who biologically it is better to use GEM/Abraxane, and as we get the SPARC data that may tell us. As we get other data on FOLFIRINOX we may determine that there are certain patients who should only get FOLFIRINOX. I think that is what we are going to learn over time.

There is still an unmet need of those patients who have a lesser performance status. Only 10% of the patients on the GEM/Abraxane study had a PS of 2, so I don’t feel comfortable extending utilizating that regimen in those patients yet, but there are a lot of PS2 patients who are under-served, who are going to still be getting only gemcitabine, in whom we now need to be looking at other palliative types of regimens and other approaches we can use to help those patients.

The fact that we have choices, that there are new regimens available and that it is not just one size fits all, I think is very exciting.

PSB: What about other gemcitabine based regimens such as GTX? Is that something that is in use commonly?

Dr Kindler: I certainly see GTX utilized in the Community, it is not a regimen of choice for me. I know it is a popular regimen in the Community. There have been many variations upon it, and it hasn’t been established in a phase 3. In fact, I saw a patient very recently treated in the community with GTX who had a PS of 0 and I was rather horrified that that PS0 patient had not received FOLFIRINOX, because I think she would actually have had less toxicity. That patient had a lot of toxicity but would have had a better outcome with FOLFIRINOX and that was based on phase 3 data.

I sense that there is still a lot of Community oncologists who are concerned about the toxicity of FOLFIRINOX, as I was initially, but as I have given it to more and more patients, and recognized – I see the patients on Day 1, first cycle 1 see them on Day 4, I see them on Day 8 – just that first cycle is challenging, so that the patient understands how they manage the diarrhea and other toxicities. Once I am comfortable that they are comfortable, then we just see them every other week.

As I am more comfortable giving this to more and more patients, I am really less intimidated by it, and so I am concerned there may be some people who are simply intimidated by it. You are comfortable with what you are comfortable with, you have a certain range of drugs, that you are used to giving and you are comfortable with it and it works well. Once you expand and try something else, you realize that’s not too bad. I hope people will feel more comfortable with regimens like that.

In terms of other GEM doublets, I think one thing the GEM/Abraxane data shows us is the validity of the meta analysis, which several years ago showed that patients with a good performance status do better with cytotoxic GEM doublets, whether it is GEM/CIS or whether it is GEM/OX or GEM/Cap there are subsets which do better with a GEM doublet, and we see that they have done better with this GEM doublet.

I hope that in the future we focus more on what is the biology, and not reflexively give gemcitabine +/- your drug here, as Jordan Berlin would say. Should you give GEM + this drug because it makes biologic sense, or should you give FOLFIRINOX + this drug or GEM/Abraxane + this drug, because it makes sense to do so from a biological stand point?

Are there subsets of patients, and maybe we should enrich? Your new wonderful targeted drug works only in patients with this wonderful target, so let’s enrich for this wonderful target and only offer that wonderful target to this subset of patients, and that happens to make sense to give with a FOLFOX based regimen so biologically we will give FOLFOX + or – your new wonderful target with said wonderful target.

I think we need to focus on that the way they are doing I-SPY in breast cancer and in other diseases.

PSB: Do you think that will happen in pancreatic cancer?

Dr Kindler: There have been many discussions about doing that. I think one problem in pancreas cancer is that it is not just a disease with one on/off switch. It is a very complex disease with much molecular heterogeneity. A very exciting, interesting presentation in the oral session today about the IL17A. That is a model, but if that is then brought out in patient systems, we may be able to target a subset of patients that way. There are many people who working on this and we hopefully will be able to. PANCAN has the goal of doubling the cure rate by 2020 and it may be achievable, but we’ll have to work pretty hard.

And finally…

The critical SPARC expression data for the phase III MPACT trial of Abraxane plus gemcitabine wasn’t available at this conference, but the presenter, Dr Daniel von Hoff assured me that it will be at ASCO in June. This analysis will potentially be critical in informing physicians whether those patients with high SPARC expression do better than those with low SPARC expression. The poster presented at this conference was based on an overall analysis of all patients, regardless of the biomarker.

