Onco Chat

What's in Placebos: Who knows? Analysis of randomized, controlled trials

Background: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting.

Purpose: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials.

Data Sources: 4 English-language general and internal medicine journals with high impact factors.

Study Selection: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009.

Data Extraction: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus.

Data Synthesis: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002).

Limitation: Journals with high impact factors may not be representative.

Conclusion: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.

via www.annals.org

 

Thanks to Bruce Lehr of the Big Red Biotech Blog for bringing this topic to my attention.

In many trials of new drugs in development such as cardiovascular, dermatology, neuroscience etc, the test agent is typically compared to a placebo with a similar formulation such as a pill, topical cream etc, but as the journal points out, rarely is the composition defined in detail. 

This is not surprising, as the authors of the paper reported that they found that only a paltry 8.2% of the 86 studies they looked at actually stated clearly what the contents of the placebo were.

Does it matter?

Well, you might think it's just a 'sugar pill', but as this article in the LA Times noted, some placebos in cardiovascular trials might consist of olive oil or other polyunsaturated oils, thereby potentially reducing cholesterol and heart disease. Certainly something to think about, as they may have unexpected effects.

Although most cancer clinical trials are typically comparing a new treatment to the standard of care, often placebo is used in the comparator combination. A recent example is the abiraterone trial reported last week at ESMO in men with advanced, castration resistant prostate cancer after prior docetaxel therapy. The study compared abiraterone (a pill) with prednisone (a steroid) to placebo (pill) plus prednisone. Based on the information provided in clinicaltrials.gov, it isn't clear what the placebo actually was.

I liked the quote from the authors in the LA Times article above:

"Perfect placebo is not the aim, rather, we seek to ensure that its composition is disclosed."

Given the placebo could have unexpected effects or at least have an impact, perhaps we should start disclosing what's actually in them.

What's hot in molecular diagnostics and biomarkers? #aacrMD #2

At the AACR meeting on Molecular Diagnostics and Cancer Therapeutics meeting in Denver, there was quite a bit of interesting scientific data coming out on cancer biology and biomarkers, so here is a quick synopsis of what appealed to me:

1. IGF-1R is over expressed in a subset of triple negative breast cancers (TNBC)

This presentation, from Witkiewicz et al., was interesting because they showed that IGF-1R might be a useful prognostic biomarker in TNBC. Usually, TNBC, which occurs in 15-20% of all breast cancers and is associated with a poorer prognosis, so finding a subgroup that might actually do better could be useful. Gene amplification was seen in 23% of the cases investigated. Caution must be exercised here, however, just because something is over expressed or amplified, does not mean that it is mutated, and therefore a potential druggable target with a therapeutic as we saw with the negative phase III results with figitumumab, an IGF-1R inhibitor in lung cancer.

What I would like to know though, is how many women with TNBC also have the BRCA1 or 2 mutation and have amplified IGF-1R? We know that targeting a cancer with one drug at one or two mutations in solid tumours has modest effects. But what if we target several things with a combination therapy, for a specific subset, then that might possibly yield different results altogether.

2. Molecular biomarker analysis using circulating tumour cells (CTCs)

Siminder Atwal, a Genentech scientist, presented her work on CTCs, with the idea of determining whether they could be used as a predictive biomarker by correlating CTCs with HER2 status in archival tumour samples. CTC's in theory should match tumour biopsies since they are cells that have shed from the primary tumour.  The Genentech scientists found that they were indeed correlated, with a high concordance (95%) using the CellSearch system. Of course, EpCAM expression can vary in some tumour types, complicating analysis and interpretation, but it looks like they saw some early hints that molecular biomarker status in CTCs are indeed reflecive of the biomarker status in patient tumours.

Predictive biomarkers allow us test whether a patient is likely to benefit from a given treatment, so the obvious and leading question is whether this work could be extended to look at eg CTC's in colorectal, lung or breast cancers to determine whether a patient is more likely to respond to bevacizumab (Avastin) or not. It would probably be easier in breast (lots of biopsy samples) and colorectal (lots of surgery providing samples).

At the moment, there is no way of telling who is most likely to respond to Avastin, so a predictive biomarker test would be really useful for clinicians before deciding on treatment, rather than having to expose thousands of patients to the systemic side effects. Given that the FDA have to make a decision by the year end on the full approval of Avastin in breast cancer, it is a shame that they likely won't have this sort of data to help guide a decision.  

3. BRCA1 mutations in prostate cancer

Gerhardt Attard gave an enlightening talk entitled, "Circulating tumor cells: Potential uses, pitfalls and challenges in their use as pharmacodynamic markers" but what struck me was not so much the fascinating information about CTCs as his mention that a subset of prostate cancer patients have the BRCA1 mutation. They tested the impact of olaparib, a small molecule PARP inhibitor from AstraZeneca, and found that all three responded.

A study open for men with prostate cancer and either BRCA1 or 2 mutations is currently recruiting patients. Given the interest with PARP inhibitors in breast and ovarian cancers, I'll be following this development with great interest.

