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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy

By on December 1, 2010

Recently, at the NY Chemotherapy Foundation symposium, Dr Phil Kantoff from Dana Farber gave a lecture on new therapeutic strategies in prostate cancer. Despite the unsociably early hour (7.30am), the room was almost packed.

While waiting for the session to start, over coffee I had some cheerful banter with some of the oncologists around me.  They expressed a keen desire for more tolerable and effective therapies for their mostly elderly patients with prostate cancer, many of whom were too frail or disinterested to really consider chemotherapy once hormone therapies ceased to work.

Several of them were really interested in, but somewhat puzzled about, the recent spate of new data on hormone therapies (abiraterone) and immunotherapy (sipuleucel-T) and how they work, after all, as one pointed out – after a lifetime of treating thousands of patients with chemo and more recently, targeted therapy – getting their heads around new technologies such as vaccines was difficult and challenging to explain to patients in simple language:

“We know that it works, but how does it work?  That’s what I’m stuck on.”

Another oncologist wondered why does abiraterone appear to work after failure of docetaxel chemotherapy?  He wanted to know if the break from hormone therapy with chemotherapy meant that the androgen receptor (AR) was still driving tumour growth and whether re-treatment with any hormone therapy would actually be beneficial?

Fast forward to Kantoff’s lecture.  He covered the basic ground well and also went through the recent trials, including the recent data from ESMO on abiraterone, the NEJM data on MDV3100 and several trials for sipuleucel-T, including the Small et al., (2006) data and the more recent IMPACT trial in asymptomatic and mild symptomatic metastatic castration resistant disease (CRPC) that showed a 4.1 month advantage over placebo, leading to approval by the FDA earlier this year.

There was some discussion of the survival data, since disease progression, measured as progression-free survival (PFS), may often not be significant, but overall survival (OS) is. Why is this?  Kantoff postulated that the time to the biological effect of sipuleucel-T may take longer than the time of measurement of progression (yes, but why?)  PFS is also a difficult thing to measure in prostate cancer

The question for me, though, is what is the mechanism behind the delayed biological effect?  How can this be explained?

In simple terms, vaccines such as sipuleucel-T rely on stimulating the bodies T-cells to fight the cancer.  It doesn’t mean that there will necessarily be any effect on the tumour size, as measured classically by RECIST, but rather the overall impact is inevitably more on immunity effects, which are probably less well understood.  Looking through the recent literature, though, I came across a most interesting article in Clinical Cancer Research:

“Wnt ligands are lipid-modified secreted glycoproteins that regulate embryonic development, cell fate specification, and the homeostasis of self-renewing adult tissues.  In addition to its well-established role in thymocyte development, recent studies have indicated that Wnt/β-catenin signaling is critical for the differentiation, polarization, and survival of mature T lymphocytes.  Here, we describe our current understanding of Wnt signaling in the biology of post-thymic T cells, and discuss how harnessing the Wnt/β-catenin pathway might improve the efficacy of vaccines, T-cell–based therapies, and allogeneic stem cell transplantation for the treatment of patients with cancer.”

We’ve covered Wnt on this blog before, so I’m not going to cover canonical signalling and the delights of Frizzled and Dishevelled in this post, but see here for more background if you’re interested in the biology.  Of relevance to this discussion, though, is a quote from the article:

“… the discovery that Wnt/β-catenin signaling is a key regulator of T-cell immunity now raises the possibility that potentiating Wnt signaling could be used to improve cancer therapies through immune-based mechanisms.”

It will be interesting to see if prostate cancer vaccines such as sipuleucel-T actually have an effect on Wnt signalling, thereby explaining the enhanced T-cell effect.

Wnt signalling has also been shown to have a pivotal role in promoting stem cell self-renewal while limiting proliferation and differentiation (see Staal et al., and Fleming et al., 2008 in the references below).  Inevitably, the biological effects on immunity can take time to take effect compared to the direct effects of say, DNA methylation or angiogenesis, and this may well explain the delay in efficacy with vaccines.  The important thing for men with asymptomatic metastatic prostate cancer is that once it happens, the effect is both prolonged and durable, thereby offering them a new therapy option prior to chemotherapy.

As for the question about re-challenge with existing hormone therapies on the market, I don’t know the answer to that, but it’s a very good question, and perhaps best covered in another blog post unless some of the oncologists reading this have any practical experience to relate?

