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Cancer Clinical Trials: Companion Diagnostics or Gene Sequencing?

Last year saw some interesting developments from MD Anderson Cancer Center in early phase clinical trials that may have a far-reaching impact on the future of cancer research as we know it:

  1. At ASCO in June, Dr Tsimberidou presented the initial results from a phase I study run by the MD Anderson Department of Investigational Cancer Therapeutics group. Instead of testing patients with a given cancer (eg lung) for individual mutations eg ALK or EGFR and then offering patients a targted drug as we normally do, they ran a broad diagnostic panel across a multitude of patients with different cancers to determine what the tumour was telling them about the aberrations and selected appropriate targeted therapies. While the study was small in size, the results were better than random selection.
  2. In September at the ECCO meeting in Stockholm, Dr Gordon Mills (Head of Systems Biology) stated in his keynote presentation that 30,000 cancer patients at MD Anderson would be screened and tested for aberrations using gene sequencing. This has huge implications for clinical trial efficiency, since they will effectively generate a powerful database that will enable them to match patients to studies based on the precise selection criteria, rather than looking at a protocol and testing new patients that subsequently come in the door for each target individually.

The other thing that many readers have asked about is companion diagnostics and whether they are the future following the recent approvals of crizotinib (Xalkori) and vemurafenib (Zelboraf) in ALK+ lung cancer and BRAFV600E melanoma respectively?

More recently, we have seen numerous papers discussing the findings from massive parallel sequencing studies (more on that tomorrow) and developments in gene sequencing, including a dramatic announcement from Oxford Nanopore on Friday regarding its novel third generation sequencing progress.

I decided to discuss these issues with Dr Razelle Kurzrock, who heads up the Department of Investigational Cancer Therapeutics group at MD Anderson.  Here’s the transcript of the interview.  Please do check out the brief audio clip too, as this highlights a very important trend for the future with gene sequencing costs/time coming down.

PSB: Could you tell us a bit more about your phase I group and what you are doing with regards to matching therapies to targets?

Dr Kurzrock: Essentially we do phase 1 studies, which can be anything from new first in human drugs that are just going from animals to patients, or really any other phase 1. It might be in experimental drugs, or new combinations of two experimental drugs, combinations of an experimental and an FDA approved drug or combinations of FDA approved drugs. It is any new study that is just a new way of looking drugs is considered phase 1. That is really what we are doing. It is sort of a large scale, we have about 128 studies and we put over 1100 patients on study last year.

But I don’t think that has really gotten people interested or that we really are at the point that we are most excited about. The idea is to do molecular profiling on patients as they come in the door, then to try to match them with the appropriate targeted drugs. Of course people have done this for individual studies, like the ALK inhibitor crizotinib, the investigators and the company looked for ALK rearranged lung cancer patients.

The thing that we are doing differently is that we are not looking for one abnormality to match with one drug. We are looking at a panel of abnormalities as patients come in the door and then decide which drug to match them to. So it is a more generalized type of way of doing things and I am sure it is the way things will be done in the community in the future. It is a really simple concept, but nobody has done it like this before.

PSB: If you have more than one abnormality will you consider combination therapy or just target the main mutation first?

Dr Kurzrock: Well, I think it is either one. If you have more than one abnormality you can consider combinations or you can try and figure out what the main one is. The concept of looking for multiple abnormalities at once is really a diagnostic concept.

As an example if you had lung cancer, we know that there is ALK rearrangement in 4% of patients, then there might be an EGFR mutation in 5% of patients and probably when we look at al lung cancer there might be 20 different mutations, subsets of patients. There may be 50, we don’t know all of them yet.

This inevitably has implications of how we test and screen patients for clinical trials, as Dr Kurzrock astutely observed in the sound bite below:

PSB: I like the idea of doing the panel, and with over 100 studies, it must make it more efficient to assign patients to the appropriate clinical trials?

Dr Kurzrock: I think it is a lot more efficient. With the caveat that this was not a randomized study, what we saw in our pilot study was that we were getting response rates that were considerably higher than what we would expect in phase 1.

Our background response rates are about 5% of our patients will get a complete or partial remission if we just do things the old way, remembering that phase 1 patients are patients that have by definition failed all therapy. They are often in good shape, but have a highly resistant and lethal tumor.

But the response rates when we did the matching was 27%. Again, this isn’t a non-randomized trial so there are biases, but it could be actually biases that might lower the response rate or biases that might raise the response rates. But the bottom line is that it was much higher than what we would have anticipated. This of course needs to undergo more rigorous testing, but we were impressed that doing this was better for our patients and actually better for drug development.

PSB: So are you using next generation sequencing to drive your diagnostic panel?

Dr Kurzrock: That’s a good question. This is an area in very rapid flux. When we presented our data at ASCO 2011, we presented first generation data where we were just doing a very small panel of mutational analysis. Essentially we presented in mid 2011, data from 2010 mainly and the field has moved so quickly. The data was especially impressive because we used this primitive, first generation way of doing things. We are now expanding to using a Sequenom panel which looks at multiple different mutations, and I think the next generation panel is going to be the one that comes on line pretty soon. All exomic sequencing, while it can be done, the bioinformatics is still complicated and that is probably not quite ready yet. I think it will be ready maybe in a year or two years, but I think that is not quite ready to be used on large volumes of patients. But, Next Gen Sequencing, although you use the methodology, you only pick a set number of genes say 300, that is probably useable at this point.

PSB: I remember talking to Gordon Mills at ECCO and he said as the cost of sequencing costs come down, the analytical costs are going to go through the roof because it gets more and more complicated.

Dr Kurzrock: The analytical costs are now the problem. But, where I disagree is having seen how rapidly this field moves, what we need now is a jump in analytical capability. So if we assume there is not going to be a jump in knowledge, it is going to go through the roof.

I have a different assumption, I think there will be a leap. People are working on this. There is going to be a leap in the way we do things. We are going to be able to do the bioinformatics very quickly and the costs will come down just like the costs of sequencing.

In the early 1990s, I remember when everybody who knew anything said we would never sequence the human genome because it was too complicated. Then by the late 1990s we had sequenced the human genome, but it cost $3Billion dollars to sequence a patient. Now it costs $5000 and one company has said they will do it for $1000. This took leaps in technology that have occurred extraordinarily rapidly in 10 or 12 years. I absolutely think those leaps will occur in bioinformatics now, which is the sticking point.

PSB: Many oncology pharma companies seen to be going down the route of developing a companion diagnostic test with a targeted therapy e.g. crizotinib and vemurafenib, but I’m wondering is that really the way of the future?

Dr Kurzrock: I think that is not the way of the future, for the reason that I said. It is an interesting thing, the diagnostic panel is a great idea, but technology is moving so fast now that the diagnostic test is going to be outmoded, if it is not already outmoded.

And it is for the reason that I mentioned. A patient walks in the door, you can not see if that patient has whatever type of cancer whether it be breast cancer or lung cancer or whatever, you can not tell by look looking at that patient which diagnostic panel to do. You just can’t know. In essence you can choose to do one diagnostic test but that will probably be 4% of patients with that disease. So what you are going to have to do is multiple diagnostic tests to cover all the realms of possibility. If you license diagnostic tests one at a time and I have to do 20 or 50 or whatever tests, it is going to be hugely expensive, plus probably you will run out of tissue and you will have to rebiopsy the patient.

