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The challenge of prostate cancer drug approval versus reimbursement

By on February 27, 2012

Arc de Triomphe, Paris

Scenes from EAU - Arc de Triomphe

Here at the European Association of Urology (EAU) congress in Paris, there are some interesting debates amongst delegates attending the meeting regarding new therapies either recently – or about to be approved – for castrate-resistant prostate cancer (CRPC).

For example:

  1. How should abiraterone and MDV3100 be sequenced pre or post chemotherapy?
  2. Would combining the two drugs post chemo be a better strategy that leads to superior outcomes?
  3. Where does chemotherapy fit into this emerging paradigm?  Do we need chemotherapy in an new era of oral therapies?  If yes, which patients should be considered eligible?
  4. How will immunotherapies such as Provenge be used once approved – before or after abiraterone in the pre-chemo setting, but likely not together given the steroid component?

Reimbursement remains a challenge in Europe

Now, these are all valid clinical questions, but there is an elephant in the room that isn’t being discussed so far (Dendreon got a lot of stick over the US price last year, which was publicly considered ‘very expensive’ or ‘too expensive’ by many thought leaders for Europe), namely, reimbursement.

Consider that the US wholesale price for Provenge is $93K and abiraterone is ~$48K, depending on how many months are needed (likely more in the pre-chemotherapy setting), you can already see that both sequencing and combinations are going to take the economic costs much higher for European health care systems.  That’s without figuring in the price for MDV3100 and Alpharadin, which have not been filed yet or cabazitaxel, which costs around $42K in the US depending on the number of cycles taken (from memory).

However, with Taxotere now generically available, it’s not hard to imagine many centres repeating docetaxel in second-line if the patient had a good response rather than administer the more expensive cabazitaxel.  In general, though, there is little doubt that the impact of either sequencing therapies, or using in combination, will add to the cumulative cost of treatment in an upwards manner.

The bigger questions for Europe in this scenario then become:

  • How to best manage available resources from the allocated healthcare pot?
  • The majority of money in cancer care is spent on the last 6 months of people’s lives – how should that be addressed ethically, economically and medically?

By the way, for American readers of this blog, please don’t call European provision ‘socialist healthcare’ – this is a silly misnomer, because:

  • It isn’t free – people pay for it – it’s deducted at source from wages in most countries
  • Several EU members such as the UK have a conservative, not socialist, Government in power
  • In Germany, a model of private providers similar to the US exists, and even in the UK additional private care can be bought through an employers offering, proving that not all European countries provide healthcare in the same way.

Abiraterone will likely be reimbursed at a discount in the UK

Meanwhile, J&J’s abiraterone is an interesting case study in point.  While approved by the EMA/CHMP, it isn’t available in all EU countries yet, as it wenders its way through the reimbursement approval process.  As I understand from delegates here, it is available in Ireland, for example, but was rejected by NICE in the UK as ‘too expensive’.

What was interesting here at EAU was learning from some EU thought leaders and competitor manufacturers that Janssen have apparently negotiated a discount of 40% of the list price in order for it to be available in the UK, although nothing official has been announced yet.

Will UK pricing have a broader impact on continental Europe?

Given the severe pan Europe economic hardship at present, one wonders how low this pricing strategy might go given that Greece is usually the lowest priced country.  If the 40% discount being bandied about here at EAU is correct, will other other EU countries look at the UK price and demand a similar discount?  It’s one thing the UK and say, Spain and Greece being 10-20% lower than Germany, but nearly half the price might upset the natural basket negotiations and wheeler dealing that usually occur.

You can almost imagine a satirical cartoon in Private Eye or The Economist, whereby jaundiced eye balls loom eerily out of a map of Europe, as each country warily looks at its usual reference baskets.

It will be interesting to watch what happens in the near future, because what happens in the advanced prostate cancer arena may have broader implications, not only for all EU countries, but also other manufacturers in the cancer marketplace.  Everyone involved is going to be following this evolution carefully.

 

Raised platelets reduce survival in ovarian cancer

During my years in Pharmaland, I often sat in waiting rooms waiting to see the Principal Investigator (PI) for one of the studies we were doing.  I would generally see them at the end of the clinic, preferring to arrive early and chat with some of the patients to learn of their experiences, the trials and tribulations of cancer therapy.  This keeps your feet on the ground – drug development is not an academic exercise, there are real people involved after all.