References:

ResearchBlogging.org Gattinoni, L., Ji, Y., & Restifo, N. (2010). Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy Clinical Cancer Research, 16 (19), 4695-4701 DOI: 10.1158/1078-0432.CCR-10-0356

Staal, F., Luis, T., & Tiemessen, M. (2008). WNT signalling in the immune system: WNT is spreading its wings Nature Reviews Immunology, 8 (8), 581-593 DOI: 10.1038/nri2360

Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, & Scadden DT (2008). Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell stem cell, 2 (3), 274-83 PMID: 18371452


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Crizotinib and ALK rearrangements in lung cancer: an interview with Dr Ross Camidge

One of the hot topics in cancer this year has definitely been the impressive clinical trial results from crizotinib (Pfizer) in ALK rearrangements seen in a small proportion of people with non-small cell lung cancer (NSCLC).  We’ve covered the data in several posts so far (see here and here if interested in the data at ASCO, ESMO and the NEJM article).

Earlier this year, Dr Jack West posted an excellent webinar with Dr Ross Camidge (University of Colorado, Denver) on his Cancer GRACE forum discussing the molecular biology of ALK rearrangements in lung cancer.  It’s well worth checking out and a great cause if you’re looking to support a non-profit that offers a lot of valuable free education for patients and caregivers (full disclosure: I’m one of the unpaid GRACE Board members).  Video, transcript and slides are all available through the link for physicians, researchers and patients alike.

Since then, the data has been presented at several meetings and some new articles have appeared in several journals, including the New England Journal of Medicine and Clinical Cancer Research (references below).  Dr Camidge is one of the clinician researchers involved in both papers, so I thought it would be a good idea to catch up with him and find out some more details beyond the clinical data.  He kindly gave up some time to answer my questions, which I have posted as italicised quotes below as part of our ongoing Making a Difference interview series.

1. Do ALK and EGFR mutations overlap or are they mutually exclusive?

They are almost mutually exclusive.  So, for example, we have shown if you exclude patients who are EGFR mutant you increase the hit rate when you then test for ALK (Camidge et al, Clinical Cancer Research, November 2010).

However, all ‘rules’ in biology have exceptions and as more people are tested rare double molecular drivers (ALK and EGFR or ALK and KRAS, for example) have been found.

The significance of these is uncertain in terms of which drugs they will best respond to (indeed the two changes may not be in all cells in the same cancer and may reflect a mixed population), but emphasises the point that, while there are various strategies you can use to find most ALK gene rearrangements, altering the cost effectiveness of the screening among other things, the only way to find all of them is to screen everyone.

2. Does the histology matter with ALK mutations? Are are there any subsets where ALK mutations predominate?

Small note: technically in lung cancer, we are mostly talking about ALK gene rearrangements, not mutations as the means through which ALK is activated to drive the cancer.  ALK mutations occur in neuroblastoma and may be one mechanism of ALK gene rearranged lung cancer developing acquired resistance to crizotinib, but they are not thought to be the primary oncogenic event in most lung cancer cases.

Ok, that said, ALK gene rearrangements, following on from the first point are most common in adenocarcinoma, in those with less than 10 pack years of smoking and who are EGFR and KRAS wildtype (same camidge ref above), in our series when all of these filteres were applied 45% of those we tested were positive for an ALK gene rearrangement.

However, as mentioned, exceptions to all of these rules exist and I have ALK-positive patients among those who were heavy smokers, who had squamous or large cell cancers, and who had co-existent EGFR and KRAS mutations – they are just rarer in these subgroups.

To use histology as one example – there are multiple studies that show that the agreement on histology between expert pathologists is at best ‘moderate’ – therefore deciding who should get a definitive test (ALK FISH) on the basis of a very non-definitive test (subjectively categorized histology) seems less than logical to me.

3. How would you describe the crizotinib data reported in the NEJM recently? How important are these results for patients with NSCLC?

The results are enormously important for several reasons.

Firstly, I believe they will encourage folk to get everyone with NSCLC who has available tissue screened for ALK – a quick back of the envelope calculation suggest about 98% of those who are ALK-positive in the US alone have not yet been tested. Progress will only happen when we finesse our off-the-peg style of oncology with some real 21st century tailor-made medical approaches.  And this will apply to many other molecular subtypes of cancer in the future, not just ALK.

Secondly, the results are now making drug companies take notice of the fact that trying out molecular sensitivity hypotheses – ie asking who does my drug really work in – is now feasible very early on in drug development and should dramatically increase the chances of successful registration, rather than trying to give one drug to everyone and then only figuring out in retrospect who it does or doesn’t work in.

Finally, the results, at last, offer true hope to those affected by cancer, offering a glimpse of an achievable future of long term control through breaking down the traditional one size fits all model.

4. What about resistance to crizotinib; do we know of any possible mechanisms yet and if so, how would this change therapeutic strategies in the future?  Could new combinations be tested in this setting to help overcome this?

Resistance does happen, but this isn’t a surprise.   Sometimes this is simply that in some parts of the body, like the brain, the drug doesn’t penetrate so well and cancer seeds lurking in these areas can grow as if they were not exposed to the drug.  In such cases, giving something like radiation treatment to the brain, but keeping the crizotinib going to keep suppressing all the disease outside of the brain, may well be the best thing to do – and we showed several examples of this actually being done at ESMO this year (see Oncology Tube).