To me the way of the future will be a multi-assay panel whether it is Sequenom or next gen sequencing, probably it will be next gen sequencing or something like that, that will look at all the possible aberrations, rather than looking at them one at a time. Ultimately it is going to run up the cost if we do it that way [with individual diagnostic tests].

PSB: If we want to help more patients then we have to figure out what the aberrations are?

Dr Kurzrock: I think in the most simple sense, this is simply diagnosis. The reason we diagnose patients and we try to figure out whether you have breast cancer, you have lung cancer or colon cancer or some other cancer, is in order to give you the best treatment. That is the reason we give you a diagnosis, also to tell you the prognosis, but we want to tell you your best treatment.

Up till now, we the way we have diagnosed patients is with a light microscope that was invented back in 1590. In the simplest sense this is just a more sophisticated way of diagnosing patients, and it as at the molecular level. It is like using a molecular microscope except the molecular microscope is Next Gen Sequencing. So we really want to know when a patient walks in the door, what do you have, what is your disease at a molecular level? You can’t do that by using one probe at time, you have to look at all the relevant gene abnormalities and then figure out which one is abnormal.

In summary…

There is no doubt in my mind that broad molecular gene profiling (or massively parallel sequencing as it is often called in research) to find aberrations in the tumours of cancer patients will be:

  1. Faster
  2. More effective

for patient clinical trial selection than the current approach of biopsies for individual targets based on a single diagnostic test.  If we want to speed up clinical trials a broader screening approach will no doubt be a better starting point than searching for small needles in a haystack.

That said, the challenges going forward are still many.  These include greater analytical and bioinformatic costs, as well as figuring out which aberrations really matter.  After all, some will be drivers, but many will be passengers that merely add noise to the signal, so targeting every aberration that appears in a panel may not actually have any effect clinically and may even induce unwanted systemic side effects.

Until we determine which aberrations are the critical targets in each tumour type or subtype, as well as identify those that develop in response to therapy (adaptive resistance), then we still have a long way to go in terms of improving our understanding of the biology underlying the many diseases that make up ‘cancer’ and improving patient outcomes with therapeutic interventions.

 

 

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A new fusion gene target in a rare soft tissue sarcoma

By on February 14, 2012

Every now and then my eye is caught by reports of new fusion genes being found in different cancers.  Often these descriptions involve researchers across multiple laboratories due to the rarity of the target.  Following a discussion on Twitter yesterday, a friend sent me the link to this interesting paper published in Science Translational Medicine.  Naturally, one of the first things that came to mind was ‘is the identified target druggable?’

Source: wikipedia micrograph of epithelioid hemangioendothelioma (from the liver)

Tanas et al., (2011) used deep gene sequencing and conventional cytogenetics to identify two genes involved in chromosomal translocation in epithelioid hemangioendothelioma (EHE), a rare vascular sarcoma that arises out of endothelial cells, namely:

  • WWTR1, WW domain-containing transcription regulator 1 (3q25) and
  • CAMTA1, calmodulin-binding transcription activator 1 (1p36).

The researchers noted that:

“CAMTA1 encodes a transcription factor that is found in all multi- cellular organisms tested and is evolutionarily conserved from Arabidopsis to humans.”

What is its function?

“Little is known about the protein’s function in mammalian cells, but in humans, the gene is expressed almost exclusively within the brain and has been implicated in memory because high amounts of CAMTA1 mRNA have been identified in memory-related regions.”

Now, there are a couple of other things to note:

  1. Not much is known about EHE, as the sarcoma was only described recently by Weiss and Goldblum (2008) in Enzinger and Weiss’s Soft Tissue Tumors. They appear to affect both sexes equally and are not age dependent, appearing in soft tissue, bone and visceral organs such as the liver and lungs.
  2. There are no current treatment options for EHE, other than surgical removal.
  3. Diagnosis of EHE is currently challenging and requires careful histological examination.

The paper is well worth reading for those interested in the challenges of fusion gene isolation, but what particularly struck me was the prevalence of the translocation in EHE compared with other sarcomas – it appears to be very distinctly different, since none of the others evaluated (nearly 30 of them, was found to have the translocation).

The presence of the fusion gene in EHE but not the other sarcomas strongly suggests a role in tumorigenesis, i.e. it’s an oncogene rather than a tumor suppressor gene.

“We anticipate that understanding the mechanism of WWTR1/CAMTA1 oncogenesis will be instrumental toward developing targeted therapy for EHE, for which none currently exists.”

There are some positive things that emerge from this research. In some ways, identification of the fusion gene in EHE may well change diagnosis and treatment options in the future for patients with the disease, much in the same way that imatinib helped to redefine the diagnosis and treatment of another rare sarcoma, gastrointestinal stromal tumours (GIST) in 2002.  Hope, as they say, is always just around the corner.

If any scientists or pharma people following this blog have something in their pipeline that may target the WWTR1/CAMTA1 fusion gene, then please let me know – it would be useful if we could crowdsource potential therapies aimed at oncogenes actively involved in tumorigenesis of rare cancers.

{UPDATE:  Bruce Shriver from the Liddy Shriver Sarcoma Initiative, patient support group since shared this link via Twitter on the background to the disease in plain English and further development of the fusion gene research – please check it out! }

References:

ResearchBlogging.orgTanas, M., Sboner, A., Oliveira, A., Erickson-Johnson, M., Hespelt, J., Hanwright, P., Flanagan, J., Luo, Y., Fenwick, K., Natrajan, R., Mitsopoulos, C., Zvelebil, M., Hoch, B., Weiss, S., Debiec-Rychter, M., Sciot, R., West, R., Lazar, A., Ashworth, A., Reis-Filho, J., Lord, C., Gerstein, M., Rubin, M., & Rubin, B. (2011). Identification of a Disease-Defining Gene Fusion in Epithelioid Hemangioendothelioma Science Translational Medicine, 3 (98), 98-98 DOI: 10.1126/scitranslmed.3002409

The role of the Androgen Receptor in breast cancer

By on February 10, 2012

This week I have been in Orlando for the American Association for Cancer Research (AACR) Special Conference on prostate cancer chaired by Drs Arul Chinnaiyan (U. of Michigan) and Charles Sawyers (MSKCC).  It was a superb meeting, probably one of the best I’ve attended since the PI3K meeting that AACR hosted in February last year.  I wrote nearly half a Moleskine of notes that vaguely resemble chicken scratch – there were so many good talks that stimulated new ideas and explained a few scientific things I also didn’t know too well.  Learning is a continuous lifetime experience, after all.

During the meeting, I had a nice correspondence with one of our regular blog readers, the thoughtful Biomaven.  Peter mentioned some data on the androgen receptor (AR) as a potential target in breast cancer following Medivation’s recent conference call.  It’s an interesting topic and one well worth discussing.  Here’s a map of the AR pathway for reference:

Source: wikipedia

The AR is not something one naturally and immediately thinks of in women, since testosterone is usually considered a manly thing.  That said, it is present in women in both normal breast epithelial cells and ~70% to 90% of invasive breast cancers.

Until recently, the link, however between AR status and breast cancer survival is uncertain and perhaps a little controversial, but Hu et al., (2011) looked at the association between the AR status and breast cancer survival in the Nurses’ Health Study (NHS) – see references at the end for the link to the article.