The Use of 18F amyloid imaging in Alzheimers Disease

Following my live tweets from the AACR molecular diagnostics and cancer therapeutics meeting here in Denver this week, some interesting offline discussions continued. A big focus here was on biomarkers and systems biology. Several readers observed that oncology seems to be ahead compared to other therapy areas.

What is interesting though, is that while oncology is heavy on science, pathways, targeted therapies and multiple mechanisms of actions, it is surprisingly low on predictive biomarkers. It does fare a little better on prognostic biomarkers, granted. In contrast, Alzheimer's Disease (AD) in many ways, seems to be almost the opposite in that various biomarkers abound, but the field lags in effective targeted drugs and a deep understanding of the underlying biology (relative to oncology that is).

One area where we are likely to see more progress in the near future is in the use of imaging biomarkers for the diagnosis of early Alzheimer’s Disease.

Several companies are currently undertaking clinical trials with imaging biomarkers for AD including Bayer with florbetaben (BAY 94-9172), Avid Radiopharmaceuticals with AV-45 and GE Healthcare with flutemetamol. All three are in phase III development.

Currently the use of Pittsburgh compound B (PiB) in combination with PET allows the imaging of beta-amyloid plaques in the brain that are indicative of AD. However, there are limitations with the use of PiB since it requires use of an on-site cyclotron.

A recent paper by Rik Vandenberghe from the Catholic University Leuven, published in the September edition of the Annals of Neurology caught my attention on this topic. It reported phase 2 trial results from the use of 18F flutemetamol imaging in AD.

In this clinical trial, sponsored by GE Healthcare, blinded visual assessments of 18F- flutemetamol scans were undertaken in 27 subjects with probable early-stage AD and mild cognitive impairment (MCI). The results showed a sensitivity of 93.1% in the ability of the scan to diagnose early AD, as compared to clinical diagnosis as the Standard of Truth (25 out of 27 patients). 18F-flutemetamol was also shown in 20 subjects to have comparable regional standardized uptake value ratios (SUVRs) when compared to 11C-Pittsburgh compound B (11C-PiB). Correlation coefficients ranged from 0.89 to 0.92.

What makes the use of the 18F-labeled PiB derivative interesting is that 18F-flutemamol does not require the use of an on-site cyclotron, unlike 11C-PiB. As the study reports this may make it easier to access PET technology for clinical trials and research into AD.

GE Healthcare have already started a phase 3 trial program with flutemetamol, so it will be interesting to see whether the promising phase 2 results are confirmed when the phase 3 data is available after the study is completed later this year.

Data from other phase III clinical trials make this an area to watch out for. Hopefully the development of imaging biomarkers that allow for early diagnosis, will insoire both more basic research into the underlying biological mechanisms and also stimulate companies develop more targeted drugs for the treatment of what is essentially a horrible, progressive disease.

 

Photo Credit: Avid Radiopharmaceuticals

Top: Elderly Patient Control

Bottom: 18F AV-45 imaging of amyloid plaque in a patient with Alzheimer’s disease

 

References:

Vandenberghe, R., Van Laere, K., Ivanoiu, A., Salmon, E., Bastin, C., Triau, E., Hasselbalch, S., Law, I., Andersen, A., Korner, A., Minthon, L., Garraux, G., Nelissen, N., Bormans, G., Buckley, C., Owenius, R., Thurfjell, L., Farrar, G., & Brooks, D. (2010). 18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial Annals of Neurology, 68 (3), 319-329 DOI: 10.1002/ana.22068

 

 

MET and KRAS amplification mediate resistance to MET inhibitors

Here's an interesting paper that was just published in Cancer Research that describes some factors driving acquired resistance to MET inhibition with small molecules.

MET inhibitors have gained a lot of attention recently (see Comoglio et al's review in the references for a good overview) and we have covered this topic a few times on this blog both in terms of the biology and also on promising inhibitors such as ArQule/DaiichiSankyo's ARQ-197, which is the leading compound in this field.

Acquired resistance is a common and limiting problem for chronic therapy with many tyrosine kinase inhibitors (TKI), not just MET inhibitors. After initial excitement at seeing some responses though, they appear to stop working. The big question is why, and what underlying mechanisms may be at play?

Of course, while the issue may be a universal one, the resistance mechanisms are not and will differ with each class of TKI and potentially even tumour types or combinations.

Background

The MET gene is disregulated in a number of different tumour types and those cells exhibiting MET amplification may offer a suitable target for drug inhibition.  Doing so results in impairment of cell growth and apoptosis.

You can read more about the biology of the c-MET pathway here.

Acquired Resistance to MET

In this important research, the authors decided to see if they could define some of the underlying mechanisms of MET resistance:

"To predict mechanisms of acquired resistance, we generated resistant cells by treating MET-addicted cells with increasing concentrations of the MET small-molecule inhibitors PHA-665752 or JNJ38877605."

The results?

They found that cells progressively amplified KRAS, which resulted in increased expression and activation of wild-type (wt) KRAS and in activation of the mitogenactivated protein kinase (MAPK) pathway:

"We show that amplification of wt MET and KRAS is found in cells of diverse histotypes, resistant to different inhibitors.