However, resistance can also occur outside the brain.  Cancers are genetically unstable and all the cells in a cancer are just a little but different from one another.  Most of the time this diversity doesn’t mean anything, but when you change the environment, by using a drug like crizotinib, that diversity lets Darwinian evolution start to play out.  Subclones that differ just enough to keep growing can then manifest as resistance, growing up while the other cells continue to be suppressed. What differences create these resistant subclones continues to be explored.

Only one mechanism has so far been reported – two separate new mutations within the ALK kinase domain that make it more resistant to crizotinib – one of which is similar to the T790m gatekeeper mutation described in EGFR mutant lung cancer that is selected out when such cancers are exposed to erlotinib or gefitinib.

However, with only a single case report we do not yet know the frequency with which this mechanism will be used by ALK positive cancers to become resistant.  If other changes become known, then conceivably rationale combinations of drugs such as crizotinib plus something against a second driver mutation, could then be explored.  Plus patients may still have many traditional chemotherapies to fall back to, just because a patient is ALK positive doesn’t mean we should abandon all our other anti-cancer strategies, we might just need to change the priority ordering of them.

5. Are ALK mutations expressed or mutated in any other cancers other than NSCLC? If so, which ones?

Yes – ALK gene rearrangements drive subsets of lymphomas, inflammatory myofibroblastic tumors (a rare sarcoma) and ALK mutations drive some neuroblastomas.  ALK expression has been reported in several other cancers, but the data that it is driving these cancers is not yet mature.

6. Are there any other ALK inhibitors in development? If so, which ones, and how might they be different from crizotinib?

There are, but most of these have not yet even entered clinical trials to date.  Companies developing them include Lilly, Novartis, Cephalon and Ariad.   Some of these claim to be more potent, eg against some of the resistant forms of ALK that might arise, but whether these drugs will be able to produce exposures high enough or tolerable enough to achieve activity against normal or these mutant forms of ALK in patients remains to be seen.

7) There’s been a lot of chatter in patient forums about some patients getting tests, thinking they were ALK positive and then being denied access to the trials because another test suggested they were negative for ALK. How accurate is the ALK test, are there many false positives? How will this work in practice with a broader population in the community, assuming crizotinib is approved and requires molecular testing for the ALK mutation as part of the approval?

Yes – for the clinical trials of crizotinib most of them require an ALK test to be positive via a specific provider (ALK FISH testing via Abbott Laboratories).  So this means folk who have tested positive through some other provider have to be retested and sometimes the two results don’t agree.  The exact false positive and false negative rates are not yet clear as only those who test positive through the central Abbott Lab get the drug, so there is no true comparator group.  That said, the original 7 phase I sites (Colorado, Boston, New York, Chicago, California, Seoul and Melbourne) also have access to the drug through the phase I route, which does not require central testing – although it does mandate FISH as the test method used.

Certainly some folk who tested positive via FISH locally but not via the central lab have responded, suggesting the central lab has had some false negative results.  The numbers are small, but in an ideal world they would be zero.  If ALK testing via means other than FISH is used, there we really do not know how the two stack up.  RT-PCR probably only detects a subset of all possible ALK gene rearrangements so may miss some who could benefit form the drug, however whether its sensitivity is so high it may also capture some that are missed by FISH testing is unknown.

Immunohistochemistry is highly variable and probably depends on the antibody used, the scoring system, the tissue preparation and the experience of the scorer.  Some nice data from the mayo clinic suggests IHC in experienced hands may be good at ruling in most positives, and ruling out most negatives, but there is still an equivocal group where the result could go either way.

Depending on what the label for crizotinib looks like if it gets approved, whose test is easiest, cheapest or best will have to be played over time.  At present the only test that has unequivocally been associated with benefit from crizotinib is the ALK FISH test and this is the test (done properly in an expert facility) that all others will have to be compared to at the end of the day.

All in all, this is a very promising development for people with lung cancer and ALK gene rearrangements. Responses in heavily pre-treated patients in the order of +60% are most unusual and thus this potentially offers another example where molecular profiling can help match the most appropriate treatment for some people with lung cancer. Dr West summed it up nicely in the his post regarding the ALK webinar with Dr Camidge:

“Though this is still a small population, the evidence is very convincing that ALK inhibitors can have a major impact for these patients, with the potential that we may also identify agents that can offer additional benefit to patients with an ALK rearrangement.”