What was the study about?

According to the authors:

“The NHS is a prospective cohort study established in 1976 when 121,700 female registered nurses from across the United States, aged 30 to 55 years, completed a mailed questionnaire on factors that influence women’s health.

Follow-up questionnaires have since been sent out every 2 years to the NHS participants to update exposure information and ascertain nonfatal incident diseases. Follow- up rate from 1976 to December 2007 is 98.9% in our study.”

Not to be confused with an population/epidemiology study from the NHS (National Health Service) in the UK!  The main goal of this study was to:

“… determine the association of AR status with survival outcomes adjusting for covariates.”

What did the research find?

Out of all the breast cancers followed (n=1467), 78.7% were AR+. Additionally, amongst the ER+ patients (n=1,164), 88% were AR+:

“AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47–0.99) and overall mortality (HR, 0.70; 95% CI, 0.53–0.91) after adjustment for covariates.”

The situation was very different in women who were ER- (n=303) though:

“42.9% were AR-. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94–2.68).”

In other words, AR+ confers a better prognosis in ER+ breast cancer.

Now, the relevance of all this research is potentially important when considering possible mechanisms of resistance to aromatase inhibitor (AI) therapy in ER+ breast cancer.  Recall that one mechanism of resistance to AI treatment is mTOR, which is why the BOLERO2 trial with an AI (exemestane) plus an mTOR (everolimus) in the relapsed setting did so well in ER+ women.  Not all of the women in the trial responded to the treatment though, suggesting that other factors may play a role in acquired or adaptive resistance.

What is the importance of AR to therapies for breast cancer?

Normally, knowing whether a particular situation has a better or worse outcome isn’t particularly helpful for patients, since it doesn’t predict which therapy might be more appropriate. However, there is some other AR and breast cancer research from Cochrane et al., (2011) which was presented to the Endocrine Society Peter referred to that tells us a bit more of the AR story:

“We postulate that ER+ breast cancers that fail to respond or become resistant to current endocrine therapies (tamoxifen or AI) may do so because they have switched from growth controlled by estradiol (E2) and ER to growth controlled by liganded AR.

We therefore sought to determine if blocking AR activity could serve as a therapeutic intervention for such tumors.”

What did they do?

Cochrane et al, (2011) stated that:

“We used breast cancer cells that express ER and AR such as MCF7 cells and a cell line that we recently isolated that contains more AR than ER.

Our data indicate that although DHT does slightly inhibit E2-mediated proliferation, DHT alone is proliferative in cells such as MCF7 with both ER and AR, and is even more proliferative than E2 when AR is more abundant than ER.”

What did the results show?

The results were a) interesting and b) a little surprising:

“We found that while both the anti-androgen bicalutamide and the triple acting, non-steroidal, AR antagonist MDV3100 block DHT and R1881-mediated proliferation of breast cancer cells, we made the novel observation that MDV3100, but not bicalutamide, inhibits E2-mediated proliferation of breast cancer cells.”

These results led the authors to conclude that:

“Anti-androgens, such as MDV3100, may be particularly useful to treat patients whose tumors fail to respond to traditional endocrine therapy despite being ER+, or who have ER-/AR+ tumors.”

Not surprisingly, Medivation announced on their recent conference call this month that they will be seeking to explore this phenomenon in clinical trials.  I think this is a logical and exciting development that is well worth a shot on goal.  We know that not all the women in the BOLERO2 trial responded to exemestane and everolimus, so other mechanisms must be at play here.  This is certainly worth exploring.

The question with the study design of me for me though, is patient selection.  How do we determine which women whose initial AI therapy leads to relapse should go onto an mTORor an AR antagonist?  I’m guessing that maybe biopsies will be part of the answer.

In conclusion…

On the positive side, it would be pretty cool if we could uncover two mechanisms of resistance to AI therapy in ER+ breast cancer and have some viable therapies to offer women once relapse or acquired resistance sets in.  It would start to offer a) hope and b) potentially prolong outcomes further as we determine ways to shut down the various escape routes and signaling pathways.  If the concept works, given that up to 30% of women with ER+ breast cancer may have AR+ signaling, then it would also be good news for Medivation and Astellas with MDV3100’s potential upside.

References:

ResearchBlogging.orgHu, R., Dawood, S., Holmes, M., Collins, L., Schnitt, S., Cole, K., Marotti, J., Hankinson, S., Colditz, G., & Tamimi, R. (2011). Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women Clinical Cancer Research, 17 (7), 1867-1874 DOI: 10.1158/1078-0432.CCR-10-2021

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Is ARN-509 (Aragon) potentially better than MDV-3100 (Medivation) in advanced prostate cancer?

By on February 2, 2012

Many readers will have noticed that the advanced prostate cancer market is rapidly becoming crowded with three new therapies (cabazitaxel, sipuleucel-T and abiraterone) already approved and several more in late stage development, including Alpharadin (radium-223) and MDV3100, both likely to file this year. In addition, others are focused on bone complications, such as denosumab, which is expected to have a tough ODAC meeting this month, and cabozantinib, a multikinase inhibitor currently in phase III trials.

Unlike breast cancer, where progression-free survival (PFS) is a used as a surrogate measure of survival, in advanced prostate cancer, overall survival (OS) has pretty much become the gold standard by which prostate cancer trials are reviewed. This makes it much easier to judge whether the drugs are having a positive effect on true efficacy, i.e. do patients live longer as a result of treatment.  PFS is particularly difficult to measure in prostate cancer, so it’s not surprising this approach has evolved as the standard measurement.

Interestingly though, Health Authority approval does not always mean reimbursement coverage, as NICE showed yesterday in declining to approve abiraterone in the UK on the grounds that it is too expensive. The BBC quoted a patient who had been on abiraterone for only three months, with a positive impact:

“I have my life back. I have a lot more energy and no pain. My quality of life is excellent. I wouldn’t even know I have cancer now, it’s that good.”

The BBC also quoted his wife, who had an excellent point:

“We know NICE has to take a lot of things into consideration, but when you have a terminal illness an extra four months is very precious.”

Source: BBC

Of course, it’s very much a case of balancing available resources with potential benefits and unfortunately, advanced stage patients will inevitably take the lion’s share in terms of budget for disease management. Post EMA approval, some local UK health providers permitted the drug to be used on an individual basis, raising the old contentious issue of the rather unfair post code lottery (zip code for Americans).

Going forward, no doubt there will be much political posturing and pressure, as you can see from Cancer Research UK, who helped fund the research, but hopefully a deal can still be struck between NICE and Janssen, the manufacturer, on price to enable British men broader access to the drug.

One of the things that has struck me lately, though, is how prostate cancer is attracting serious research focus, such that a heterogeneous disease is slowly being more segmented based on the underlying biology of the tumour. Examples include Arul Chinnaiyan’s superb work on the TMPRSS2-ERG fusion gene and Charles Sawyers’ work on the Androgen Receptor.

Thanks to Sawyers work we now know that the old terminolgy ‘androgen independent’ prostate cancer is an incorrect way of descibing advanced disease because as Clegg et al., (2012) described Scher et al’s original research findings in 2005:

“Despite administration of androgen-depleting therapies, continued androgen receptor (AR) signaling is a common feature of CRPC, attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors.”

