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A couple of articles in the latest Cancer Discovery looked at some rather promising, and perhaps a little unexpected, findings pertaining to epigenetic therapy.

What are epigenetics?

If you read up on epigenetics in the medical journals, you will come across some of the most dense and complex articles I’ve ever come across in cancer biology. That said, there are a few readable examples around such as Bird’s (2007) short insight piece in Nature.

Personally, I tend to think of epigenetics – in very simple terms – as changes in gene function that can occur without a change in the sequence of the DNA. This means that we see things such as DNA methylation (where something new is added) and gene silencing (where something important is somehow switched off or lost). A classic change in cancer that often appears in many tumour types is PTEN loss, for example.

As Rodriquez-Paredes and Esteller (2011) noted in their editorial,

“No one doubts that tumorigenesis is a consequence of not only genetic but also epigenetic alterations…

Cancer epigenomes are characterized by global changes in DNA methylation and covalent histone modification patterns.”

 

What types of epigenetic therapy are there?

While some readers might be vaguely familiar with DNA methylating agents and histone deacetylase inhibitors (HDAC), there are quite a few other types in preclinical development including:

  • histone methyltransferase inhibitors
  • histone kinase inhibitors
  • sirtuin inhibitors
  • microRNA-related compounds

and others, to name a few.

Currently, however, there are a couple of epigenetic therapies that have been approved (eg SAHA or vorinostat), which belongs to the histone deactelyase class of inhibitors (HDAC) indicated for CTCL, while another is the DNA methyltransferase inhibitors (eg azacitadine/Vidaza and decitabine/Dacogen), which are approved for the treatment of MDS and AML, respectively. There are also several other HDACi in development, including entinostat (Syndax), which has shown activity in breast and lung cancers (see Huang et al., 2009 as an example) and panobinostat (Novartis), which is being evaluated in both hematologic malignancies and solid tumours (prostate and melanoma).

Yet what really caught my attention in the paper by Jeurgens et al., (2011) and the accompanying editorial (see references below) was that these two therapy classes are being evaluated in combination for… lung cancer. You likely won’t find HDACs or DNA methyltransferase inhbitors in the top 30 of therapies used for lung cancer at present, but that may change sooner than you think.

Background to epigenetics in lung cancer

To put this story in context, the authors (see Brock et al., 2008) previously identified a potential gene signature for recurrence associated with stage I lung cancer after surgical resection:

“Analysis of DNA methylation in tumors and mediastinal lymph nodes from a series of patients with surgically resected stage I NSCLC defined several prognostic markers associated with rapid tumor recurrence.

Four gene targets of tumor-specific epigenetic silencing, CDKN2a, CDH13, APC, and RASSF1a, were identified as strongly associated with disease recurrence and death, both singly and in combination.

Methylation of any 2 of these 4 target genes in tumor and mediastinal lymph nodes conferred a markedly worse prognosis in patients with stage I lung cancer (P < 0.001), similar to patients with stage III disease.”

As far as I’m aware, to date the clinical data with epigenetic therapies has been reported in hematologic malignancies such as leukemia, lymphoma and MDS. This is the first time we’ve seen some meaningful data in solid tumours.

What about the latest clinical trial in lung cancer?

Jeurgens and colleagues at Johns Hopkins conducted:

“A phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non–small cell lung cancer.
This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy.”

The NSCLC patients (n=45) were mainly smokers or former smokers (n=40) with primarily adenocarcinoma (n=34) who had been heavily pre-treated (median of 3 prior therapies).

Median overall survival in the entire group was 6.4 months, which compared favourably with the expected 4.0 months in historical controls.

“Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.”

These responses in a small subset of patients were fascinating – the most dramatic response was seen in one patient who experienced a complete response (CR) that lasted for 14 months. A further 10 people had stabilisation that lasted at least 12 weeks (1 for 14 months and another for 18 months).

Moreover, the four gene signature referred to earlier turned out to be potentially useful as both a prognostic and predictive biomarker:

“Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035).”

One patient who did particularly well on the combination therapy was subsequently re-challenged with chemotherapy and had such a good response that the nodules in his lungs reduced significantly.  After being diagnosed in December 2006 with stage IV NSCLC, he was still alive and well to tell his astonishing and heartwarming story on the press conference five years later.