References:

ResearchBlogging.orgKwak, E., Bang, Y., Camidge, D., Shaw, A., Solomon, B., Maki, R., Ou, S., Dezube, B., Jänne, P., Costa, D., Varella-Garcia, M., Kim, W., Lynch, T., Fidias, P., Stubbs, H., Engelman, J., Sequist, L., Tan, W., Gandhi, L., Mino-Kenudson, M., Wei, G., Shreeve, S., Ratain, M., Settleman, J., Christensen, J., Haber, D., Wilner, K., Salgia, R., Shapiro, G., Clark, J., & Iafrate, A. (2010). Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer New England Journal of Medicine, 363 (18), 1693-1703 DOI: 10.1056/NEJMoa1006448

Camidge, D., Kono, S., Flacco, A., Tan, A., Doebele, R., Zhou, Q., Crino, L., Franklin, W., & Varella-Garcia, M. (2010). Optimizing the Detection of Lung Cancer Patients Harboring Anaplastic Lymphoma Kinase (ALK) Gene Rearrangements Potentially Suitable for ALK Inhibitor Treatment Clinical Cancer Research, 16 (22), 5581-5590 DOI: 10.1158/1078-0432.CCR-10-0851

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What's new in Biosimilars?

By on November 29, 2010

Biosimilars are very much a hot topic of late.  They are approved new versions of innovator biopharmaceutical products, following patent expiry.  Essentially, this is like a generic version of the biologic product, hence their alternative name, follow-on biologics.

Recently, the FDA approved the Momenta/Sandoz’s follow-on versions of sanofi-aventis’s Lovenox, a low molecular weight heparin (LMWH), used to prevent and treat deep vein thrombosis or pulmonary embolism.   The patent expired in July 2010 and approval was given on July 23rd.  Reports in the press suggest that erosion of the brand was both fast and steep, with a 60% shift in market share to the cheaper versions almost overnight.

At present, the FDA doesn’t have a recognised approval system for follow-on biologics, so the process is somewhat fuzzy.  I’m not sure why the FDA approved Momenta’s versionof enoxaparin, but not Teva or Amphastar’s, although inevitably, there was a lot of noise surrounding the issue in the press over the last year.  I’m not going to go into the details of the shenanigans over this, but a quick Google search will offer more information than many will have time to read!

What was interesting to me was that Momenta scientists published an interesting paper in Nature Biotechnology (reference below) on Chinese hamster ovary (CHO) cells.   CHO cells are the most common cells used to synthesise recombinant proteins used in many drugs and are extremely well studied.  Previously, however, CHO cells were thought to lack the biosynthetic ability necessary to synthesize a particular glycoprotein, but the Momenta scientists found otherwise, underlining their expertise and research in this field.

These players – Momenta, Sandoz, Teva and Amphastar – probably have the lead in follow-on biologics for now, so they will be interesting companies to watch out for as the patent cliffs in biologics begins to hit big Pharma between now and 2015.

Now, while the FDA still doesn’t have any official regulations for follow-on biologics, the European Medicines Agency (EMA) has begun to tackle the issue head on, posting draft guidelines last week.  You can check them out online.  According to the EMA:

“The Agency has released the draft guideline on similar biological medicinal products containing monoclonal antibodies for a six-month consultation period.

The guideline lays down the requirements for medicines containing monoclonal antibodies that claim to be similar to another such medicine already marketed.

Comments on the draft guideline can be submitted to the Agency up to 31 May 2011.”

Unfortunately, I haven’t had time to digest the EMA proposals yet, but we will post a full synopsis in a future blog post soon.

If you have any thoughts, comments or questions, please feel to add them in the comments below.

References:

ResearchBlogging.org Bosques, C., Collins, B., Meador, J., Sarvaiya, H., Murphy, J., DelloRusso, G., Bulik, D., Hsu, I., Washburn, N., Sipsey, S., Myette, J., Raman, R., Shriver, Z., Sasisekharan, R., & Venkataraman, G. (2010). Chinese hamster ovary cells can produce galactose-α-1,3-galactose antigens on proteins Nature Biotechnology, 28 (11), 1153-1156 DOI: 10.1038/nbt1110-1153

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Happy Thanksgiving

By on November 25, 2010

It’s that time of year when America shuts down for a few days and enjoys some time for family, football and rather too much food.

Here, we’ll be enjoying those most British of delicacies – crisp roast potatoes and parsnips with some trimmings including cranberry sauce.  For those of you interested in food and internationalism, check out my friend @divabiotech’s blog post on her Global menu for the day, yum!

In the meantime, for those of you who do celebrate Thanksgiving, I’m raising a delicious glass of Prosecco and wish y’all a happy and peaceful weekend.  Normal blogging will resume on Monday.