Some of those patients were really sick, with quite advanced disease, maybe with a year or less to live by conventional estimates and yet they were entering a clinical trial, or seeking to get into one with great hope.  Over time, one would meet some of those patients repeatedly, to be greeted with good cheer and the latest round in their stories. These shared moments are precious, you learn little snippets of their journey back to health and what it’s really like to go through various regimens. I cannot tell you how thrilling it was to meet some of the sickest patients several years later and learn that the greatest thing you ever hear in an oncologists surgery – that they were in remission.

To this day that still gives me goosebumps.

One of the things that often came up in those brief chats though, was the lab results, with various counts being up or down.  Some of these matter, some don’t.  The one that always puzzled me was raised platelets because on asking the doctors, few ever really seemed concerned about the levels, unless they were too low (thrombocytopenia) to undergo their next round of treatment.  The scientist in me, however, always wondered about raised platelets – what do they do and do they have an impact on outcome?

This week, a paper has been published in the New England Journal of Medicine by Anil Sood’s group at MD Anderson Cancer Center that begins to address this very issue of raised platelets or thrombocytosis in cancer therapy.

The crux of the research was nicely summed in the MD Anderson press release:

“Highly elevated platelet levels fuel tumor growth and reduce the survival of ovarian cancer patients.”

Now that may sound a little dramatic but I was curious to know why does this happen, so this morning I talked to Dr Sood to find out more about his groups research:

PSB: This exciting research was about the impact of elevated platelets, can you tell us why this happens and what the consequences are?

Dr Sood: We looked at the clinical implications and found that patients who have higher platelet counts tend to live for a shorter time period and beyond that we asked how is it that these platelet counts are going up?  We did a number of studies, including human material as well as laboratory experiments, and figured out that tumors can produce certain growth factors such interleukin-6 (IL-6) that stimulate the liver to produce this factor called thrombopoietin, which stimulates platelets counts.  That’s the paracrine or complex circuit that promotes high levels of platelets in cancer patients.

PSB: What was the basic underlying mechanism behind this?

Dr Sood: The mechanism here was that the tumor derived IL-6 stimulates thrombopoietin production.  Thrombopoietin will stimulate megakaryopoeisis through the bone marrow, which will then stimulate platelet production.  We did some experiments to also figure out that if you could block this from occurring, could you reduce or could you block platelet levels from going up.  We did a number of experiments using both siRNA as well as an antibody that blocks interleukin-6.  If you block either of those you can abrogate the platelet counts from going up.

We also worked with collaborators in UK where they had used this same antibody that we used for animal experiments, in a clinical trial and they found that platelets come down when patients are treated with an IL-6 blocking antibody.  That gave us further evidence that this mechanism seems to be operative where it is important for platelets.

PSB: Are there IL-6 antibody therapies available for community oncologists to treat their patients.

Dr Sood: Not yet.  It is something, especially in the context of ovarian cancer, that is undergoing clinical development, so they need to be carefully developed.

The other question is an antibody such as that adequate in itself, or does it need to be combined with a cytotoxic or with a chemotherapy drug?  In some of our preclinical experiments that we included here, there was the suggestion that combining it with chemotherapy was even more effective than just using the antibody alone.

PSB: When oncologists see patients with high platelet levels do they currently treat them in any way?

Dr Sood: Not really any differently.  It is something that we have simply known for a long time.  In this context, given especially that these patients tend to have aggressive behavior (of the tumour), there is a lot of potential clinical implications, but again this is relatively new, so I think we need to do additional work to really figure out what are the best approaches to treat these patients.

Is it better to combine an IL-6 antibody, specially in those patients who have high platelets, along with chemotherapy?  Can drugs like even aspirin or things like that that interfere with platelet function, could those have implications?  There are data that would suggest that patients who are on a daily aspirin tend to live longer in the context of cancer patients. These type of things need to be developed further.

PSB: Could the high platelets cause inflammation?

If you can’t see the soundbite audio clip, click here.

PSB: Where is your research going next?

Dr Sood: In many directions!  This has opened a lot of questions for us. We found that platelets are not restricted to the blood system, but that they can in the tumor microenvironment also traffic.  We want to understand how is that survival can be effected?  I don’t think that the survival is effected just because these patients are getting more blood clots, or something like that.  I think that the platelets can provide growth factors for cancers, which we are trying to understand.