Overall, the authors rightly concluded that:

“This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.”

Emphasis mine.

While these results are very exciting, they are also preliminary and will need to be validated in larger scale clinical trials along with the blood biomarkers for clinical response. They do offer a very strong proof of concept for the combination of epigenetic therapy with a DNA methyltransferase inhibitor and an HDAC inhibitor with clear activity in a subset of patients.

What do these results mean in practice?

Personally, I thought these results were absolutely fascinating and offer us a glimpse into the future where we can utilise epigenetic therapies to:

  1. Effectively repair damaged DNA in tumours
  2. Offer low dose therapies with fewer side effects that give a respite from chemotherapy, while doing more good than harm
  3. Enable sensitization of subsequent therapies to improve outcomes
  4. Predict which patients are most likely to respond to epigenetic therapies, while sparing those unlikely to from any systemic side effects

To get a good clinical perspective of what these results mean, I spoke with Dr Jeff Engelman, Director, Center for Thoracic Cancers at Mass General in Boston. He described the data as ‘impressive’:

“I don’t think this is going to impact the practicing oncologist today, but from a scientific stand point, from an oncology development stand point, from a future stand point, it is I think impressive to many of us, to me.

Seeing that epigenetics could have a dramatic effect even on a subset of lung cancers, we’ve never seen epigenetic modulators have such an effect on solid tumors, so it really opens the door that this may be another type of therapy that we will be able to employ for the right patients.  A totally different type of approach.”

He also went on to put the story in a broader context, which I thought was very helpful:

“It is somewhat analogous to the first trials with EGFR inhibitors where had we treated 40 patients with those we would have seen a few great responses.”

“With EGFR, it was given to tons of patients, and there was a subset that responded, and it took a couple of years to find out why. Then all of sudden, boom everything makes sense and we go forward. This feels more like that, we have seen some great responses and now need to figure out why.”

Clearly, the gene signature identified by Brock et al., (2008) in stage I patients needs to be validated in a broader population of patients in clinical trials, but at least it offers a starting point to try and determine which patients with lung cancer might respond to epigenetic therapy. I think Engelman is correct here; once we determine the right biomarkers of response and how often they occur, then patients with lung cancer can be screened and appropriate therapy offered, whether that be EGFR therapy, ALK therapy, or something completely different such as treatment with epigenetic drugs.

The amazing thing is how much progress is being made of late in lung cancer and that’s very good news indeed. I look forward to hearing more about this story and also the other slices or targets as they are identified and the story evolves further.

References:

ResearchBlogging.orgBird, A. (2007). Perceptions of epigenetics Nature, 447 (7143), 396-398 DOI: 10.1038/nature05913

Brock, M., Hooker, C., Ota-Machida, E., Han, Y., Guo, M., Ames, S., Glöckner, S., Piantadosi, S., Gabrielson, E., Pridham, G., Pelosky, K., Belinsky, S., Yang, S., Baylin, S., & Herman, J. (2008). DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer New England Journal of Medicine, 358 (11), 1118-1128 DOI: 10.1056/NEJMoa0706550

Huang, X., Gao, L., Wang, S., Lee, C., Ordentlich, P., & Liu, B. (2009). HDAC Inhibitor SNDX-275 Induces Apoptosis in erbB2-Overexpressing Breast Cancer Cells via Down-regulation of erbB3 Expression Cancer Research, 69 (21), 8403-8411 DOI: 10.1158/0008-5472.CAN-09-2146

Juergens, R., Wrangle, J., Vendetti, F., Murphy, S., Zhao, M., Coleman, B., Sebree, R., Rodgers, K., Hooker, C., Franco, N., Lee, B., Tsai, S., Delgado, I., Rudek, M., Belinsky, S., Herman, J., Baylin, S., Brock, M., & Rudin, C. (2011). Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non-Small Cell Lung Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0214

Rodriguez-Paredes, M., & Esteller, M. (2011). A Combined Epigenetic Therapy Equals the Efficacy of Conventional Chemotherapy in Refractory Advanced Non-Small Cell Lung Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0271

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“Scientists at Dalhousie University in Nova Scotia have identified a key mechanism of metastasis that could lead to blocking tumor growth if their findings are confirmed.”