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Cancer Cell Seeding – a new hypothesis from Larry Norton

By on November 24, 2010

At the annual NY Chemotherapy Foundation symposium the other week, one of the highlights for me was listening to Larry Norton (MSKCC) give a 30 minute keynote entitled:

“Cancer Cell Seeding: a hypothesis with therapeutic implications”

He talked at length about what he described as some of the breast cancer mysteries, namely the puzzles associated with:

  1. Phenotypic consistency (hyperplasia, anaplasia, rapid growth, angiogenesis, large tumour size, invasion, metastases and latency)
  2. Disorderly order
  3. Unclear clear margins

Several main points were then raised from this quick synopsis:

  • The phenotypic elements are so inextricably linked that they must be related, but how?
  • Sentinel node mapping proves that progression is orderly. Yet it isn’t! How?
  • RT must kill cells that are beyond clear margins.  How do they get there? What is their relationship to distant recurrence?
  • That RNA expression is prognostic and predictive challenges the notion of tumour-initiating cells being rare.

These issues or assumptions may be true or not true so the question then becomes how are we going to solve them?

Norton noted that one way these concepts may be related is that the tumour is essentially metastasing to itself and showed a nice schematic from 2006 that he and Massague used in their Nature Medicine paper.  Tumours thus grow by metastasis back to itself and will promote increased growth and bigger tumour size:

However, it took until late 2009 to research and publish proof that this idea is true (see reference below for the paper):

The other concept that caught my attention is the idea of a ‘toxic sponge’ that followed on from this as Norton was putting the story back together in terms of breast cancer.  In short, the primary tumour and region act as a sponge for circulating tumour cells.  When the sponge is removed or sterilised, circulating tumour cells seek distant sites since they cannot metastasise back to the primary tumour anymore.  Seeding the new sanctuary sites may also create reservoirs for feeding future distant metastases.  Research is now underway to determine whether RT has accelerates or potentiates the metastasis process in the long run.

All in all, a very interesting and well put together talk.

ResearchBlogging.org Norton L, & Massagué J (2006).  Is cancer a disease of self-seeding? Nature medicine, 12 (8), 875-8 PMID: 16892025

Kim, M., Oskarsson, T., Acharyya, S., Nguyen, D., Zhang, X., Norton, L., & Massagué, J. (2009).  Tumor Self-Seeding by Circulating Cancer Cells Cell, 139 (7), 1315-1326 DOI: 10.1016/j.cell.2009.11.025

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DNA methylation and microRNA expression in pancreatic cancer

By on November 22, 2010

Pancreatic cancer is particularly nasty, mainly because there is no easy way to detect it by screening or biomarkers in the general population, symptoms are often insidious and thus the cancer is sadly not picked up until the advanced stages.  Less than 20% of people present with early stage disease, meaning they are small, resectable and therefore treatable.

It is clear that more progress beyond incremental improvements will come as we learn more about the biology of the disease and develop accurate tests for early diagnosis.  The big question, though, is what subtle, and not so subtle, changes are happening with tumorigenesis and pathogenesis?  If we can understand the process we might be able to figure out some appropriate markers and develop a diagnostic test, since many people will not have the classic risk factors, making screening in the general population difficult.

With all this background in mind, I noticed an interesting paper recently from Cancer Research:

“… there is a need for sensitive, specific, and accurate tests that would facilitate the rapid diagnosis of pancreatic cancer and its precursors.  New candidate markers have been described in recent years that have been evaluated in serum and in pancreatic secretions and ductal brushings to detect local pancreatic neoplasia, but more accurate markers are needed.”

What’s also interesting is that following some recent posts on microRNA (see lung cancer and general information on miRNA for examples), it seems that almost every other article is about miRNA in some shape or form when I check out journals.  Maybe it was there before but I’m only just seeing it after writing about it.

As Li et al., pointed out in their paper, we know that DNA methylation and miRNA expression are important in pancreatic cancer pathogenesis, but what precisely is happening?  In their experiments, they found that:

“We identified two members of miR-200 family, miR-200a and miR-200b, that were hypomethylated and overexpressed in pancreatic cancer.”

Downstream, other changes were also taking place:

“We also identified prevalent hypermethylation and silencing of one of their downstream targets, SIP1 (ZFHX1B, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition.”

What does this mean in short?

“The elevated serum levels of miR-200a and miR-200b in most patients with pancreatic cancer could have diagnostic utility.”

It will be interesting to see where these ideas go, particularly in high risk populations.