Obviously, you don’t want to reduce or completely eliminate platelets because they are an essential part of our body, but if we can block this kind of abnormal thrombocytosis from occurring then that might have implications for therapy as well.  The other thing we are asking is that since platelets are elevated in a fraction of cancer patients, can these be also useful as a biomarker, so we are trying to do studies to look at that aspect. There are many directions this research opens up.

Summary:

Although thrombocytosis has obviously been known for a long time, it’s really only now that we are starting to have a clearer idea of the potential negative impact of raised platelet levels in cancer patients.  The survival curves between normal platelets and thrombocytosis in ovarian cancer were dramatically significantly different in the paper (P<0.001).

Obviously these results would need to be confirmed in randomised trials before making a more definitive conclusion from a patient perspective.  That said, the results from Stone et al., (2012) do suggest that while raised platelets can influence survival in ovarian cancer, there may be some therapeutic options down the road to address this, possibly with an  IL-6 antibody added to chemotherapy.

The anti-IL-6 antibody used in this elegant research (and the early study at Barts) was siltuximab (J&J), although a quick search of the clinical trial database revealed no US studies in ovarian cancer.  In the paper data from UK patients were included (see also Coward et al., (2011) in the referencs below, as the MD Anderson press release noted:

“In a clinical trial conducted at the Barts Cancer Institute, Queen Mary, University of London, the team also found that treatment of 18 ovarian cancer patients in a phase I/II clinical trial with siltuximab, an antibody to IL-6, sharply reduced platelet counts over a three-week period.”

It will be interesting to see if approach is subsequently tried in a larger scale trial with ovarian patients who have thrombocytosis to confirm the positive impact.  Certainly, the clinical rationale is there.  For those of you interested in the role of IL-6 in ovarian cancer further, a recent paper by Coward et al., (2011) from the group who did the phase I/II trial of siltuximab in ovarian cancer is well worth a read (see references below).

References:

ResearchBlogging.orgStone, R., Nick, A., McNeish, I., Balkwill, F., Han, H., Bottsford-Miller, J., Rupaimoole, R., Armaiz-Pena, G., Pecot, C., Coward, J., Deavers, M., Vasquez, H., Urbauer, D., Landen, C., Hu, W., Gershenson, H., Matsuo, K., Shahzad, M., King, E., Tekedereli, I., Ozpolat, B., Ahn, E., Bond, V., Wang, R., Drew, A., Gushiken, F., Collins, K., DeGeest, K., Lutgendorf, S., Chiu, W., Lopez-Berestein, G., Afshar-Kharghan, V., & Sood, A. (2012). Paraneoplastic Thrombocytosis in Ovarian Cancer New England Journal of Medicine, 366 (7), 610-618 DOI: 10.1056/NEJMoa1110352

Coward, J., Kulbe, H., Chakravarty, P., Leader, D., Vassileva, V., Leinster, D., Thompson, R., Schioppa, T., Nemeth, J., Vermeulen, J., Singh, N., Avril, N., Cummings, J., Rexhepaj, E., Jirstrom, K., Gallagher, W., Brennan, D., McNeish, I., & Balkwill, F. (2011). Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer Clinical Cancer Research, 17 (18), 6083-6096 DOI: 10.1158/1078-0432.CCR-11-0945

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

4 Comments

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

3 Comments

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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On KRAS, NF-kB activation and pancreatic cancer

By on January 31, 2012

Pancreatic cancer as many readers know, is one of those cancers that is generally diagnosed later than most in stage IV and as a result, has a poor prognosis, often only a year or so from diagnosis.

It has been known for a decade that constitutive Kras and NF-kB activation is one of the signature changes in the disease in the majority (80-95% ) of patients. Kras is a particularly important gene because it is often involved with on-off signaling of other genes. In addition, mutational inactivation of a key tumour suppressor gene (Ink4a/Arf) also occurs in over half (50-75%) of pancreatic adenocarcinomas. What is not known, however, is what are the key signaling pathways downstream of Kras and how they relate to pancreatic cancer.