In other words, the AR is very much an oncogenic driver of the tumour’s survival.

This week, we saw promising data for MDV3100, an AR antagonist in the post chemotherapy setting but what of the pipeline beyond abiraterone and MDV3100?

Previously, we came across Aragon’s ARN-509 AR antagonist, which is much further behind in phase I/II clinical trials. Sawyers and Michael Jung, the co-inventors of MDV3100 while at UCLA also developed (along with several other scientists) additional AR compounds, the most promising of which became ARN-509. Aragon is a privately held company formed out of the UCLA discovery with the intent of developing and commercialising this compound.

The obvious question arises – is it a ‘me-too’ or potentially better than MDV3100?

Preclinical data has just been published in Cancer Research by Clegg et al., (2012) addressing this issue. They argued that, based on their findings:

“In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100.”

Of course, preclinical data doesn’t always translate to the clinical setting, but my first reaction was ‘Whoa!’

Let’s take a look at the agent in more detail.  ARN-509, like MDV3100, is a pure antagonist of the androgen receptor, unlike bicalutamide (Casodex), which has both agonist and antagonist properties.  The idea behind this is that there will be less resistance and greater therapeutic potential for more comprehensive binding with the receptor.

We know from work in Sawyers lab that MDV3100 targets splice variants, which have been shown to cause resistance in CRPC, but we don’t yet know how ARN-509 will fare on that front.

So why did Clegg et al., (2012) suggest that ARN-509 might be superior to MDV3100?

“Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations.

Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists.”

In other words, it’s much more potent and has a greater therapeutic index; these things are important clinically. It also has a longer half-life:

“ARN-509 exhibits low systemic clearance, high oral bioavailability and long plasma half-life in both mouse and dog, supporting once-daily oral dosing.”

Androgen deprivation therapies are more commonly used in castrate-sensitive disease, so this begs the question of whether there is anti-androgenic activity in the non-castrate setting:

“At higher doses of 30 mg/kg/day, robust tumor-regression (>50% reduction in starting tumor volume) was observed in 6/8 ARN-509-treated animals, similar to regressions observed in mice castrated on the day treatment initiated.”

The promising results led the researchers to conclude that:

“ARN-509 is a next generation anti-androgen selected for pre-clinical and clinical development based on its efficacy and pharmacodynamic profile in mouse xenograft models of CRPC.”

They also stated that:

“Unexpectedly, given a similar in vitro profile, ARN-509 is more efficacious per unit dose- and per unit steady-state plasma-level in mouse models of CRPC than MDV3100.”

In other words, ARN-509 is a next generation AR antagonist with a good efficacy and PK profile in mouse xenograft models of CRPC.  It’s clinical development, although further behind abiraterone and MDV3100, will be well worth watching over the next few years.

In summary…

While there has been a lot of activity in the advanced prostate cancer market lately with new approvals making a difference to the lives of men with prostate cancer, there are also several other promising near term agents in development, as well as some potentially more potent and effective treatments in early clinical development.  What we have seen to date is merely the beginning of new advances in R&D.

The early and advanced prostate cancer markets are likely to see some significant changes over the next 24 months, as new products based on rational drug design and an improved understanding of the biology of the disease make it to market.

More on prostate cancer coming soon!

All this new data is very timely, considering on Monday I’m off to the AACR Special Conference on Prostate Cancer, jointly chaired by Drs Chinnaiyan and Sawyers.  I’ll be interested to learn what new events are emerging as biological targets and what factors can help us predict response to treatment.  If you’re going to this meeting do stop and say hello, it’s always good to meet new people in the field.

References:

ResearchBlogging.orgClegg, N., Wongvipat, J., Tran, C., Ouk, S., Dilhas, A., Joseph, J., Chen, Y., Grillot, K., Bischoff, E., Cai, L., Aparicio, A., Dorow, S., Arora, V., Shao, G., Qian, J., Zhao, H., Yang, G., Cao, C., Sensintaffar, J., Wasielewska, T., Herbert, M., Bonnefous, C., Darimont, B., Scher, H., Smith-Jones, P., Klang, M., Smith, N., de Stanchina, E., Wu, N., Ouerfelli, O., Rix, P., Heyman, R., Jung, M., Sawyers, C., & Hager, J. (2012). ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Research DOI: 10.1158/0008-5472.CAN-11-3948

Scher, H. (2005). Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis Journal of Clinical Oncology, 23 (32), 8253-8261 DOI: 10.1200/JCO.2005.03.4777

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Update on Medivation’s MDV3100 in advanced prostate cancer

This weekend heralds the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting in San Francisco, although ASCO held their press briefing today to provide an update on some of the key topics.

For those of you interested in Alpharadin (radium-225) in castrate-resistant prostate cancer (CRPC), check out the update of Dr Oliver Sartor’s presentation, which is covered on Biotech Strategy Blog.

The key topic that most interested me though, was Dr Howard Scher’s update on Medivation’s Androgen Receptor antagonist, MDV3100, in CRPC.  Previously, Medivation announced that the data showed an improvement in median overall survival (OS) of 4.8 months and this is still solid (Note: J&J’s abiraterone was approved by the FDA based on an OS of 3.9 months in the same population and must be taken with prednisone).

Three new things were important in this presentation though:

  1. There has been some previous concern about the risk of seizures, after they were reported in an earlier trial, but that was at much higher doses.  In this study, the now standard (and much lower) 160 mg dose of MDV3100, demonstrated low levels of seizures (0.6%), which is very reassuring and not something I think many will worry too much about.
  2. MDV3100 has a nice effect not only on OS, but also median time to confirmed PSA Progression, i.e. 8.3 months vs. 3.0 months for placebo (HR 0.248, P<0.0001). Yes, I had to do a double take at that HR – it’s quite phenomenal!
  3. Aside from PSA drops, patients often like to know if their tumour is shrinking or not as evidence of activity and progress. Dr Scher showed the soft tissue response by CT/MRI imaging. There was a 28.9% response rate with MDV3100 compared with 3.8% for placebo (P<0.0001).

From this data we can definitely say that patients lived longer, saw a positive impact on their PSA levels, and felt better compared to placebo. In terms of serious adverse events, there were fewer in the MDV3100 arm (28.4%) versus the placebo arm (33.6%). There were also slightly more discontinuations in the placebo (7.0%) than MDV3100 (3.8%) cohort.

Overall, I wasn’t at all surprised when the host, Dr Nicholas Vogelzang (Medical Director of the Developmental Therapeutics Committee of US Oncology) exuberantly said he had only one comment to Dr Scher’s presentation of the MDV3100 data,

“Wow, that’s very impressive! It’s unprecedented.”

For once, I thought that ‘impressive’ was actually an understatement to apply to a cancer drug.

I also talked to Dr David Hung, CEO of Medivation afterwards. Many readers will remember my interview with Dr Charles Sawyers, the co-inventor of MDV3100, last year about the science behind the development. It was nice to see Medivation’s side of the R&D story, which has gone pretty rapidly so far.

PSB: Are you going to be filing soon based on this data?

David Hung: We are having a pre-NDA meeting with the FDA. Once we have that meeting we will be able to give much more concrete guidance on when we will be filing.

PSB: Some of the pre-chemo trials have started, would they be due to report some data soon?