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The inaugural report goes out later this month on advanced Pancreatic Adenocarcinoma, where I’ll be providing deeper insights and analysis relating to the market landscape and what the potential new developments with Abraxane, masitinib and S1 mean to both the Academic and Community settings:

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Will ASCO GI herald a new era for pancreatic cancer?

Today I’m heading off to attend the ASCO GI meeting in San Fransciso, and in particular, the pancreatic cancer sessions on Friday.

Source: ASCO

The event promises to be an interesting day with a keynote from Margaret Tempero (UCSF), as well as Daniel van Hoff (TGEN) presenting the much awaited nab-paclitaxel (Abraxane) data in advanced pancreatic ductal carcinoma and a poster on masitinib from the French researchers.

Many of you will recall the excitement expressed at ESMO in this data, although the topline data in the Celgene press release on the MPACT study this week suggests the overall responses were good rather than great.

For years, we’ve seen many doublets come along in combination with gemcitabine in clinical trials and largely fail. This is a very difficult disease to treat, with many patients sadly only lasting a year or less from diagnosis. Partly this can be traced back to the insidiously of the disease with it’s vague symptoms, and partly to the degree of oncogenic addiction to KRAS, which induces resistance and ensures the survival of the tumour.

The key with both the Abraxane and masitinib data will be in the details around potential biomarkers – and whether higher responses are seen in those subgroups or not. In Celgene’s case, it is hoped that patients with high SPARC expression will show better survival, while AB Science have annnounced the finding of a key biomarker of response with out offering any details until the presentation, we will see what each has to offer on Friday.

The other leading question is tolerability. Although gemcitabine is widely considered the standard of care for most patients and is well tolerated, younger patients are often given the FOLFIRINOX regimen upfront, which can lead to better responses at the cost of much higher toxicities, including hospitalisation.

If either Abraxane or masitinib demonstrate a similar survival advantage as FOLFIRINOX, a biomarker for selecting patients and an acceptable toxicity profile, then we may see a change in prescribing in this landscape in the not too distant future. For Celgene, the road ahead may be easier given the drug is already available for breast and lung cancers, whereas AB Science may need another trial with the biomarker first. Time will tell.

The ASCO GI meeting is at Moscone West, a huge black spot for wifi and AT&T reception at the last two cancer conferences I’ve attended there, so there’s unlikely to be much live tweeting.

I will, however, be producing a new report on the advanced pancreatic cancer landscape soon after the event, complete with insights and analysis, so if you would like to receive an early bird warning of this, please fill in the sign up form in the right hand margin.

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Prospect of Abraxane in Pancreatic Cancer excites ESMO 2012

By MaverickNY on September 30, 2012

One of the most interesting highlights of this ESMO for me has actually not been some new data or science that was presented here, but the sense of anticipation about the forthcoming nab-paclitaxel (Abraxane) data in pancreatic cancer.

The pancreatic cancer KOLs are a relatively dour group, much as melanoma specialists were until the advent of BRAF inhibitors. It’s largely a function of toiling away in a known graveyard zone with few effective therapies to offer patients and their families and then, suddenly, a new breakthrough is borne that re-energises the sub-specialty and propels it forward again.

I was therefore mildly surprised to find that the rare corporate symposia I attended on Friday afternoon was:

a) packed to the gills with standing room only and
b) the KOLs in an excited and feisty mood.

It was clear that something interesting was up.

Whilst it was made abundantly clear by the panel that the final data isn’t yet available, all of the KOLs presenting were at pains to say in their presentations it will be in “a few weeks” or “very soon” so thankfully we won’t have long to wait for the press release.

It is unlikely full details will be available until the data is presented at a major conference though, possibly ASCO GI, but we should at least have some indication whether it is positive or negative. After all, they sometimes do get a sense from their own patients whether one arm is doing better than the other or not, even if they don’t know until unblinding if it is a successful combination or a futile one.

The issue of futility is a real one i.e. did the patients on the treatment arm do worse than than the standard? We were vividly reminded of that today when Dr Dan Petrylak presented the phase III MAINSAIL data in castrate resistance prostate cancer, which demonstrated that patients receiving docetaxel and prednisone plus lenalidomide did worse than docetaxel and prednisone plus placebo. It is a risk and certainly can happen!