Earlier this month though, Ling et al., (2012) published some new data in Cancer Cell advancing our knowledge in this area:

“Our findings reveal that KrasG12D-activated AP-1 induces IL-1a, which, in turn, activates NF-kB and its target genes IL-1a and p62, to initiate IL-1a/p62 feedforward loops for inducing and sustaining NF-kB activity.”

They also noted the impact of this process, namely:

“IL-1a overexpression correlates with Kras mutation, NF-kB activity, and poor survival in PDAC patients.”

In other words, dual feedforward loops of IL-1a (induced by AP-1) and p62 are responsible for the IKK2/b/NF-kB activation by KrasG12D.

The group also observed:

“Our results show that TSC1 and FOXO3a pathways are involved in Kras-induced PDAC.”

In other words, they promote tumorigenesis.

What does this data mean?

In practice, this research suggests that several approaches might be potentially useful:

  • Inhibiting mutated Kras (specifically KrasG12D) may be a viable therapeutic target in pancreatic cancer.
  • Since IL-1a overexpression correlates with poor survival in PDAC patients, pharmacologic targeting of IL-1a may also be a useful strategy to consider.

Kras mutations appear in a number of cancers, including pancreatic and colon cancers, where in the latter case, they have been shown to cause resistance to EGFR inhibitors.  To date, strategies to target Kras have been disappointing at best.  There are also a number of MEK and other inhibitors being evaluated in pancreatic and other cancers, but I’m not sure that targeting downstream of RAS will have any effect in these cases, if mutated RAS upstream is the main issue:

Source: ReactionBiology

MD Anderson summed up this data in pancreatic adenocarcinoma nicely in a succinct press release describing the feedforward loops as a ‘vicious circle’ i.e.:

“A self-perpetuating loop of molecular activity that fuels pancreatic cancer by promoting inflammation, development of new blood vessels and blocking programmed cell death.”

 

References:

ResearchBlogging.orgLing, J., Kang, Y., Zhao, R., Xia, Q., Lee, D., Chang, Z., Li, J., Peng, B., Fleming, J., Wang, H., Liu, J., Lemischka, I., Hung, M., & Chiao, P. (2012). KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma Cancer Cell, 21 (1), 105-120 DOI: 10.1016/j.ccr.2011.12.006

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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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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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What's hot at SABCS – Update 1

By on December 8, 2011

Yesterday evening brought a flurry of news around the New England Journal of Medicine articles for the BOLERO2 and CLEOPATRA trials, but out of respect to the presenters, I hate talking about the actual data before its being presented. Call me old fashioned if you like, but it seems odd moving up deadlines for the publication ahead of the presentations instead of releasing them on the day and is a little disrespectful of the journal towards the presenter and attendees.

I will therefore discuss the data for BOLERO2 and CLEOPATRA studies in detail after they have been presented today and tomorrow, respectively. For those of you interested in the study designs and their potential implications, you can check out my brief video highlights in the meantime.

Yesterday at the San Antonio Breast Cancer Symposium (SABCS) brought some really intriguing biology data that are well worth discussing:

  • Notch inhibition to reduce AI resistance
  • HER2 mutants
  • Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

Notch inhibition

Perhaps one of the most intriguing presentations (to me) yesterday at SABCS looked at combining a Notch inhibitor plus an AI to reduce breast cancer resistance in preclinical models.

This is an interesting idea that is worth exploring because resistance to oral therapies, including AIs, is a common problem. Understanding the potential mechanisms of resistance should therefore lead to new trial designs and logical combinations.

In this research, the presentation focused on early data on combining MK-0752 (notch) plus hormone therapy. Interestingly, it also finally mentioned the magic word, biomarkers! I think this is a combination we will here much more about going forward.

In his award lecture, Dr Carlos Arteaga correctly observed that the medical community has not done a good job with ER+ drug-resistant disease. This situation is slowly changing as the BOLERO2 data has shown and other mechanisms of resistance will no doubt follow now that more attention is being focused on it.

HER2 mutants

Dr Boulbes from MD Anderson presented the results of some elegant research identifying three mutants to HER2, namely:

  • D808N
  • V794M
  • L726F

All three phenotypes displayed aggressive tendencies. Both the V and L phenotypes showed a dramatic lack of phosphorylation and the latter may be related to the development of HER2 resistance. Data was shown in relation to lapatinib, a HER2 small molecule TKI, which is known to develop resistance to treatment over time.