David Hung: We haven’t given any timelines on any of our other trials.

PSB: When I interviewed with Charles Sawyers previously, he said that many pharma companies were not interested in what is now MDV3100. What did you see in it when many others said “no”?

David Hung: Charles didn’t approach me. I found him! I had read, with great interest, his work on the AR. I was very familiar with his Nature Medicine publication in 2004 showing that overexpression of the AR is a significant molecular change in patients with castration resistant disease. While I think a lot of people thought that targeting the AR would create just another AR antagonist, like casodex, the data suggested to me there was more here.

Because, in Charles’ lab by being able to over-express the AR, we were able to much more carefully assay and screen compounds for their ability to block androgen receptor signaling very thoroughly. And we found in the process that a number of compounds in the series that we were testing had ability to not only block just AR binding by testosterone, which is something that Casodex does, but unlike Casodex these compounds were able to inhibit nuclear translocation as well as DNA binding and activation by the AR.

I am an oncologist by training and was pretty familiar with this area, so when I saw the compounds and saw the data in more detail, I didn’t agree that it would just be another casodex like molecule. I thought the mechanisms suggested that this drug could be special, so when I went ahead and licensed the drug back in 2005. We then took the program forward rapidly through development. We had to do all the standard pharmacokinetics, metabolism, tox, formulation work, then take it into a clinical trial as quickly as we could, led by Howard Scher. So, we were able to develop the molecule very quickly.

One of the differences with MDV3100 over weaker AR antagonists such as bicalutamide, is it’s ability to target splice variants. This was a surprising but important finding. I asked Dr Hung about them:

PSB: Does that potentially mean that the patients in the current trial data presented by Dr Scher, may actually do better over time or is the 4.8 months OS probably going to be the final number?

David Hung: Well, I won’t know the answer to that until I unblind the PREVAIL trial. What is very interesting from our phase 1 / 2 data is that the time to PSA progression in post-chemo patients in that data set is about 203 days. Yet, the time to PSA progression in the pre-chemo patients was 4x longer than that, 812 days, suggesting that the drug may have even more robust activity upstream than it does downstream. Downstream it already has robust activity. We will be greatly looking forward to seeing the PREVAIL data, because that is the pre-chemo population. If we can recapitulate our phase 1 / 2 results, that would be great news for patients.

PSB: At AUA last year, I heard from Charles Sawyers that if you inhibit the androgen receptor, you often activate the PI3-Kinase pathway. His colleague Neil Rosen had also noticed that if you inhibit PI3K, you activate androgen receptor in prostate models. So Charles was saying in their joint paper that the logical thing to do would be to combine an androgen receptor inhibitor and a PI3K-inhibitor to potentially reduce the resistance and hopefully improve outcomes. Is that the kind of combination you might consider in the future?

David Hung: We actually are. You point out exactly the kind of things that we think about. We look to see how our drug works and we look to see what mechanisms might possibly complement our drug. That is the way we think about potential combination studies that we might do.

All this is very exciting news for both Medivation (and commercial partner Astellas), as well as patients with advanced prostate cancer. I hope that the discussions with the FDA go well and we will see a filing, perhaps even with Accelerated or Priority Review in the near future. Based on the data so far, the data clearly shows that MD3100 can make a difference to the lives of men with advanced prostate cancer.

Next week, I’ll be at the American Association for Cancer Research (AACR) Special Conference on Prostate Cancer, jointly chaired by Charles Sawyers (MSKCC) and Arul Chinnaiyan (Michigan) to learn more about the biology of prostate cancer. It promises to be both a timely and exciting meeting!

References:

ResearchBlogging.orgChen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, & Sawyers CL (2004). Molecular determinants of resistance to antiandrogen therapy. Nature medicine, 10 (1), 33-9 PMID: 14702632

Carver, B., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., Arora, V., Le, C., Koutcher, J., Scher, H., Scardino, P., Rosen, N., & Sawyers, C. (2011). Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer Cancer Cell, 19 (5), 575-586 DOI: 10.1016/j.ccr.2011.04.008

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FDA approves Roche hedgehog inhibitor vismodegib/Erivedge in basal cell carcinoma

By on January 30, 2012

It’s been quite a roller coaster ride for Hedgehog inhibitors of late.

Infinity Pharmaceuticals Last week, brought negative data as Infinity announced that their phase II trial with saridegib (IPI-926) had been stopped for futility in pancreatic cancer.  This trial sought to determine the impact of the hedgehog in combination with gemcitabine over gemcitabine alone in advanced pancreatic cancer.  Unfortunately, the trial was stopped for futility, meaning the control arm was doing better than the treatment arm.

All is not lost for pancreatic patients though, as Roche/Genentech have a phase II trial currently recruiting patients with the triple combination of gemcitabine, nab-paclitaxel and vismodegib.  Previously, we have discussed the impact of Abraxane on removing the stromal layer in pancreatic cancer in animal models using nanotechnology to enable therapy to work and I think this may be a more promising approach in the long run.

In contrast, there was good news this morning as the FDA approved Roche/Genentech’s vismodegib, now known as Erivedge, in advanced basal cell carcinoma (BCC) who are not candidates for surgery or radiation and for patients with metastatic disease.

The original PDUFA date was scheduled for March 8th, so this is an early approval, but one that is not entirely unexpected given the promising results previously presented at medical conferences over the last 12-18 months.

The goal of the trial was to measure overall response rate (ORR).  In final analysis, the results showed that 30% of the metastatic patients experienced a partial response (PR), while 43% of patients with locally advanced disease experienced a complete (CR) or partial response.  These results represent a clear advance for patients with this disease and studies are also ongoing looking at new combinations to overcome resistance and hopefully, extend outcomes further.

For those of you interested in pricing, it looks as though Erivedge will be $7500/month so that would be estimated $75,000 for typical 10-month course of treatment (HT Ruth Coxeter, CNBC).

Links:

FDA Press Release

Genentech Press Release 

 

A new opportunity for vemurafenib in BRAFV600E colon cancer

By on January 26, 2012

There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.

The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.

One of the unsolved scientific conundrums that arose in my interview with Dr Gordon Mills (MDACC) at the European Multidisciplinary Cancer Congress (EMCC) meeting in Stockholm last September centred around the RAS pathway, and the BRAFV600E mutation, in particular.

Dr Mills astutely noted that while vemurafenib (Zelboraf) has shown activity in patients with advanced melanoma with the BRAFV600E mutation, he raised the important question why did we not see similar activity in mutated colon cancer?  Of course, one obvious conclusion might be that the target isn’t critical to the tumour’s survival… or is it?  The challenge though, is that these patients do particularly poorly, and usually that is a sign that the mutation is actively driving aberrant activity. Therein lies the quandary, leaving many researchers such as Dr Mills puzzled at the discrepancy and asking why?

This week I’ve been doing a series on colorectal cancer and it is quite by coincidence that today we learn more about the science of colon cancer and BRAFV600E mutations since Pralahad et al., (2012) have just published a Letter in Nature explaining that their research actually suggests that resistance mechanisms might be one of the culprits:

“We performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition.”

This finding surprised me because melanoma typically has low levels of EGFR expression, unlike more epithelial cancers:

“We compared EGFR expression in a panel of BRAF(V600E) mutant melanoma, colon cancer and thyroid cancer cells. Melanoma cell lines indeed express low levels of EGFR.