My assumption though, is that the nab-paclitaxel data is positive since a first cut of the analysis could be available by now, especially if the data will be announced soon. Why else would there be such warm enthusiasm from a well respected panel? Here are some examples of the sentiments expressed:

Dr Tempero: “We are on the verge of something exciting”

Dr Scheithauer: “The results are really good with nab-paclitaxel!”

Dr Ducreux: “The improvements in treatment of pancreatic cancer will come from new chemotherapies and combos.”

Dr Hidalgo: “The phase III (nab-paclitaxel) data will be available in a few weeks.”

Hidalgo discussed the role of SPARC in tumour growth and metastasis – it increases metastatic cell aggressiveness and is also involved in feedback loops involving angiogenesis see recent post on gemcitabine and nab-paclitaxel. SPARC expression can exist in both the stroma and the tumour. It has also be shown to correlate with improved overall survival and gemcitabine response. Reduction in SPARC by nab-paclitaxel leads to increased uptake by gemcitabine by removing the stromal barrier.

In concluding his presentation on the biology of pancreatic cancer, Dr Hidalgo emphasised the importance of targeting the stromal layer, which acts as a barrier protecting the pancreas and that “nab-paclitaxel appears effective.” Since one follows the other, the clues to what they all clearly knew were there.

You can read the Storify that Pieter Droppert of Biotech Strategy Blog collated from the live tweets of the session.

For those of you interested, I previously wrote about the preclinical evidence for nab-paclitaxel blasting through the stroma back at AACR in 2009. The scans from the animal models pre and post nab-paclitaxel were pretty impressive. You could instantly see the rationale for effectively blasting it out, thereby providing a haven for gemcitabine to work more effectively by increasing apoptosis and increasing tumour regression. It should be noted that while nab-paclitaxel has been shown to affect the stromal layer, whereas gemcitabine does not.

Hidalgo described how the combination of “nab-paclitaxel and gemcitabine shows interesting clinical and tissue effects” while showing some impressive PET scans of response. He went on to say that, “what I hope is the combination will be improved based on a median OS in the 10, 11 month range.”

In summary…

We’ll find out very soon whether the KOL expectations are correct, but if true, the combination of nab-paclitaxel and gemcitabine could potentially lead to a new standard of care. In turn, there are several impacts that will likely result from positive data:

1) It will provide a new chemotherapy doublet for future trials to be compared to. This will raise the bar in pancreatic cancer for new entrants including Threshold’s agent, TH–302, that is also attracting a lot of attention here at ESMO.

2) Positive news regarding doubling of overall survival will be particularly good for patients suffering from this terrible disease.

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Update on bavituximab in non-squamous lung cancer

By MaverickNY on September 11, 2012

Last Friday, Peregrine announced their initial phase IIb results with bavituximab in second line non squamous non-small cell lung cancer (NSCLC). The topline results were most interesting to say the least, since the company suggested that adding bavituximab to docetaxel in second line doubled the rate of survival in these patients. The data was presented by Dr David Gerber (University of Texas, Southwestern in Dallas) at the Chicago meeting of the Multidisciplinary Symposium in Thoracic Oncology in the late breaking session.

What is bavituximab?

Bavituximab is a monoclonal antibody that targets phospholipid phosphatidylsterine (PS), which exists in the membrane of vascular endothelial cells.

In normal conditions, PS is hidden in the inner membrane, but in cancer conditions, the tumour microenvironment can cause the PS cells to also be expressed on the outer membrane. It is thought that chemotherapy can also heighten the PS exposure in the tumour microenvironment, leading to reduced anti-tumour responses.

Bavituximab’s role is to bind to the activated PS on the outer membrane, essentially blocking PD mediated tumour suppression. This is an immune effect, similar to PD–1, whereby it allows the body to recognise the presence of cancer and stimulates it to fight the tumour.

What was the trial design?

The phase II trial randomised patients with non-squamous NSCLC (n=121) to receive one of the following:

1) Docetaxel 75mg/m2 3qw + placebo for up to 6 cycles (n=40)
2) Docetaxel 75mg/m2 3qw + bavituximab 1mg/Kg qw for up to 6 cycles (n=40)
3) Docetaxel 75mg/m2 3qw + bavituximab 3mg/Kg qw for up to 6 cycles (n=41)

Each of the groups then received maintenance therapy ie placebo or bavituximab (1 or 3mg/Kg) until progression.