AACR press release

Loved this opening to an AACR press release about a key paper (freely available for anyone to download – see the reference session below) that was just published in Cancer Research by David Waisman’s group.

Now, before getting into the technical details, I was reflecting recently on both my recent awesome trip to the MD Anderson basic research campus at Smithville, Austin where a lot of research into tumorigenesis is conducted and pointed questions from patients about why their hasn’t been enough progress in treating and curing metastatic breast cancer.

There are several obvious reasons for this:

  1. We need to understand more about the basic mechanisms underpining function, never mind work out what role various proteins have and how they interact in health and disease before we can even think about clinical progress.
  2. As we learn more about the basic process of tumorigenesis, so we can start to apply those findings to clinical research and translational medicine in developing better predictive biomarkers that are clinically meaningful.
  3. If we have excellent biomarkers, an understanding of the processes and the targets involved, thus we should have clearer targets that suggest more logical combinations to treat disease and essentially slow or even undo the process of metastasis.

Quite frankly, based on the little we really know about the underlying biology of advanced disease, I’m sometimes surprised the results are as good as they are. That’s not to say we’re doing great, becasue clearly there is a lot of improvement that can be made, but sometimes we should stop and look at how far we’ve come and ask serious questions about what we really need to know now that can help progress things?

With all that context in mind, the current published research from Phipps et al., (2011) is worth looking at because it advances our thinking a little more. In the past, people have focused on cancer cells, thinking they were the main thing that mattered. What’s interesting about this research is that it shows how important other cells, such as macrophages, are in the tumorigenesis process:

“There is an increasingly large body of evidence correlating tumor-associated macrophage (TAM) density with poor prognosis in a varied number of solid tumors.”

 

Source: wikipedia

We also know from basic research that macrophages are critical in driving tumour growth, invasion, and metastasis.  Macrophages are like the Pacmen of cells – think of them moving around the blood stream chomping things in their wake.  The thing is, there are always macrophages in tumours – so how do they get from the bloodstream to the tumour?

The current paper details the key role that the macrophage cell surface protein, S100A10, plays in mediating macrophages, thereby allowing them to move to the site of tumour growth. This process is obviously essential to tumour development and angiogenesis.

What also struck me though, was the research also detailed what happened in animals without the S100A10 protein:

“Growth of murine Lewis lung carcinomas or T241 fibrosarcomas was dramatically reduced in S100A10- deficient mice compared with wild-type mice.

Emphasis mine.

What does all this data mean?

In order to either slow or stop metastasis in its tracks, we need to understand the whole process better, thereby finding the weaknesses and chinks in the tumour.

These results clearly show the important role that S100A10 has in facilitating macrophage activity.

Now, S100A10 is a protein and proteins often (but not always, since some of them are currently thought to be undruggable) make very good targets for therapeutic intervention.

Of course, these results clearly need to be reproduced and confirmed by other groups, but if confirmed, they potentially give us some targets to aim at. For example, we could either look at blocking the macrophages in some clever way or target the S100A10 protein directly with a rationally designed targeted therapy. These apparoaches might potentially slow, or even stop, tumour growth.

What if we found some strategies that were effective?  Maybe we could take the approach further and actually use it as a prevention strategy in high risk patients to actually prevent the development of metastasis occurring?

Time will tell, but personally, I was rather heartened by the this wonderful piece of research this morning.

References:

ResearchBlogging.orgPhipps, K., Surette, A., O’Connell, P., & Waisman, D. (2011). Plasminogen Receptor S100A10 Is Essential for the Migration of Tumor-Promoting Macrophages into Tumor Sites Cancer Research, 71 (21), 6676-6683 DOI: 10.1158/0008-5472.CAN-11-1748

This morning I was reading a fascinating paper on lung cancer and one of my favourite proteins, CRKL, from the group of prolific lung researchers at Mass General, Dana Farber, MIT and the Broad Institute in Boston:

“Over-expression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death.”

Cheung et al., (2011)

We also know that one of the mechanisms of resistance to gefitinib is over-expression of CRKL in EGFR-mutant cells by activating ERK and AKT signaling.

What was interesting about this research was the observation:

“We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present prior to treatment.”

Emphasis mine.