This is the first time I think HER mutant phenotypes have been reported to my knowledge and if validated clinically, they will represent a breakthrough in our understanding of how HER2 resistance develops, but more importantly, suggest directions for potential therapeutic strategies to overcome it.

Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

HER3 has not received a lot of attention relative to its more popular HER2 cousin, largely because it is tricky to target. However, at this meeting, Dr Garner et al., showed that an anti-HER3 antibody (Novartis) nicely shrank breast cancer tumours in immunocompromised mice.

The presenter observed that the alpha-HER3 mAB recognizes and stabilizes HER3 in the inactive conformation. I was left wondering whether HER2 and 3 pairing / dimerization was shut off or something else was going on?

Dr Cook subsequently showed some clear data whereby HER3 is required for HER2 cancer growth in genetic engineering animal model. This was a very nice piece of research.

What was interesting was that Dr Garner also showed that alpha-HER3 can combine w/ trastuzumab plus a PI3K inhibitor to improve efficacy in trastuzumab-resistant settings. This caught my attention because earlier this year at the AACR PI3K special meeting, Neal Rosen (MSKCC) noted that targeting PI3K activated HER3 as one mechanism of resistance in the breast cancer model they were using and thus speculated that combined inhibition of HER3 and PI3K would lead to reduced resistance. Looks like his hypothesis was correct 🙂

And that was just the first full day of presentations with much more to come!

In the meantime, you can follow the conversations remotely using our tracking tool, accessible here on the blog.

Check back tomorrow for more updates on cancer biology and clinical trials from SABCS.

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Gone to dog drug heaven…

By on November 29, 2011

That was the quaint phrase used by one of the presenters at the recent AACR-EORTC-NCI Molecular Targets meeting in San Francisco.

Apparently, some drug or two was considered, too toxic (fair enough) or lacking in efficacy, hence the requisite binning of a multi-million dollar program to the scrapheap.

Yesterday’s post, however, reminded me that maybe sometimes, it’s not that the efficacy was lacking but the clinical trial design or tumor type or even line of therapy was the best one.  Let’s consider a couple of recent ideas here:

  1. The aurora kinase inhibitor PHA-739358 didn’t show any efficacy in adenoncarcinoma of the prostate, but the target, aurora kinase A may be a key one in some neuroendocrine tumours of the prostate.  These are very different subsets requiring a different approach to patient selection criteria and screening, which might potentially lead to a higher response rate in a small subset.
  2. At the above AACR meeting, I was discussing mTOR inhibitors in breast cancer with a few people.  Everyone noted how interesting it was that Wyeth’s temsirolimus failed to show any efficacy in a large phase III trial in women with ER/PR+ newly diagnosed breast cancer when given an aromatase inhibitor and the mTOR.  In contrast, Novartis took a different approach and used the AI and mTOR combination in second line therapy using everolimus and exemestane and saw dramatic responses. Why the difference?  Well, mTOR is known to cause resistance to AI over time, so it would make more sense to add it in later, rather than upfront.

There are many many other examples like this.  Sometimes, the key is in better understanding of the underlying processes from basic research.

For me then, dog drug heaven might not always be due to a poor molecule, but a failure to figure out where and how the drug might have worked effectively.  Dr Len Saltz (MSKCC) summed this up nicely at the NY Chemotherapy Symposium earlier this month:

Now, while Dr Saltz was specifically discussing the potential role (or lack of) for PI3K inhibitors in colorectal cancer, I do think his maxims hold very true for any targeted agent being evaluated in the clinic and something that cannot be emphasized enough.

The first point is obvious, but many sadly seem to miss it!  More preclinical and translational research is key to determining what the targets are and which ones matter in which tumor types.  Without that rational approach, you might as well throw mud at a wall and see what happens.  The second point speaks to the therapeutic index of the drug and whether we are shutting down the pathway enough to stop aberrant activity.  The final point is absolutely crucial – is the target a driver or a passenger?  If it’s the latter, the first two will not matter a jot no matter what we throw at it, in fact all that happens there is more toxicities are introduced and that’s not a good thing for the patient on the receiving end.

These issues become even more pertinent when we consider how regimens and increasingly, clinical trials, are moving more towards double and perhaps even triple combination therapies in an effort to shut down a pathway more completely.

In the meantime, the dog drug heaven days will likely continue.

 

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