ResearchBlogging.org Li, A., Omura, N., Hong, S., Vincent, A., Walter, K., Griffith, M., Borges, M., & Goggins, M. (2010). Pancreatic Cancers Epigenetically Silence SIP1 and Hypomethylate and Overexpress miR-200a/200b in Association with Elevated Circulating miR-200a and miR-200b Levels Cancer Research, 70 (13), 5226-5237 DOI: 10.1158/0008-5472.CAN-09-4227

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Amgen receives approval for denosumab (Xgeva) in SRE for cancer

By on November 19, 2010

After hearing Amgen’s denosumab (Dmab) was approved late yesterday for skeletal related events (SRE) in the oncology solid tumour indications (but not multiple myeloma) and is now named Xgeva, I was tempted to write a Fun Friday post on how Pharma brand names make the mind boggle lately as you can see a few weird looking names have emerged this year alone.  Seriously, some of them look as though they’ve been hastily put together from Scrabble tiles sometimes, or represent words more usually associated with the old Soviet Eastern bloc countries, never mind figuring out how they ought to be pronounced!  {Update: this one is pronounced x-GEE-va not x-JAY-va as a European might think ;)}

According to the NY Times, the Wholesale price for Dmab in the oncology setting will be $1650 per month, making it around double the price of Zometa (Novartis).  Still, the good news for patients is that Amgen do have a patient assistance program for it and I understand from several sources that Amgen has a co-pay program that offers Xgeva to the patient with no co-pay the first month and only $25 afterwards.  There are apparently no income limits to participate, which if true, would be most unusual.  {Update: here is the link to actual details of the coupon program.}

At the NY Chemotherapy Foundation Symposium last week, several oncologists I spoke to said that a high price would be a significant barrier to use, so it would be reserved for those who do not respond or tolerate Zometa, or have poor renal function.  Urologists would probably be more interested in Xgeva, since Zometa is an infusion product and they tend to refer patients to the oncologist for this.  Xgeva, as a subcutaneous therapy, would therefore potentially be a more convenient option for urologists who have patients that progress to symptomatic metastatic prostate cancer.

The other interesting thing I noticed from the data presented on Dmab at the NY Chemotherapy Meeting, was that while time to SRE was significantly improved with Xgeva compared to Zometa, there was no difference in survival between either therapy, as measured by both progression-free survival (PFS) and overall survival (OS).  There is a risk that oncologists will look at that data and see no meaningful benefit in survival at twice the price for their cancer patients.  We’ll see what unfolds over the next few months, although the slow uptake of Prolia in the non-oncology setting does not portend well for Amgen.

Meanwhile, this week  I’m in the office working on client reports instead of having fun at cancer conferences such as the EORTC-AACR-NCI Molecular Targets meeting that is currently ongoing in Berlin 🙂

A couple of interesting stories in preclinical or early phase development have caught my eye from the meeting so far.

The BBC wrote about nanocarriers and brain cancers, based on some research in mice, for example.  We’ve previously covered nanotechnology at other AACR meetings (in pancreatic cancer), and this is probably one of my favourite disruptive technology concepts to emerge over the last twelve months.  It may be a while before something is actually approved for use in human cancer though.

Another interesting item was data on a new PARP inhibitor, MK-4827, from Merck.  I first posted on the science behind PARP inhibition way back in 2006, with quite a few subsequent posts on the clinical data since (you can find them all by using the Search widget on the right and typing PARP.   Three main compounds have already emerged with a growing body of clinical data, mainly in breast and ovarian cancers:

  1. Olaparib (KuDos/AstraZeneca)
  2. Iniparib (BiPar/Sanofi Aventis)
  3. Veliparib (Abbott)

We can now add the Merck compound to the growing list of PARP inhibitors with data in human trials from phase I and beyond.  According to the ECCO press release, the new data extends beyond breast and ovarian cancers:

“In a Phase I trial conducted at the H Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumours such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers.  Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.”

These patients had metastatic, advanced disease, typically already received treatment with several other therapies and had experienced recurrence.  In this setting, response rates are expected to be low given the high tumour burden:

“The researchers saw anti-tumour responses in both sporadic and BRCA1/2 mutation-associated cancers.  Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment.  Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.”

Of course, it’s still early days yet in a phase I trial, but it will be interesting to see how this new class of cancer agents evolves over the next couple of years.

Photo Credit: Amgen

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American Society of Hematology Meeting 2010

By on November 18, 2010

I’m currently wading through the ASH abstracts on leukemia, lymphomas and myeloma and probably won’t have time to put out a substantial post today.  The meeting is only two weeks away, how time flies!

You can search and check out this year’s abstracts and schedule online here.

This year, I’m actually doing ASH in Orlando and then the San Antonio Breast Cancer Meeting back to back, what was I thinking?  The good news is that the annual Hot Topics and pipeline posts for both events will appear here on the blog soon.

If there are any ASH abstracts on targeted therapies that you would particularly like discussed in a future post, please feel free to add your suggestions/requests in the comments below.

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Mutated gene linked to poor survival in AML

By on November 17, 2010

According to a paper in the New England Journal of Medicine, a gene, DNA methyltransferase 3A (DNMT3A), has been found to be frequently mutated in a subset of patients (~22%) who have Acute Myeloid Leukemia (AML).  The gene has previously been associated with both foetal development and also formation of adult blood cells.  Not surprisingly, these patients often have significantly worse outcomes than patients who have normal copies of the gene.