We do know that:

  • Adaptive resistance to treatment is a common problem with kinase inhibitors
  • Some lung cancer tumours acquire the T790M mutation, which is known to confer resistance to EGFR therapies
  • Several groups have also reported other known resistance mechanisms may also occur with the EGFR T790M mutation, including MET amplification and CTNNB1 (β-catenin) mutations.

Cheung et al., (2011) tested to see if the PI3K-AKT pathway was specifically involved with CRKL resistance:

“We examined whether treatment with the PI3K inhibitor GDC-0941 suppressed growth of CRKL–over-expressing HCC827 cells in response to gefitinib. Cells were exposed to GDC-0941 alone or in combination with gefitinib. Combined treatment with GDC-0941 and gefitinib resulted in a substantial decrease in the relative proliferation of CRKL–over-expressing HCC827 cells compared to gefitinib treatment alone.”

The answer was yes, activation of PI3K-AKT signalling contributes to CRKL-induced EGFR inhibitor resistance.

It would therefore be very interesting to see what happens in the clinic to a subset of lung cancer patients with CRKL amplification who are treated with an EGFR and PI3K inhibitor to see if this reduces resistance to treatment and improves outcomes. Trials with the combination are indeed ongoing, although I think they are in a more general population of patients with EGFR driven lung cancer. Based on these findings, a subset analysis might prove to be rather instructive here.

What do these results mean?

This study strongly suggests that CRKL may well be a valid therapeutic target:

“These observations show that CRKL over-expression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.”

“Although CRKL amplifications occur in a relatively small fraction of NSCLC, the finding that a similar fraction of NSCLC with translocations involving ALK respond to treatment with crizotinib indicates that targeting genetic alterations present even in a subset of NSCLC may have clinical importance.”

The general idea that CRKL could act as an oncogene in other cancers with CRKL amplifications is also an intriguing idea that needs be explored further.

The paper is very well written and worth checking out for those interested in EGFR mutations, resistance to therapy and development of new therapies.

References:

ResearchBlogging.orgCheung, H., Du, J., Boehm, J., He, F., Weir, B., Wang, X., Butaney, M., Sequist, L., Luo, B., Engelman, J., Root, D., Meyerson, M., Golub, T., Janne, P., & Hahn, W. (2011). Amplification of CRKL induces transformation and EGFR inhibitor resistance in human non small cell lung cancers Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0046

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, & Jänne PA (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.), 316 (5827), 1039-43 PMID: 17463250

Sequist, L., Waltman, B., Dias-Santagata, D., Digumarthy, S., Turke, A., Fidias, P., Bergethon, K., Shaw, A., Gettinger, S., Cosper, A., Akhavanfard, S., Heist, R., Temel, J., Christensen, J., Wain, J., Lynch, T., Vernovsky, K., Mark, E., Lanuti, M., Iafrate, A., Mino-Kenudson, M., & Engelman, J. (2011). Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors Science Translational Medicine, 3 (75), 75-75 DOI: 10.1126/scitranslmed.3002003

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“Ipilimumab is not recommended for the treatment of advanced (unresectable or metastatic) malignant melanoma in people who have received prior therapy.

The Committee was satisfied that ipilimumab meets the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.

The Committee acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need.

Despite the combined value of these factors the Committee considered that the magnitude of additional weight that would need to be assigned to the QALY gains for people with advanced (unresectable or metastatic) melanoma would be too great for ipilimumab to be considered a cost-effective use of NHS resources.”

NHS NICE Guidance

In other words, it’s too expensive and the NHS doesn’t want to pay the £80K ($120K) sticker price. This news is no great surprise given the cost-benefit ratio when considering that there is no way to tell who might benefit most from treatment upfront.

The is, however, a huge difference between hope and false hope, as NPR Shots astutely noted when discussing Avastin in breast cancer earlier this week and in some ways that sentiment applies here too. By this I mean it would be much more compelling to both patients and NICE if an oncologist could talk about a new therapy in specific and useful terms.

Examples of doctor-patient conversations about treatment in the near future might look more like this….

Either:

“You have an 70-80% chance of responding to this therapy because you have X (mutation, translocation, biomarker etc), where this drug has been shown to be highly effective and extends life by over 2 years in many of our advanced patients with this disease to date.”