Moreover, unexpectedly, we observed that resistance to treatment was reversible and that the alterations leading to resistance were lost after drug withdrawal."

This is a very important finding because it may well be helpful for designing future clinical studies, either in combination or in sequence, to reduce the potential for resistance emerging with MET inhibitors, thereby improving the potential for better long term outcomes with treatment.

"Our results suggest that MET and KRAS amplification is a general mechanism of resistance to specific MET inhibitors given that similar results were observed with two small inhibitors and in different cell lines of different histotypes."

Impact

My favourite part of this story was not just the identification of potential mechanisms of MET resistance, but some hints of how the learnings from the data could be applied:

"Because specific anti-RAS drugs are not available, we tested the ability of compounds acting downstream RAS (such as U0126, PD325901, and sorafenib) to impair cell viability. We observed that cells resistant to MET inhibitors that underwent KRAS amplification are indeed sensitive to these drugs."

Clearly, our ability to not only predict potential mechanisms of resistance, but also devise strategies for overcoming or preventing it, is crucial for improved clinical development with these agents as well as providing a clear rationale for other inhibitors still in research.

Where there's a viable target, there's a way forward.

 

References

Cepero, V., Sierra, J., Corso, S., Ghiso, E., Casorzo, L., Perera, T., Comoglio, P., & Giordano, S. (2010). MET and KRAS Gene Amplification Mediates Acquired Resistance to MET Tyrosine Kinase Inhibitors Cancer Research DOI: 10.1158/0008-5472.CAN-10-0436

Comoglio, P., Giordano, S., & Trusolino, L. (2008). Drug development of MET inhibitors: targeting oncogene addiction and expedience Nature Reviews Drug Discovery, 7 (6), 504-516 DOI: 10.1038/nrd2530

LKB1 is a master kinase in cancer

"LKB1 is a master kinase"

What a great subheader in a paper last year by Reuben Shaw (journal link below).

Liver kinase B1 (LKB1) first got my attention at the AACR lung cancer meeting in San Diego earlier this year, when a couple of translational researchers mentioned it during informal discussions about how it might play a critical but subtle role in lung cancer and potentially other cancers.

Looking at the literature, LKB1 was first identified as a tumor suppressor gene on human chromosome 19p13, responsible for the inherited cancer disorder Peutz-Jeghers Syndrome (PJS).  However, the interest at the AACR meeting centred around it being one of the most commonly mutated genes in sporadic human lung cancer, including some subtypes of non-small cell lung carcinoma (NSCLC).

Of course, being very interested in potential druggable targets, I was trying to get my head around this particular kinase.  Several scientists and researchers explained to me patiently that LKB1 is involved in energy levels and metabolism, rather than cell signalling per se, so it kind of went by the wayside as other interesting targets came up lately, associated with small molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies.

Still, the fact that LKB1 and AMPK control cell growth in response to environmental nutrient changes stuck in the back of my mind while I quietly wondered whether it would eventually have it's day.

Fast forward to an AACR press conference this morning about the role of metformin, a biguanide therapy for managing hyperglycemia and diabetes, in the role of chemoprevention.  I'm going to write more about that meaty topic in another more detailed post tomorrow, but what fasinated me was the mention by Dr Michael Pollak about metformin altering cell energy levels, ie a control system that senses cell energy supplies and low reserves.  

It was also mentioned that the activation of the LKB1-AMPK pathway downregulates gluconeogenesis.  This process represents the export of energy from hepatocytes to the organism in the form of glucose.  In turn, this reduces blood glucose concentration, which results in a secondary decrease in insulin level.  

Essentially, the inhibition of hepatic gluconeogenesis is now felt to be a key process underlying the utility of biguanides in the therapy of type II diabetes.

What is interesting on several levels is:

• Studies showing raised levels of free or circulating IGF1 may be associated with an increased risk of developing cancer
• Epidemiology studies amongst people with diabetes taking metformin who may have a lower risk of developing cancer

Of course, when we look at the broader picture, we can see the interactions across several pathways, which makes the whole situation highly complex:

Source: University of Dundee

Clearly, there is now enough evidence to warrant researching the effects of metformin in cancer prevention, especially given that it is orally available, has had no long term safety issues and is now generically available.  These factors, coupled with a greater understanding of the biology of the involved pathways may make a productive new area of cancer research.

Tomorrow, I will cover the latest research involving metformin for chemoprevention in colorectal and lung cancers in more detail.

 

Shaw RJ (2009). LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta physiologica (Oxford, England), 196 (1), 65-80 PMID: 19245654

Shackelford DB, & Shaw RJ (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature reviews. Cancer, 9 (8), 563-75 PMID: 19629071

Nanoparticle drug delivery helps reduce tumour metastasis

Nanotechnology is a topic that fascinates me, ever since hearing some interesting data in pancreatic cancer at the American Association of Cancer Research (AACR) meeting last November on Molecular Targets in Boston.