The primary endpoint of the trial was response rate and the secondary endpoints included PFS, OS, safety and duration of response.

Where were the centres?

Aside from University of Texas Southwestern in Dallas, other US sites included Hershey, several regional cancer centres and a number of community oncology sites, presumably US Oncology. Internationally, the centers included sites in Russia, India and Ukraine.

The trial details can be found in the clinical trials database.

What did the results show?

Based on the company’s press release, the interim data analysis appeared to suggest that adding bavituximab to docetaxel doubled the overall survival from 5.6 months with docetaxel/placebo to 12.1 months in the pooled bavituximab arm. Each active arm was 11.1 and 13.1 months for 1 and 3 mg/Kg respectively. I’m not sure that the individual arms were significantly different from docetaxel alone or just the pooled data, which naturally doubles the N number and hence power in determining the difference. That’s quite a different proposition to start with.

While these results are not unheard of, they require caution for a number of reasons. We need to remember that they are reminsicent of other, similar small company phase II trials in lung cancer such as Antisoma’s ASA–404, where an increase of 8 months or so in the phase II study was not repeated in a large scale randomised phase III trial. I do think there is enough here from the current bavituximab study to warrant testing the immunotherapy in phase III RCT, but I would urge caution in extrapolating the results at this time.

What are the potential issues with this study?

a) Small phase 2 trials in oncology are fraught with bias, which often disappears when tested on a larger scale in reputable US and EU centers.

b) Not all patients in Eastern Europe are aggressively treated to progression upfront in the same way they are in the US, in other words they may be relatively undertreated, which can influence the subsequent outcome.

c) We don’t have a breakdown by country of the results across groups – did the Eastern EU and Indian patients do better than the US ones? How many patients came from each country that participated and in which arm?

d) It is always tricky to extrapolate from small N numbers of this size, especially when no data for how well the groups were matched in terms of prognostic factors is provided beyond age, performance status etc. There was, howver, a noticeable lower number of caucasians and a higher number of asians in the 3mg bavituximab arm, for example. Would this affect the results? Who knows in a small sample!

e) No mutational analysis was made available – this means more patients with a poorer prognosis could confound the data in the 3 groups and we have no idea why some patients did better than others.

f) The amount of prior Avastin varied across the groups – from 20% (placebo) to 18% and 15% in the bavituximab arms and although not significant in a small sample size, the groups should have been better balanced for this. I would be very wary if these numbers were repeated in a much larger scale trial, especially when considering the bleeding events were higher in the bavituximab 1mg group, which also received more prior Avastin than the 3mg group but a lower number overall any adverse events or grade 3+ events.

g) It’s also difficult to interpret these data in a small sample size, especially when you consider that the toxicities in the docetaxel plus bavituximab 1mg group appear to be better than docetaxel alone. This make little sense to me.

When considering the efficacy data, there are also some other noticeable anomalies:

1) The differences in PFS are small (3.0, 4.2 and 4.5 months) between the three groups but the OS curves show a more dramatic difference. This is normally an obvious red flag – you wouldn’t predict this to happen from the marginal PFS data based on central review.

You can see the OS data as shown on Yahoo Finance:

2) The other odd thing about the PFS data is that at around month 7, the curve for the 3mg bavituximab arm suddenly drops below the 1mg arm and parallels the placebo arm, yet the OS is still better in the bavituximab arm compared with docetaxel alone? Crossover does occur in trials, but it does seem an odd drop and leads me to wonder why and what happened at that point? In addition, with immunotherapy there is usually a delayed effect rather than an upfront effect so one would expect the results in the bavituximab arm to prolong over time if the agent is working effectively.

3) While PFS of 3–4 months for a docetaxel combination is normally acceptable in second line, I would have expected the OS to be longer than 5–6 months for docetaxel alone. It is possible, however, that MOS has not yet reached and these data will improve over time since 10–11 months is a realistic target. If median OS has not yet been reached since this is interim data, then we need to wait and see what the final data will be – with and without bavituximab – since any initial benefit seen before MOS can potentially disappear over time.