So what actually happens in melanoma?

“Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition.”

Ah, our old friend, feedback loops!  These have an uncanny knack of popping up in advanced cancers, as the cancer attempts to ensure it’s survival and overcome the targeted therapy, causing adaptive resistance to treatment in their wake.

You may be wondering how common is this mutation in colon cancer then? Well, Pralahad et al., (2012) observed:

“Our data suggest that BRAF(V600E) mutant colon cancers (occur in) approximately 8–10% of all colon cancers.

Note: bracketed bold addition mine.

What does this data tell us?

In short, a combination of vemurafenib and an EGFR inhibitor, such as erlotinib, cetuximab or gefitinib, might be a useful clinical approach to try therapeutically in patients with colon cancer harbouring the BRAFV600E mutation.  Of course, Roche/Genentech have both vemurafenib and erlotinib (Tarceva) in their portfolio, so it would be interesting to see whether proof of clinical concept could be established quickly in a phase I clinical trial.  EGFR inhibitors tend to be rather quirky though, and it remains to be seen whether a small molecule (erlotinib, gefitinib, afatinib) or a monoclonal antibody (cetuximab, pantitumumab) would be the ideal partner for vemurafenib in this setting.

While there is much yet to be done in R&D to advance the scientific research, this important finding teaches us that there is hope for this subset with a generally poorer prognosis yet.

I look forward to following the future clinical progress to see if a viable new combination treatment emerges in BRAF V600E mutated colon cancer – watch this space!

References:

ResearchBlogging.orgPrahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R., Bardelli, A., & Bernards, R. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR Nature DOI: 10.1038/nature10868

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Gene mutation and resistance to chemotherapy in colorectal cancer

By on January 5, 2012

This week’s New England Journal of Medicine (NEJM) contained a fascinating article on how a specific gene mutation known as Transcription factor AP-2 epsilon, TFAP2E–DKK4, appears to be responsible for inducing at least some of the resistance to chemotherapy that occurs during treatment of colon cancer.

At first sight, I wasn’t sure from the abstract if they were referring to either adaptive resistance to therapy or whether genetic changes already present limited the effectivenes of the treatment.

Further reading of the full article more specifically pointed to the latter:

“Epigenetic alterations underlying the pathogenesis of colorectal cancer have been reported by several groups. These alterations include hypomethylation and hypermethylation of DNA as well as histone modifications, all of which have a profound effect on transcriptional gene regulation. The role of these molecular alterations in response prediction and treatment resistance are far less well known.”

For readers interested in more background on histone modifications, check out a previous post on epigenetics first.

What did this research show?

There were a couple of interesting findings in this study, which involved both cell lines and also cancer patients:

“TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin.”

Fluorouracil (5FU) is one of the key bedrocks of chemotherapy when combined with either oxaliplatin (as FOLFOX) or irinotecan (as FOLFIRI), so any epigenetic changes present that limit it’s effectiveness will have a negative impact on the overall treatment response.

The impact of DKK4 was first shown in cell lines by Xi et al., (2006), but this is the first time I think it has been reported in human patients with colon cancer. The research also uncovered some other important findings:

“In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P<0.001).”

I’d like to see these results validated on a larger scale, but if replicable, they will have a huge potential impact on clinical practice. If a patient is found to have the TFAP2E mutation, then there will be little point in exposing them to the rigours of chemotherapy with their not inconsiderable side effects if there is little chance of response. A clinical trial or other alternatives such as targeted therapies (EGFR, VEGF) might be a better option in this case.

“Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79).”

It’s amazing how just a small change (hypo = positive, hyper = negative in this particular example) can have an enormous potential impact on the probability of response to chemotherapy.

Because the TFAP2E-dependent resistance was found to be mediated through DKK4, the authors suggested that patients who have colorectal cancer with TFAP2E hypermethylation could be approached differently. In other words:

“Specific targeting of DKK4 in these individuals may therefore be an option for overcoming TFAP2E-mediated chemoresistance.”

That, however, may be easier said than done and here’s why – DKK4, or Dickkopf 4, is associated with canonical Wnt signalling and beta-catenin/Tcf-4, which is not the easiest thing to target using currently available approaches. It may be a little while before we see some progress on the R&D front, but certainly the good news is that we at least have some valid targets to aim at.

What do these results mean?

It has long been known that patients vary considerably in their response to treatment and what this research clearly shows us is that genetic changes, specifically the presence of the TFAP2E–DKK4 mutation may explain why some patients with colorectal cancer fare better with chemotherapy than others. In other words, it portends a poorer prognosis and overall response to treatment.

It will be interesting to see if new epigenetic therapies develop in the near future to try and essentially overcome and reverse the histone modifications that impact the treatment response.

References:

ResearchBlogging.orgEbert, M., Tänzer, M., Balluff, B., Burgermeister, E., Kretzschmar, A., Hughes, D., Tetzner, R., Lofton-Day, C., Rosenberg, R., Reinacher-Schick, A., Schulmann, K., Tannapfel, A., Hofheinz, R., Röcken, C., Keller, G., Langer, R., Specht, K., Porschen, R., Stöhlmacher-Williams, J., Schuster, T., Ströbel, P., & Schmid, R. (2012). TFAP2E–DKK4 and Chemoresistance in Colorectal Cancer New England Journal of Medicine, 366 (1), 44-53 DOI: 10.1056/NEJMoa1009473

Xi, Y., Nakajima, G., Schmitz, J., Chu, E., & Ju, J. (2006). Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer BMC Genomics, 7 (1) DOI: 10.1186/1471-2164-7-68

ASH 2011 Update #2 – Non Hodgkins Lymphoma

By on December 21, 2011

I’ve been busy with other things offline since the last blog update from the American Society of Hematology (ASH) meeting in San Diego, but will be catching up on my notes from the conference over the next few days.

In addition, my colleague Pieter Droppert has already posted his topline impressions of the meeting on the companion Biotech Strategy Blog, which readers may be interested in:

  1. Ponatinib in CML
  2. Update on new advances AML and FLT3
  3. Interesting posters – BTK and PI3K

Meanwhile, I thought it would be a good idea to look at the pipeline developments in non-Hodgkin’s lymphomas (NHL) that I particulalry liked at ASH:

PI3K inhibitors

Pieter’s choice of PI3K as a hot topic turned out to be rather prescient given that:

a) Intelikine announced last night that the company is being bought by Millennium-Takeda in a deal worth $190M upfront with $120M in additional milestone payments. This is a great transaction all around, enabling clinical development to now begin for Intellikine’s two remaining PI3K-mTOR and selective isoform inhibitors and since Takeda have research facilities locally in San Diego, this will enable work to continue with minimum fuss and relocation.

b) As of this morning, Exelixis announced they have licensed their PI3K-delta inhibitor in preclinical development to Merck. This deal features an upfront payment of $12 million, but the company will be eligible for potential development and regulatory milestone payments for multiple indications of up to $239 million in the future.

Another PI3K inhibitor in the news is Calistoga’s CAL-101 (now owned by Gilead), a delta selective isoform inhibitor being evaluated in indolent NHL. At this meeting, the phase I data was presented in a poster. The patients enrolled to date (n=37) included those with follicular lymphoma, small lymphocytic leukemia and marginal zone lymphomas, all of whom had received prior therapy for their disease. In this study, CAL-101/GS-1101 was given in combination with rituximab and/or bendamustine to determine the safety profile.