Someone kindly sent me a paper from PNAS recently (link below), from 2008, which got my attention essentially because:

"Integrin aBv3 is found on a subset of tumor blood vessels where it is associated with angiogenesis and malignant tumor growth. We designed a targeted aBv3 nanoparticle (NP) encapsulating the cytotoxic drug doxorubicin (Dox) for targeted drug delivery to the expressing tumor vasculature."

Now, giving doxorubicin by the normal route of administration results in noticeable weight loss and other side effects when given systemically.  Using nanotechnology, a 15-fold increase in anti-metastatic activity without concomitant weight loss, which is very interesting indeed.

The authors noted that integrin could represent an ideal vascular targeting receptor since it is highly expressed on the angiogenic endothelium and expression of this receptor on tumor vessels correlates with disease progression.  This was first shown by Gasparini et al., in 1998 (see reference source below).

Meanwhile, in this 2008 study, the researchers used models from renal cell and pancreatic carcinoma to determine the effectiveness of the nanoparticle delivery system. Given that the results appear better with metastatic rather than primary tumour growth, I wondered if anyone was looking at this concept with currently approved drugs for metastatic disease?

A quick search for nanoparticle and cancer in the clinical trials database brought up mostly trials associated with nanoparticle paclitaxel (Abraxane) from Abraxis ($ABII). Of course, one of the challenges here is that in animal research, drugs and nanoparticles can be injected directly into the tumour thus avoiding systemic effects, whereas in human research, nanoparticle drugs are more typically combined with regular drugs and infused as normal.

It was, hover, no surprise to learn earlier this year that Abraxane is looking promising in 2nd line advanced pancreatic cancer as a single agent after failure of gemcitabine-based chemotherapy.  At AACR last year, researchers from Mass General showed that Abraxane targets the tumour stroma, depleting it, thereby reducing the impediment to chemotherapy.  The Nab-paclitaxel utilises endogenous albumin pathways via binding of the albumin to secreted proetin acid rich in cysteine or SPARC.  Interestingly, pancreatic cancer is known to overexpress SPARC and therefore offers a logical target for the drug.  Abraxis reported in May that the median overall survival was 7.3 months, which is impressive in a very hard to treat refractory population.

I wonder what the Nab paclitaxel data would look like in front-line treatment in combination with gemcitabine?  Or what about using it in advanced renal cancer with any of the half dozen drugs already approved but with limited effectiveness? Would adding a nanoparticle delivery system such as Abraxane to the mix reduce metastasis, deplete the stroma and improve access to the tumour for the anti-angiogenic agents?

Overall, it's an interesting technology concept for improving drug delivery and we're still at relatively early stages of research.  Hopefully, we'll hear more about nanotechnology and the broader application of new combination nanoparticles to cancer treatment in the near future.  It takes significant investment, creativity in trial design and an intensive yet broad research program to drive results though. Celgene ($CELG) have since bought Abraxis and may be more willing to aggressively invest in the growth of this interesting drug.

I must say that the AACR Molecular Targets and Cancer Therapeutics meeting every November is one of my all time favourites, but it alternates with Europe every other year and will be in Berlin this November, so depending upon my schedule I may not be able to make it this time :(

 

Murphy, E., Majeti, B., Barnes, L., Makale, M., Weis, S., Lutu-Fuga, K., Wrasidlo, W., & Cheresh, D. (2008). From the Cover: Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis Proceedings of the National Academy of Sciences, 105 (27), 9343-9348 DOI: 10.1073/pnas.0803728105

Gasparini G, Brooks PC, Biganzoli E, Vermeulen PB, Bonoldi E, Dirix LY, Ranieri G, Miceli R, & Cheresh DA (1998). Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 4 (11), 2625-34 PMID: 9829725

Evidence for role of microRNA in Melanoma

Twitter is great for highlighting interesting journal articles, as I found when Edward Winstead from the NIH shared this paper from PLOSone on the importance of microRNA in melanoma in his Twitter stream (thanks, Ted!).

There has been a lot of interest in melanoma lately, with the rise of a couple of interesting new compounds targeting different mutations or kinases including CTLA4 by ipilimumab (BMS) and B-RAF by PLX-4032 (Plexxikon/Roche).  

You can see some of the recent data I've blogged about here, here and here.  

At the moment, we're waiting for the new data from PLX-4032 at a melanoma conference later this year and BMS may be filing their phase III data in ipilimumab by the end of this year after some promising reactions to the data presented last month in the plenary session at ASCO.  In addition, GSK also have some compounds in earlier development that are generating interest.

How does the new data in PLOSone connect with melanoma?

Well, it's an aggressive and highly malignant cancer and scientists have long wondered how melanoma cells travel from primary tumours on the surface of the skin to the brain, liver and lungs, where they become more aggressive, resistant to therapy, and deadly. This ultimately makes treatment and control of the disease very challenging.

In Feb 2009, an article in PNAS (see reference below) suggested that the culprit might be a short strand of RNA called microRNA (miRNA) that is over-expressed in metastatic melanoma cell lines and tissues. It is also known that the Microphthalmia associated transcription factor (Mitf) is an important regulator in melanocyte development and has been shown to be involved in melanoma progression. The new data reported in PLOSone this month takes our understanding a little further and shows that microRNAs are also involved in regulating Mitf in melanoma cells. 