Overall:

These data are very early and offer both hints of promise and portends to future doom (ie a negative phase III trial). Three things I would like to see:

1) Full data analysis with median rather than interim OS for the phase II trial
2) Subset analysis by country and prognostic factors such as mutational analysis
3) Phase III results from a randomised controlled trial involving US and EU academic centres that eliminates inevitable phase II bias

I would also caution readers to avoid extrapolating too far from interim data from small phase II trials based on the Antisoma experience in NSCLC!

ASCO 2012 Update 2: Overcoming resistance in metastatic melanoma

By MaverickNY on June 29, 2012

Following on from my preview of the 2012 American Society of Clinical Oncology (ASCO) meeting, I am now working through updates on some of the hot topics.

I’m delighted to announce The Chemical & Engineering News blog ‘The Haystack’, have published my second guest post on advances in metastatic melanoma.

This is a devastating disease that has seen very few advances over the last decade since the approval of dacarbazine (DTIC) until last year when the FDA approved two new therapies in vemurafenib (Zelboraf) for patients with the BRAFV600E mutation and ipilumumab (Yervoy), an immunotherapy that targets CTLA4.

Since then, we’ve realised that the inevitable happens – patients tumours become resistant to single agent TKI therapy because adaptive resistance pathways are activated and cross-talk with the MAPK kinase pathway often occurs. The question of how we can improve on the encouraging results seen so far was explored in new trials in Chicago?

For those of you interested, you read my summary on The Haystack about the new developments in metastatic melanoma from ASCO, which includes dabrafenib, trametinib, anti-PD-1 and others.

For those who missed it, I also wrote a guest post about the ASCO 2012 data on overcoming resistance in non-small cell lung cancer.

May I take this opportunity to wish all my American readers a very enjoyable July 4th Independence Day weekend!

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A surfeit of riches in CLL and NHL: on bruton kinase and PI3K delta inhibitors

By MaverickNY on June 27, 2012

This week I’m attending an interesting 2-day conference on PI3K at the New York Academy of Sciences (NYAS).

It brings together a broad faculty of researchers in the field looking at novel aspects of the PI3K-Akt-mTOR pathway in depth.

One aspect that has become clear with these compounds is that there’s probably more that we don’t know than we do – it’s a highly complex network of nodes and cause-effect that needs to be unravelled.

We do know a few things though, for example, PI3K and mTOR are often activated in advanced disease and can cause resistance to therapy as we have seen with aromatase inhibitors in ER+ disease and trastuzumab in HER2+ breast cancer. We also know that inhibiting PI3K or mTOR can lead to activation of compensatory pathways that serve to drive oncogenic signalling and tumour survival. It’s complicated!

The most advanced agent in the PI3K class is probably Gilead/Calistoga’s GS-1101 (formerly CAL-101), which is a delta isomer inhibitor being evaluated in B-cell hematologic malignancies such as mantle cell lymphomas (MCL), indolent NHL and CLL. After promising phase I and II trials, it has now moved into randomised controlled phase III trials.

Yesterday, Langdon Miller (Gilead) gave a nice overview of the GS-1101 program. One couldn’t help but marvel at the waterfall plots obtained to date, along with the before and after pictures of a women in her 40’s with refractory CLL – a dramatic difference – she looked like a completely different person! Of course, there are a number of questions that need to be addressed next:

Is survival prolonged in heavily refractory patients accustomed to immunotherapy?
How reproducible and durable are these responses on a large scale?
How can the redistribution of the lymphocytes be addressed? Will chemotherapy help here?
Is there value in combining a PI3Ki with immunotherapy in earlier stage disease?

All of these questions are being evaluated in the next phase of the GS-1101 clinical trials. I was impressed with the progress and where Gilead are going with the compound.

There are some questions that remain in my mind though. CLL and iNHL have an embarrassment of riches in pipeline agents at the moment, with several promising compounds in development.

The obvious rival to PI3K delta inhibitors are the bruton kinase inhibitors (BTK) such as Pharmacyclics/J&J’s ibrutinib (PCI-32765), which reported impressive data at ASH last December, followed up by new data at ASCO on the combination of ibrutinib with an approved CD20 antibody, ofatumumab.