The big question is whether the combination with chemoimmunotherapies would lead to added or overlapping toxicities – the authors, de Vos et al., concluded that answer was no and a good efficacy signal was seen:

“GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy.”

On the basis of this study and a prior phase I trial that determined the dose (150mg/BID), further continuation of the program in this indication appears warranted:

“The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with iNHL.”

 

Anti-CD20 monoclonal antibodies

Rituximab was the first targeted cancer drug following its approval back in 1997 and has shown how important targeting CD20 has been in lymphomas and more recently, chronic lymphocytic leukemia (CLL). At this meeting, we saw an interesting new development in lymphomas from Roche/Genentech in GA101 (obinutuzumab). This is essentially a follow-on biologic to rituximab. In a previous post prior to ASH, I looked at the key questions that need to be addressed in order to displace rituximab, namely more activity in rituximab refractory patients, more efficacy/better side effect profile up-front or broader activity across several diseases.

What are the key differences between rituximab and obinutuzumab you might ask and does this impart any clinical benefit?

Well, rituximab is a humanised type I monoclonal antibody, whereas obinutuzumab is a humanised type II glyco-engineered antibody, both target CD20. What’s the difference between Type I and II? Well, according to Robak, 2009:

“GA-101 binds with high affinity to the CD20 type II epitope, resulting in the induction of antibody-dependent cytotoxicity that is 5- to 100-fold greater than observed upon treatment with rituximab.”

The proof of the pudding is always in the clinical data, especially randomised head-to-head trials. There were over a dozen abstracts on GA101 at ASH, but the most important one in this context was a phase II GAUSS trial from Sehn et al., which randomised patients with indolent B-Cell NHL to receive either rituximab or obinutuzumab in the relapsed setting:

Gauss trial schematic courtesy of Roche

And the result? The authors concluded that:

“Treatment with GA101 in patientss with relapsed NHL resulted in higher response rates compared to rituximab as assessed by both investigators and the IRF at an early time point.

GA101 was well tolerated, although a higher rate of IRRs was noted, the majority were grade 1/2 in severity and did not result in significant differences in treatment discontinuation.”

Where IRR is infusion related reactions.

This data is promising for obinutuzumab, but still very early – we will still need to see what happens in a larger scale phase III trial with more patients before we can draw more definitive conclusions. That said, I found the GAUSS trial data very encouraging indeed.

Bruton’s Kinase Inhibitors

In the first update, I highlighted how Bruton’s Kinase inhibition (BTK) was one of the exciting new emrging pathways in chronic lymphocytic leukemia (CLL), but new data was also presented on the leading BTK inhibitor, PCI-32765 (Pharmacyclics/J&J), in lymphomas.

The preliminary phase II data in mantle cell lymphoma (MCL) presented by Wang et al., in 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) with a median of two prior treatment regimens (range:1-5).

Initial efficacy data was reported:

“The objective response rate (ORR) is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort.”

The side effect profile seen to date was also described:

“Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765.”

I thought these results were encouraging – with good tolerability and encouraging signs of efficacy – certainly worthy of exploring in a randomised phase III trial in this indication. This is an agent we are probably going to hear a lot more about in the near future.

And finally…

There were a lot of new developments emerging at this meeting, particularly in the poster sessions and also in both phase I and II trials. It was impossible to keep up with everything, so this post is just a flavour of some of the abstracts either of us did manage to take in.

The challenge, as always, with ASH is their insistence of holding all the critical oral sessions on biology and therapy in leukemias, lymphomas, myelomas and myeloproliferative diseases almost on a single day, making it absolutely impossible to see/hear all the new and exciting data. Monday is, therefore, always a manic day. It’s a strange contrast from the long lulls on the Sunday where some of the oral sessions could have been hosted, perhaps the biology sessions, thereby freeing up a more flexible schedule for the clinical data on Monday. There is some weirdness and also dismay in seeing a biology and clinical session for the same topic (eg CML, Multiple Myeloma, Lymphomas or FLT3 in AML) clashing. Not everyone is a specialist, certainly the community oncologists who attend are not. This is silly scheduling and means that people presenting in a biology session often miss the clinical update for a trial they were a PI in, while attendees like me are regretably forced to choose from one or the other.

Sadly, not everyone can stay until Tuesday morning when a few more key oral sessions that include new data are held, for a meeting that began on Friday. This is issue compounded by no virtual meeting facility, one of ASCO, AACR, ECCO and even the NY Chemotherapy Symposium’s great online service whereby you can catch up with sessions you missed later. For me, this is a critical and integral part of modern cancer meetings.

I hate missing out on great or important data and hope that ASH will seriously consider virtual meeting access for future meetings – it really does help attendees – otherwise if you didn’t catch the sessions they are gone forever!  Personally, I was still watching (and enjoying) presentations I missed at AACR and ASCO in July, long after both meetings finished, and really appreciated their excellent webcasts/virtual meetings.

One of the sad things for me was it turned out to be the first time in many years that I skipped the Plenary session as there were some odd choices this year that simply didn’t resonate with me. For example, making Mylotarg, a drug withdrawn by the FDA recently, one of the meeting highlights made little sense to me because:

a) it will have no immediate clinical or even scientific impact for the practising oncologist and
b) there were far more dramatic results that I thought were worthy of broader dissemination

Overall though, this was a good ASH meeting from the point of view of exciting new data in phase I and II trials; clearly the oncology pipelines are beginning to show some early promise, but it was disappointing not to see more of them prominently highlighted. There were quite a few other abstracts I liked, but this overview should give a good flavour of some of the novel agents emerging for the treatment of NHL.

For those wanting information on Hodgkins Lymphomas, I’ll cover those in a separate post as there was too much data to cover both in one post.

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What’s hot at SABCS – Update 2 – advanced breast cancer

By on December 10, 2011

After a number of basic research and science sessions over the last two days (see the Update 1 post on the science that intrigued me for more details), but the last two days heralded some excellent clinical sessions, in both oral and poster forms. These included the presentation of the much anticipated update to the BOLERO-2 trial, which was also published in the New England Journal of Medicine online and the CLEOPATRA study, also published in the same journal.  One of the more impressive posters that caught my eye was the ENCORE 301 study, which provided an update to the entinostat data in ER/PR+ HER2- advanced breast cancer.

Many of you will have read the wire and news articles released in a barrage on Wednesday evening with the NEJM publications ahead of the presentations on Thursday and Friday, but I wanted to put them in context of what we know so far and why these studies are both elegant and important.

Why am I fascinated by these particular studies?

Drug resistance can develop either upfront or is acquired in response to treatment over time.  The latter is also known as adaptive resistance, as the tumour evolves certain strategies to ensure it’s survival.  This is one reason why many people will have a different response to the same treatment.

In simple terms, if we can figure out ways to:

  1. Either delay the development of resistance up-front in treatment naive patients by enabling more comprehensive pathway suppression
  2. Or switch to a new logical combination regimen once resistance has developed

then we may be able to prolong patient outcomes and survival further.  To me, these kind of rational approaches make much more sense than merely throwing random chemotherapy doublets of choice at the problem.  These two strategies are very much at the heart of the three impressive studies mentioned above.  Let’s look at them in a little more detail.