Many of you will remember Döhner’s breakdown at ASH last year of some AML phenotypes based on a Blood paper from 2009, which illustrates both the simplicity and complexity of the underlying situation.  What’s particularly interesting is that it was clear they had no idea yet which were relevant drivers and which were passengers of the disease.

In the current research, an attempt was made to link the mutation to outcomes:

“Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations…

After discovering a frameshift mutation in DNMT3A with whole-genome sequencing, we conducted a study to determine whether DNMT3A is recurrently mutated in AML samples and whether DNMT3A mutations are associated with poor survival.”

This is important, because the authors concluded:

“DNMT3A mutations are recurrent in patients with AML and are associated with poor event-free and overall survival, independently of age and the presence of FLT3 or NPM1 mutations and regardless of the type of mutation or genetic location. This finding strongly suggests that DNMT3A mutations are probably relevant to the pathogenesis of AML.”

Impact of the findings:

The overall frequency of the DNMT3A mutation was approx. 22% in the study, particularly amongst those people with an intermediate risk profile (none were in the favourable risk category), making it a sizeable target from a potential therapeutic standpoint.

In the short term, the clinical consequence of the data means that people with AML who have the mutated DNMT3A gene are more likely to be selected for more intensive therapy earlier in treatment or for intensive clinical trials, until a more viable therapy option emerges.

References:

ResearchBlogging.orgLey, T., Ding, L., Walter, M., McLellan, M., Lamprecht, T., Larson, D., Kandoth, C., Payton, J., Baty, J., Welch, J., Harris, C., Lichti, C., Townsend, R., Fulton, R., Dooling, D., Koboldt, D., Schmidt, H., Zhang, Q., Osborne, J., Lin, L., O’Laughlin, M., McMichael, J., Delehaunty, K., McGrath, S., Fulton, L., Magrini, V., Vickery, T., Hundal, J., Cook, L., Conyers, J., Swift, G., Reed, J., Alldredge, P., Wylie, T., Walker, J., Kalicki, J., Watson, M., Heath, S., Shannon, W., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M., Link, D., Graubert, T., DiPersio, J., Mardis, E., & Wilson, R. (2010).
Mutations in Acute Myeloid Leukemia New England Journal of Medicine DOI: 10.1056/NEJMoa1005143

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Sometimes in cancer research there really is hope

By on November 16, 2010

This post was chosen as an Editor's Selection for ResearchBlogging.orgIt’s easy to forget that oncologists (whether medical, radiation or surgical) and hematologists deal with death and dying every single day, it’s sadly an integral part of the daily job.  Sometimes though, something comes along that offers hope or perhaps a glimmer of possibilities that life might be significantly extended beyond what is considered usual.

As a marketeer, I was also lucky enough to be a small part of one of those moments in the brief history of time.

Much of the data we see in oncology is about small incremental improvements – a few weeks here, a few months there.  We rarely hear about the stunning improvements of a several years though, because they mostly belong to rarer diseases, but occasionally something bigger than the sum of the parts comes along.

Way back in 1999 when I arrived in the US, I found myself in an empty office with a huge book (De Vita’s Principles and Practice of Oncology) on the desk and a list of about a dozen compounds and people associated with each project team.  One of those was an early phase I compound called STI571, which later became known as imatinib (Gleevec), a breakthrough treatment for chronic myeloid leukemia (CML).

People often ask what it’s like to be involved with new product development. The short answer is it’s a bit like a roller coaster – you have to learn to terminate the also-rans early and reinvest resources in more promising projects and of course, picking the winners from the losers is never as easy as it looks, as well as drive and motivate a diverse bunch of people so that great teams are formed.   It’s about quiet leadership, inspiring others to go above and beyond rather than rah rah management, which tends to be more about politics and self interest than anything else.  Basically, it means getting everyone on board, move the project forward expeditiously and navigate the challenges along the way and have some fun together as well, because:

  1. you spend 12 hours a day in their company
  2. you really want this to end well for patients
  3. be a meaningful experience for all involved.

On bad days, fire drills for someone else’s urgent licensing project/evaluation may well derail you from your focused efforts.

On good days, you get to meet the physicians involved in the clinical trials, hear their stories, you meet real patients in the clinics and hear their stories too…  about hope, endurance, fear, the funerals they planned and the genuine wide eyed wonder of various test results that show the drug is working and they’re actually on the long road to recovery and getting their life back.  At that point, everyone cries, even the cynical curmudgeonly ones.

This is ultimately what many of us really live for in the Pharma industry – an opportunity to make a real difference to people’s lives and help them beat the odds.