This got me thinking…

1) If we assume that both agents are lucky enough to get approved by the FDA sometime in the near future, how will oncologists and hematologists decide which agent to give which patient? Can patients be stratified in any way in order to define selection for treatment?

2) Is there any data on whether combining these agents together would be synergistic? (I don’t think so, yet)

3) If a PI3K-delta and a BTK inhibitor were synergistic preclinically, what are the chances emerging of a combination trial between the four companies involved in the development of GS-1101 and ibrutinib? Sadly, a cynic would shake their head and say very low, but we need an answer on 2) from academic research before we get too excited.

4) What are the mechanisms of adaptive resistance in patients to both classes of agents in CLL and NHL? If we know the answer to this critical question, then rational combinations could be investigated further.

5) Would combining GS-1101 with CD20 antibody immunotherapies such as rituximab and ofatumumab be an interesting approach to see if better response rates and outcomes will be achieved? These are indeed being planned, along with a combination with bendamustine, another drug often used in relapsed/refractory NHL and CLL.

6) How will sequencing be important? If a patient is eligible for either therapy, which one should be tried first? This area is rather murky right now.

We’ve come a long way so far with both of these compounds, but there’s still an even longer way to go before we have some clarity on how they might change clinical practice and help improve outcomes for patients with NHL and CLL.

This is definitely an exciting area to watch out for, even if we have more questions than answers right now.

ASCO 2012 Update 1: Advanced Lung Cancer

By MaverickNY on June 26, 2012

It’s been a crazy busy time since the American Society of Clinical Oncology (ASCO) meeting earlier this month.

This year’s meeting had a lot of hidden gems in both the tumour oral and poster sessions, which will be covered in a series of blog posts.

One theme that clearly emerged was how much effort is being devoted to identifying the causes of acquired resistance to a variety of TKI single agent therapies in order to determine logical combination strategies for the clinic.

Two areas that stood out for their combined translational-clinical efforts at this years ASCO were advanced lung cancer and metastatic melanoma.

I’m delighted to announce that my first guest blogs are appearing on Chemical and Engineering News this week on these topics. For those of you interested in advanced melanoma, check back on PSB on Thursday for the link.

The good news is that the lung cancer one has posted today. Some of the topics from ASCO 2012 covered in the post include:

Does a pan-ErbB inhibitor produce better results upfront than chemotherapy?

What new advances are there for patients with KRAS mutations?

How do we overcome ALK resistance? 

Does chemotherapy produce better responses than Tarceva for EGFR wild-type in second-line NSCLC?

You can check it out here!

Interested in the PI3K-AKT-mTOR pathway in cancer research?

By MaverickNY on June 20, 2012

Here’s a quick update on the next conference I’m planning to attend in New York next week. It’s hosted by the New York Academy of Sciences (NYAS) in their downtown New York headquarters by the World Trade Center, which has fantastic panoramic views of uptown Manhattan and Brooklyn from the 40th floor. More importantantly though, judging by the last few meetings I’ve attended there on cancer metabolism and a most fascinating lecture on ink and tattoos from Carl Zimmer, it should be a very good event and well worth attending.

The latest conference is a two day affair on “Inositol Phospholipid Signaling in Physiology and Disease” otherwise known as the PI3K-AKT-mTOR pathway, which is a key process that is dysregulated in many cancers:

The organizing committee of William Kerr (Suny), Christina Mitchell (Monash Univ) and Christian Rommel (Intellikine) have done an excellent job putting together a comprehensive program that covers a wide variety of related topics from both academia and industry across the globe.

I’m really looking forward not only to the science feast, but also to the networking opportunities to mix and mingle with some of the top researchers in the PI3K field, including Lew Cantley (Harvard), Neal Rosen (MSKCC), Bart Vanhaessebroeck (Barts, London) and David Solit (MSKCC) amongst many others.

For those of you interested in registering for this event, you can obtain a 15% discount when you click on the graphic or link above and enter the coupon code INOSITOL15 on checkout, as I’m delighted to say Icarus Consultants was invited to be one of the media partners for the event.

For those who cannot attend, I’ll post a short synopsis of the conference on PSB after the event later next week. In the meantime, I hope to see you there!

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