BOLERO2

BOLERO-2 is the acronym for the breast cancer trials of oral everolimus and the updated safety and efficacy data were reported here at the San Antonio Breast Cancer Symposium (SABCS), although it should be noted that the NEJM article is based on the phase III ECCO data previously presented by Jose Baselga in September.

The trial design, though, remains the exactly same – patients were randomised to receive with everolimus plus exemestane versus placebo plus exemestane to determine whether the mTOR added anything to the AI alone.

The rationale behind this trial is that mTOR is a known cause of resistance to AI therapy, so the combination targets both the ER, which is driving the tumour proliferation, and mTOR targets the adaptive resistance pathway.  Shutting down both pathways should lead to improved survival, which we clearly saw at ECCO (6.5 months extra survival as measured by PFS).

The latest data presented by Dr Gabriel Hortobaygi (MDACC) confirmed that the responses continue to be durable, with an improvement in the PFS with the combination arm now up to 11.0 months, up from 10.6 months at ECCO. The results for the exemestane control arm remained the same at 4.1 months. This means that the improvement in survival with the mTOR now offers a median 6.9 months extra benefit.  OS had not yet been reached and therefore was not reported.

My view? These are excellent results from a well designed trial with a logical and elegant design given that we know mTOR is one of the adaptive resistance mechanisms to AI therapy and confirm that the original hypothesis was a valid one.

That said, what we don’t know is who will most benefit from the combination i.e. which women are more likely to respond. I’d love to know whether the really good responders had higher mTOR levels or overexpression or whether there is something else that would help us determine the likely responders for several reasons:

  • mTOR isn’t the only acquired resistant pathway to AI – there are others – so hopefully a way to determine who would be the ideal candidate for mTOR therapy will emerge from retrospective analysis.
  • A quarter (26%) of both arms received prior chemotherapy – did these women do better or worse when given the AI-mTOR combination compared with those who only received hormonal therapies?
  • This combination will not be cheap, considering the likely costs of everolimus alone without the AI could easily be ~$7K/month and the cost of exemestane must be added to that.

These points aside, I do think these results are impressive and good news for an advanced population of women who may not want to even consider chemotherapy – the current data suggests that many will get more time with this approach.  Expect to see Novartis filing for everolimus approval in advanced breast cancer with the FDA before the year is out.

ENCORE 301

In the same patient population of ER/PR+ HER2- women, there was an update to the phase II ENCORE 301 trial with the HDAC inhibitor, entinostat, that we blogged in more detail at the recent AACR Molecular Targets meeting.

What was new about the data here was an update on the overall survival (OS) data. Remember, in San Francisco the PFS for the entinostat arm (comparable to the everolimus-exemestane arm in BOLERO2) was 8.5 months in the women with high acetylation, an excellent predictive biomarker of response.

Now, I was wondering why the OS has still not yet been met in the BOLERO2 trial here and realised why with the updated entinostat data:

 

Entinostat OS in ENCORE 301

As you can see above, based on a medium follow-up of 23 months, the OS has improved in these patients in the phase II trial from 19.8 to 26.9 months, an improvement of 7.1 months of life.

We’ve all seen so many trials where the benefit is a mere 1-3 months, so to see several trials in advanced breast cancer where the survival is measured in 6-7 months is breathtaking.  Long may this trend continue with more rationally designed combinations and robust trial designs!

The entinostat phase II data certainly provides a good efficacy and safety signal to continue development and I was delighted to see that Syndax are moving forward to a confirmatory phase III trial in 2012.  I’m very much looking forward to watching how this study progresses, although we obviously won’t know the results for a while.

CLEOPATRA

The CLEOPATRA study looks at a completely different patient population than BOLERO and ENCORE.  In this situation, it’s looking at women were treatment naive, not refractory, who also needed to be HER2+ to enter the study.

As discussed in the What’s Hot at SABCS review prior to the meeting, pertuzumab is similar to trastuzumab in that it is a monoclonal antibody to HER2, but also differs in that it acts in a different part of the HER domain from Herceptin and also prevents pairing of HER2 and 3 dimersiation:

HER dimerization, source: NEJM

The idea behind combining pertuzumab and trastuzumab upfront is to enable a more comprehensive shutdown of the HER2 pathway and delay the resistance setting in.  By doing this, PFS should increase.

Dr Jose Baslega presented the results of the CLEOPATRA trial for the first time to a packed and highly excited audience in San Antonio.  Unfortunately, I wasn’t there as I was en route to the American Society of Hematology (ASH) meeting, but like many, I was eagerly reading the tweets and reactions from the attendees.

The Roche press release summed up the essence of the data nicely:

“The median PFS improved by 6.1 months from 12.4 months for Herceptin and chemotherapy to 18.5 months for pertuzumab, Herceptin and chemotherapy.

Overall survival (OS) data are currently immature, with a trend in favour of the pertuzumab combination.”

In short, another stunning six month leap in survival in an entirely different patient population of advanced breast cancer.  This is the sort of data those of us working in the industry live for and hopefully, things will continue to get better because clearly thought leaders such as Martine Piccart (at the the NY Chemotherapy Symposium) and Jose Baselga (at SABCS) are already dreaming and envisioning a world in which women with HER2+ breast cancer can be treated without chemotherapy at all.  Now that would be a wonderful thing indeed and I really hope to see it happen sooner rather than later.

One thing that hasn’t been factored into the equation is the antibody drug conjugate T-DM1 and how that relates to pertuzumab and trastuzumab.  The phase III trial MARIANNE is currently enrolling patients and may offer us an answer to that question in a couple of years time.

For those of you interested in some expert commentary, the NEJM published an excellent editorial from Dr William Gradisher (Northwestern, Chicago) accompanying the BOLERO2 and CLEOPATRA studies which is well worth reading (see references below).

In summary…

These three studies all show how rationally designed and elegant studies based on solid science can lead to large leaps in improvement in survival in the clinical setting.  Roche have already filed the BLA for pertuzumab and Novartis are expected to file everolimus in advanced breast cancer soon.  Syndax are already planning their phase III trial for entinostat.

It’s a very good period for ER/PR+ HER2- and HER2+ advanced breast cancers – from that perspective, this year’s San Antonio Breast Cancer Symposium was very uplifting and one of the more exciting meetings of the last five years.

References:

ResearchBlogging.orgBaselga, J., Campone, M., Piccart, M., Burris, H., Rugo, H., Sahmoud, T., Noguchi, S., Gnant, M., Pritchard, K., Lebrun, F., Beck, J., Ito, Y., Yardley, D., Deleu, I., Perez, A., Bachelot, T., Vittori, L., Xu, Z., Mukhopadhyay, P., Lebwohl, D., & Hortobagyi, G. (2011). Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1109653

Baselga, J., Cortés, J., Kim, S., Im, S., Hegg, R., Im, Y., Roman, L., Pedrini, J., Pienkowski, T., Knott, A., Clark, E., Benyunes, M., Ross, G., & Swain, S. (2011). Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1113216

Gradishar, W. (2011). HER2 Therapy — An Abundance of Riches New England Journal of Medicine DOI: 10.1056/NEJMe1113641

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