With that background, you may all be wondering where I’m going with this post.  The answer is simple.  Last night I was checking out the latest Blood Journal online and spotted a paper from Tim Hughes and the International Randomized Study of Interferon and STI571 (IRIS) investigators.  It describes the latest update from the trial, which opened to accrual in early 2000, ten years ago.  I had goosebumps waiting for the article (see reference below) to load – an update a decade on from initiation of  a cancer trial? How many times do you hear about that in the news?  You don’t, typically.

What was the article about?

“This study examines the prognostic significance of early molecular response using an expanded dataset in chronic myeloid leukemia patients”

One of the most important measurements in CML is Major Molecular Response or MMR, which refers to the level of transcripts in the blood ie BCR-ABL is less than 0.1%. The lower the levels the better, due to a lowered leukemic burden and risk of relapse.

What does the data now tell us?

“Serial molecular studies demonstrate decreases in BCR-ABL transcripts over time.”

In short:

“Patients with BCR-ABL transcripts >10% at 6 months and >1% at 12 months had inferior EFS and higher rate of progression to AP/BC compared with all other molecular response groups. Conversely, patients who achieved major molecular response by 18 months enjoyed remarkably durable responses, with no progression to AP/BC and 95% EFS at 7 years.”

Broader impact of this data:

Prior to the approval of Gleevec, people newly diagnosed with CML had maybe a typical lifespan of 3-4 years with interferon, longer with stem cell transplants, but with a high cost in terms of long term side effect management and maybe a year or less if unfortunately diagnosed with accelerated or blast crisis CML.  These days, the outlook is much better.  According to some of the investigators I’ve spoken to recently, a  few of the original patients who entered the accelerated phase trials in 1998/1999 are still alive, which is amazing when you consider it’s over 10 years on.  They’ve not only beaten the odds  but for many, they were able to live a fairly normal life, something none of us imagined in those days.  For newly diagnosed patients, the TKIs now means that 10 years (not weeks or months) extra life is a reasonable and realistic goal to aspire to.  For most people, there are also 3 excellent choices whereas before the choice of interferon or stem cell transplant was much starker.

This is the first time I’ve really been convinced by the data that there is compelling evidence for a strong association between the degree to which BCR-ABL transcript numbers are reduced by kinase therapy and long-term clinical outcome. This is something Tim Hughes has been raising for several years, with the idea that people who achieve a deep molecular response are more likely to sustain better long term outcomes. Before, it very much a theory or even a hope, now it’s reality.

This data also has a major impact on the second generation TKI’s, because both nilotinib (Tasigna) and dasatinib (Sprycel) have both been shown to be superior to imatinib in frontline (newly diagnosed) CML in terms of earlier and deeper responses.   Now,  we don’t have any long term survival data beyond 18 months to two years for either of the 2nd generation TKIs compared to 7 or 8 years survival data for Gleevec, but this new evidence suggests that attaining a sustained MMR is ultimately best for the long term health of people with CML.

In general efficacy terms, it’s like going from a drug that offers 90% response rates to ones that incrementally improve it to say, 93 or 94%, but the real impact is at the molecular level because if you can achieve an MMR, ie reach what Tim Hughes called the ‘safe haven’ at ASCO, you are less likely to relapse.  For the first time I can see that being a real advantage for the 2nd generation TKI’s over Gleevec, since the MMR data with the second generation TKI’s is superior to Gleevec.  That said, for people who are doing well on Gleevec and have attained a good molecular response, there is no reason to change.

The future:

There are also several other TKIs in development, including bosutinib (Pfizer) and ponatinib (Ariad).  Ponatinib is particularly exciting because it inhibits the rare T315I mutation, which none of the others do and is currently in phase II clinical trials.  This is one to watch out for in the future.

Either way, they’re all good drugs and I’m personally delighted to have been a smart part in the early development of one of them; it’s a privilege to have worked with some great investigators and as well as learning from many wonderful people dealing with cancer.

With this new data and scientific evidence, I can see the mantle is finally passing on to a new generation of therapies.  To have one great drug approved for CML that made a genuine difference is truly amazing, to have 3 approved is incredible and there a few more still in development.  For people living with CML, there is indeed Hope.

References:

ResearchBlogging.org Hughes, T., Hochhaus, A., Branford, S., Muller, M., Kaeda, J., Foroni, L., Druker, B., Guilhot, F., Larson, R., O’Brien, S., Rudoltz, M., Mone, M., Wehrle, E., Modur, V., Goldman, J., Radich, J., & , . (2010). Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS) Blood, 116 (19), 3758-3765 DOI: 10.1182/blood-2010-03-273979

Disclosures:

I’m a former employee of Novartis and worked on the early development and original launch of Gleevec in CML and GIST.  My opinions are my own, but I’m clearly biased by the incredible experience 🙂  Novartis has also been a client, but was not involved in any way with this post.

Author owns no shares in any of the companies mentioned.

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