The authors concluded that:

"miR-148 and miR-137 present an additional level of regulating Mitf expression in melanocytes and melanoma cells. Loss of this regulation, either by mutations or by shortening of the 3′UTR sequence, is therefore a likely factor in melanoma formation and/or progression."

What this means is that the microRNA's involved may offer new therapeutic targets in order to either reduce the development of resistance or aggressive progression and metastasis (ie spread of melanoma) to other organs. In order words, future research may involve the addition of microRNA therapy to optimise outcomes.

For now, microRNA is very much a research on the rise but it won't be long before we start seeing the first RNA based therapies in the clinic based on a solid scientific research rationale.  As our understanding of the complex biology improves, so does the chances of developing a multi-factorial strategy to combat the devastating disease.

For those of you interested in this exciting field, I'll cover a more basic primer on microRNA and RNA therapeutics in development in a future blog post.

Photo Credit: Wikipedia

Haflidadóttir, B., Bergsteinsdóttir, K., Praetorius, C., & Steingrímsson, E. (2010). miR-148 Regulates Mitf in Melanoma Cells PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011574

Segura, M., Hanniford, D., Menendez, S., Reavie, L., Zou, X., Alvarez-Diaz, S., Zakrzewski, J., Blochin, E., Rose, A., Bogunovic, D., Polsky, D., Wei, J., Lee, P., Belitskaya-Levy, I., Bhardwaj, N., Osman, I., & Hernando, E. (2009). Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor Proceedings of the National Academy of Sciences, 106 (6), 1814-1819 DOI: 10.1073/pnas.0808263106

The Long Tail of Cancer Research

"What's really amazing about the Long Tail is the sheer size of it. Combine enough nonhits on the Long Tail and you've got a market bigger than the hits." 

Source: Chris Anderson, Wired

The other other day, while barely lucid in the early hours of the morning, I was thinking about the herd instinct, the tendency to follow the masses and the counterpoint to that, i.e. the long tail.

If you're wondering what the long tail is, think of those statistical distribution plots where everything is bunched around the median, creating 50% on one side and 50% on the other.  At either end the plots tail off into infinity.  That's the long tail.  

The long tail looks small at first, but creative marketers realise that added up (as Chris Anderson's quote above shows), you can in effect still have quite a large niche market while every one else focuses on minute shares in the middle.

I first realised the long tail effect as a sales rep in the tough anti-cholesterol market.  You can spend fruitless hours chasing the majority of the primary care doctors who see reps but don't remember you when the relevant patient appears, or you can carefully invest time in the ones who don't see reps but are busy with appropriate patients and eventually crack if you try enough times. Once convinced, they often switch wholesale and your job is done with a smaller group of physicians who others can't see :-).

If we apply the principle of the long tail to cancer research, we can see things more clearly.  In the old days, the majority of patients got treated pretty much the same with various chemo doublets, irrespective of whether they might work or not.  In fact, in many cases, there wasn't even biomarkers such as ERCC1 to determine which patient should get platinum or not, but things are changing and now it's much easier to make these decisions and start segmenting patients according to their biochemical profile and make decisions based on the profile.

Today, we can take this niche idea to treatment a lot further.  

In colon cancer, for example, we now know that patients with wild type KRAS are more likely to respond to an EGFR therapy than those with mutant KRAS. However, in lung cancer, the old adage was that erlotinib (Tarceva) was best suited for patients who were female, asian, non-smokers with adenocarcinoma is giving way to a more precise definition, i.e. do they have the EGFR mutation or not? If they do, they're more likely to respond, irrespective of smoking status. Offering these patients maintenance treatment may also be an effective treatment strategy that impacts outcomes.  

We can see this effect in other cancer types too.  Trastuzumab (Herceptin) is approved for women with Her-2 breast cancer, imatinib (Gleevec) and other TKIs such as dasatinib (Sprycel) and nilotinib (Tasigna) for Philadelphia-chromosome positive chromic myeloid leukemia (CML).

Histology is a very crude way to select patients, but looking at the aberrant mutations essentially creates niche long tail opportunities to treatment for pharma and biotech companies.  Patients who are more likely to respond to a given therapeutic get appropriate treatment, without having to expose others who would not to unnecessary systemic effects. This is a win-win solution all around.  

Why?  

Well, it's good news for patients as you increase the chances of successful outcomes rather than relying on hope alone.  It's also good news for manufacturers because smaller patient populations ultimately involve fewer patients in clinical trials, thereby making clinical development more cost effective and as cancer therapy moves from an acute to chronic disease, so longer term revenues are generated despite a small patient base.

As more oncology companies start looking at their pipelines, we can see many asking the critical questions - which patients are more likely to respond to a given treatment and why?  As we learn more about the underlying biology of the disease, so companion diagnostics are also evolving in sophistication and sensitivity.

The other marketing advantage of developing niche targeted therapies and diagnostics is that often, you see less competition for smaller subsets of disease because it creates a high barrier to entry. Diagnostics also create barriers to entry because of the extra costs involved in their development.  For smaller biotechs this can be prohibitive, and many are more actively seeking Pharma and Biotech partners to fund late stage research and clinical trials.  Overall, the long tail opportunities offer big and small hurdles, depending on the circumstances.  

Roche's VEGF monoclonal antibody bevacizumab (Avastin) has a very high barrier to entry in colon cancer, for example, as other VEGF inhibitors have fallen by the wayside, unable to beat the results already obtained by the first to market drug.  

At the other end of the scale, the barrier to entry is much lower in renal cell cancer with numerous targeted therapies now approved for a relatively small niche indication, including sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor), pazopanib (Votrient) and bevacizumab (Avastin), probably reflecting the improvement over IL2, without completely reducing unwanted side effects or dramatically improving efficacy.

Some of the marketed therapies mentioned in this post are now billion dollar blockbusters despite cancer being a relatively niche market opportunity compared to the much bigger primary care markets such as metabolic or cardiovascular disease, proving that there are valuable nuggets to be found, even in the long tail.  

The future in cancer research is not in broad acting systemic chemotherapies that target normal cells as well as cancer cells, but in the niche development of better and less toxic targeted therapies based on the underlying biological abnormalities with easy to use diagnostic technology based on fluid-based biomarkers.  To achieve this though, will take a lot of bright smart people with expertise in oncology who dare to think differently and boldly, whether they be scientists, marketers or clinical research professionals.

Watch this space!

Two new cancer drugs approved - cabazitaxel and nilotinib

Yesterday brought two new approvals in a day from the FDA in completely different cancer types.

In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule.  This approval comes hot on the heels of Dendreon's sipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.

What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break.  It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.

The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none.  Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists. 

Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.

The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over. 

Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.

Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).  

If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?  

What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly. 

Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.  

It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates - in this case - complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).

Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year survival data will evolve.

Disclosure:  I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :).  Many thanks to @erohealth for proofreading suggestions.

Betterness is Good Business even for Pharma

"Good Businesses" are not judged solely by better sales, profits, equity returns and sharholder value - these becoming old measures on their own.  Investors are increasingly asking  "So you made a profit - yawn - but did you also make an impact?"  This is what it takes to outperform today and tommorrow.

What about Big Pharma? Or little Pharma for that matter.

Aren't these companies founded on the ideals of delivering novel life-changing treatments to patients, transforming science into therapies, to serve patients, to deliver meaningful benefits to consumers, and to improve the quality of life?

How does this square with off-label marketing, physician payola schemes, manufacturing failures resulting in product shortages, contaminated or adulterated product, massive corporate lay-offs and outsourcing jobs elsewhere?"

via thebigredbiotechblog.typepad.com

Bruce Lehr of The Big Red Biotech Blog wrote a nice blog this morning that made me sit up and take notice.  He's right; some areas of the industry could do well to clean up their act and focus on the important things that matter rather than skimping on quality or indulging in fluff n puff marketing. And some people wonder why Pharma is held in such distain akin to oil or tobacco companies?

Meanwhile, in the oncology arena, we're always running head to head trials, figuring out how to beat the standard of care and improve overall survival. In other words, finding the compounds that give an edge and make an impact.

It's easy to forget that many other areas of the Pharma business live in fear of not winning, not making blockbuster revenues and thus run an inordinate number of placebo controlled rather than head to head trials. After wading through a mass of non-oncology data at the weekend, I was left wondering, "How on earth do you prove your product is better in that situation?"

If you can't beat the competition, why bother?

Which takes us back to the original review article from Umair Hague in the HBR on why Betterness is Good Business and how great companies focus on the stuff that matters, rather than just profitability and increased shareholder value.

So, I think I'll stick with the dog eat dog mentality in oncology, where we focus more on people and trying to make a difference to the lives of people with cancer. If your compound doesn't beat the standard of care it effectively dies in that indication. My firm belief is if you focus on bettering the competition, the rest will follow naturally and organically. That doesn't mean that some don't fall off the wagon and transgress into the dreaded off-label promotion though.

Still, maybe the rest of Pharma could learn a thing or two from oncology?

ASCO 2010 Preview #2: PI3K and mTOR inhibitors

One of the interesting things about scientific conferences such as AACR and ASCO is that everyone looks at the same data differently as if it were through a kaleidoscope.

Brand marketers focus on their competition by tumour type or disease, scientists look at specific mechanisms or pathways, investors look at particular companies and so on. 

Someone asked me the other day how I analyse the data.  I hadn't really thought about it much until then, but on reflection what I'm interested in is trends and how research evolves from a big picture science view so that means I look at pathways like a true biochemist.  This also teaches us where the gaps are and what opportunities may arise in the future.  It's not exactly rocket science, but it is a useful approach sometimes.

Image via Wikipedia

One of the clear trends emerging at AACR the other week is that dual inhibition of both the PI3K-mTOR and RAS-ERK pathways may be necessary in some cancers such as melanoma to reduce cross-talk, feedback and feedforward loops, drug resistance and loss of PTEN gain of function, just as one might also target IGF-1R and EGFR to reduce cross-talk and add in another inhibitor, eg MEK or AKT.

Given the increasingly critical role of MEK and AKT in various combinations in the future to reduce the potential for drug resistance occurring, this bodes well for a host of companies.  I wasn't, therefore, surprised to see Novartis snap up Array's MEK inhibitor (ARRY-162) given they already have an mTOR on the market (everolimus, Afinitor), two PI3-kinases in development and others including a RAS inhibitor.  Having a MEK inhibitor as well may therefore give them a lot of flexibility with different combinations in multiple cancer types if this approach pans out. 

Merck are also following a similar approach with their mTOR inhibitor, ridaforolimus, which they have finally grabbed commercial control of from their partner, Ariad.  Let's not forget they also have an AKT inhibitor, dalotuzumab and a MEKi through their partnership with AstraZeneca to play with too.

This is all good news for several biotech companies though, if some big Pharma companies start catching onto the trend and realise they need may a PI3K-mTOR inhibitor and a MEK or AKT inhibitor to stock up in their pipeline before the field gets too crowded.

Which companies might have new and interesting data in this area?

Well, Keryx and Aeterna Zentaris, Semafore, Calistoga, Intellikine and a few others all have PI3K inhibitors in development, while Exelixis have a deal in place with sanofi-aventis for XL147 and XL765 and Roche/Genentech have a pan-PI3K inhibitor, GDC-0941.  Novartis have two (BEZ235 and BKM120). Some of these compounds are single PI3K inhibitors and some are dual inhibitors of PI3K-mTOR.

Looking at the ASCO abstract titles, Exelixis appear to have the most abstracts in this area this year, so it will be interesting to see what sort of data they have across a range of different tumour models and early phase I results in solid and hematologic malignancies, with a variety of different combinations. 

One session I'm really looking forward to at this year's ASCO is a Clinical Science Symposium entitled, "Paths for Clinical Development of PI3K Inhibition" with some of the heavyweights in the field such as Neil Rosen (MSKCC), Skip Burris (Sarah Cannon), Jose Baselga (Spain) and Carlos Arteaga (Vanderbilt).  Arteaga is presenting a talk in that session entitled, "Next steps in clinical development of PI3K inhibitors?"

More later on this blog after the posters and the data become available at the meeting.

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• Aeterna Zentaris Presents a Poster on its Dual Inhibitors for PI3K and Erk, as well as an Oral Presentation Reporting Data on Selective Erk Inhibitors, at AACR Annual Meeting (newswire.ca)

Is there a better model for health care?

Recently, I've been doing so much research and analysis of advanced cancers, it struck me that we spend millions of dollars on healthcare at the end of life when it likely won't have much impact, yet the real change happens when we catch and treat, or preferably prevent, diseases such as cancer earlier.  This is not exactly rocket science.

Maybe we need a change in approach?

By that, I mean a greater focus on prevention, health and wellness rather than medicate and palliate end of life care.

How much of illness is as a result of poor body management, for want of a better term?  Obesity, cardiovascular disease, sedentary lifestyles and lack of exercise all take their toll.

Most people don't do anything until a major wake-up call comes, but by then, it may well be too late do much.

What we need is a wellness model and people educating themselves to take better care of things earlier and having more responsibility for their choices.  After all, we can't expect an unlimited pot to be available at the end of the rainbow to cover the inexorable rising cost of treatment.  That's totally unrealistic and impractical.  

Eventually, the pot runs out and there is no more.

What then?

Clinical trials for cancer patients

Earlier this week I was reading Fierce Biotech's excellent article about the human face of the drug industry and was surprised to learn about one of the requests from the women with breast cancer who were featured in the post:

"All three women were frustrated by the lack of available clinical trials for Stage IV patients."

Given that most cancer drugs are tested in the advanced stage first, I would have expected more there than earlier stage disease.

It's interesting first to look at how many trials there are for common conditions.  In the NIH database, I searched for some common diseases and came up with the following:

Cancer is by far the most active category in the clinical trials I searched for; in fact, all the others added up to 32,260, a bit more together than cancer alone.

So I decided to check the databases out further, but along the way I came across some frustrations. Firstly, if you go to the NIH site, you can't actually search by stage of cancer type easily.  You can search by Phase (ie phase of clinical trial) but that's not the same thing as disease stage:

Ugh.  Ok, off to the more cancer specific forum at the NCI, which accesses the same trial database but has a different front end for search, surely that would be more useful?

 

Again, you can search for all sorts of things (hidden for space reason) except stage of disease!

To find the actual list of trials you want out of 25,885 available for all CANCER as a condition, you have to click on the search box for CONDITION and type in words like 'metastatic', 'advanced', 'stage IV' for example.  But how many people would know or actually think of that?

 

Using breast cancer as an example, we can find all trials involved with the disease and how many studies are for advanced stage disease:

Breast Cancer 

- All: 3,618

- Metastatic OR Advanced OR Stage IV: 1,267

Thus 45% of breast cancer studies, or nearly half, are in later stage disease.

There is a nifty little feature that maps out the location of those studies as well for great context under the Map button:

Inevitably, most of those studies are run in the USA, but it's good to see improved access for women with breast cancer in other parts around the world too.

Of course, many of those trials may have completed, been suspended or finished enrolling. Fortunately, you can hide non-active trials, so this brings the 1,267 number down further to 576 studies globally open for advanced breast cancer, and from the map tab, 380 are open in the US, 167 in the EU and only a paltry 29 in the ROW:

 

That's a far cry from the massive 25,000 global cancer studies we started off with!

FDA conducting safety review of commonly used prostate cancer drugs

This morning I received the usual hodge podge of alert emails, which I only just got round to checking and nearly fell off my chair when clicking through to one from the FDA that brought me up with a start:

There's been a lot of news out there lately about obesity and diabetes, as well as the excitement of Dendreon's new vaccine for prostate cancer, Provenge, which was approved last Thursday to much fanfare. 

It's therefore a little shocking to see the FDA's initial safety analysis of hormone therapies, which have been pretty much the bedrock of treatment for early stage prostate cancer for many years, including several are now available as generics:

"Preliminary review suggests an increase in the risk of diabetes and certain cardiovascular diseases in men treated with GnRH agonists."

You can find out more here.  Yikes.

It will be interesting to see how the FDA separated out the effects of natural aging and a sedentary lifestyle from real long term drug effects.

Who knows, but Provenge may well turn out to have other hidden benefits such as less risk for diabetes or stroke, but we won't know until we see more data in the earlier, non-metastatic setting.

Perhaps I'm being cynical, but I can just see some ambulance chasers starting another class action lawsuit...

Update on Multiple Myeloma: are molecular remissions possible without a transplant?

By strange coincidence this morning I was listening in to the Celgene R&D Day presentations including an update on their plans for their iMiD therapies thalidomide (Thalomid) and lenalidomide (Revlimid), while reading a couple of interesting papers about Millennium-Takeda's bortezomib (Velcade) that were just published in the Journal of Clinical Oncology last month and another this week for the treatment of multiple myeloma. All three of these drugs have changed the treatment of multiple myeloma from a certain death sentence to a treatable disease.

I'll post more about the Celgene pipeline in a later post, but the papers are well worth sharing and discussing.  One report looked at the phase III data for the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial.  This study was presented at the recent American Society of Hematology (ASH) meeting in December (see previous post), but the paper now includes updated survival data in a large cohort of 682 people:  

"With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%.  Response rates to subsequent thalidomide (41% v 53%) and lenalidomide based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. 

Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months."

The bold for emphasise is mine, but anytime you see a greater than 30% reduced risk of death from a treatment, one is bound to sit up and take notice, especially if you have a loved one suffering from the disease.  

What do these results mean?  Well, in practice they clearly demonstrate that VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent therapy for myeloma.  What was particularly encouraging is that first-line bortezomib use does not induce more resistant relapse, which is also important for people sufffering from the disease. 

The combination of VMP used upfront therefore appears more beneficial than first treating with conventional agents such as melphalan and prednisone and saving bortezomib and other novel therapies until relapse.   Historically, oncologists often leave the big guns in their back pocket, but the data from this trial may well change their thinking about treatment strategies in multiple myeloma, at least.

The second paper examined the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included the combination of bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTD) in people with multiple myeloma who responded to autologous stem-cell transplantation (auto-SCT).  Although the results are more preliminary - this was a phase II trial with only a small number of patients (n=39) - they are very encouraging indeed.  

This study is particularly important because it may be the first to document the occurrence of persistent molecular remissions (almost undetectable disease) in a proportion of people with multiple myeloma treated without allogeneic transplantation.  To put this is context, until now, a transplant was the only known curative treatment that has been shown to induce molecular remission, so to achieve that state with therapy alone is something that will give many people goosebumps.

Why?

Because SCT are associated with 20% treatment related mortality alone, so if that number can be reduced by excluding the risk of death, then it offers hope not just for those who are ineligible for a transplant, but as another option for those who are.

The researchers also noted that:

"The major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs."

That's all sorts of awesome news, albeit in a small study, but it does augur well for the future if the results can be repeated in a phase III study.

Ladetto, M., Pagliano, G., Ferrero, S., Cavallo, F., Drandi, D., Santo, L., Crippa, C., De Rosa, L., Pregno, P., Grasso, M., Liberati, A., Caravita, T., Pisani, F., Guglielmelli, T., Callea, V., Musto, P., Cangialosi, C., Passera, R., Boccadoro, M., & Palumbo, A. (2010). Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma Journal of Clinical Oncology DOI: 10.1200/JCO.2009.23.7172 

Mateos, M., Richardson, P., Schlag, R., Khuageva, N., Dimopoulos, M., Shpilberg, O., Kropff, M., Spicka, I., Petrucci, M., Palumbo, A., Samoilova, O., Dmoszynska, A., Abdulkadyrov, K., Schots, R., Jiang, B., Esseltine, D., Liu, K., Cakana, A., van de Velde, H., & San Miguel, J. (2010). Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial Journal of Clinical Oncology DOI: 10.1200/JCO.2009.26.0638