Or:

“This drug may do more harm than good in your case, as it has been shown to effectively target X (mutation, translocation, biomarker etc), which you do not have, and therefore, are unlikely to respond. I believe it would be better to consider these alternatives in your situation… “

We all know about heterogeneity – it’s the very underpining of what makes a cancer survive despite our best efforts to tame it until we can subset into more homogenous and predictable groups.  This means that offering a broad therapy to all patients with a given advanced cancer without any idea of its predictive value is fast becoming a misnomer in today’s world of emerging targeted therapies.  Now, manufacturers (marketers even) might think it’s better not to ‘limit’ their market opportunity, but the reality is many healthcare systems are looking at ways to limit treatments to where it’s needed most, not only for cost reasons, but also to direct resources where they are more likely to work. The current model is not sustainable in the long run.

Of course, if a predictive biomarker was available to determine which patients are more likely to respond to ipilimumab, then the QALY calculation would be considerably different, and possibility even within the realms of the current guidelines.

That’s a whole different ballgame, but hopefully one that will begin to emerge as we have seen with new targeted therapies such as vemurafenib (Zelboraf) in BRAF V600E malignant melanoma, crizotinib (Xalkori) in ALK-positive advanced lung cancers and everolimus (Afinitor) in combination with exemestane in ER/PR+ HER2- breast cancers that have relapsed after initial aromatase inhibitor therapy.

It will be interesting to see how NICE handles all of those situations in the future, since they are all targeted agents showing a significant impact on a patients ability to live longer,with a more precise, and therefore, limited patient definition.  As a Brit and a scientist, I may have reasonable expectations that NICE will make a rational and logical decision in the face of limited resources, but this is also tinted with a large dose of healthy scepticism after the trastuzumab (Herceptin) debacle in HER2-positive breast cancers that lead to the utterly ridiculous and unfair post code lottery in the UK.

We are not talking absolute costs here, but the relative costs of seeing real efficacy benefits of six months or more in those patients most likely to respond, while at the same time giving an offering that truly extends life in a meaningful fashion without exposing too many to the toxic side effects of a given treatment. Dealing with cancer is tough enough without being treated with a regimen that had absolutely no hope of helping people live longer and feel better.

“Women with high-grade ovarian cancer live longer and respond better to platinum-based chemotherapy when their tumors have BRCA2 genetic mutations.”

MD Anderson Cancer Center press release

That statement got my attention last night while browsing the cancer news on Twitter! Many thanks to the Provost, Ray DuBois, for sharing it.

Recently, much of the focus has been on finding biomarkers associated with prognosis or response to tyrosine kinase inhibitors and other targeted agents, including PARP in breast and ovarian cancers. It is therefore fascinating that a marker of better prognosis should emerge with chemotherapy.

Given the recent controversy over the whole BRCA1/2 issue and whether there is any clinical significance, with Yang et al., (2011) noting that:

“It has been hypothesized that BRCA-deficient patients will likely have higher survival rates because of an improved response to platinum-based chemotherapy.”

Tan et al., (2008) did indeed observe that epithelial ovarian patients had better response rates than controls if BRCA-ness was present:

“BRCA-positive patients had higher overall (95.5% v 59.1%) and complete response rates (81.8% v 43.2%) to first line treatment, higher responses to second and third line platinum-based chemotherapy (second line, 91.7% v 40.9%; third line, 100% v 14.3%).”

These values were all highly significant.  The researchers therefore set out to see whether this would result in improved outcomes and:

“Determine the relationships between BRCA1/2 deficiency (ie, mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole-exome mutation rate in ovarian cancer.”

Taking a look at the Kaplan-Meier overall survival curves in Yang et al’s (2011) JAMA article (link below), the women who had either the BRCA1 or BRCA2 mutation clearly did better than those who were BRCA wild-type (WT) ie no mutation was present. This is a very important finding and it certainly does help to explain why mixing a heterogeneous population in a clinical trial is never a good idea. Imagine if the BRCA mutation status of the women is unknown – you could end up with unbalanced groups that can affect your outcomes based on the therapies randomised. By this, I mean a control group with chemotherapy alone could theoretically do better than one with a targeted therapy included if the groups were unbalanced for BRCA status.

Now, the current data are limited to high-grade serous ovarian cancer cases, but it would obviously be most interesting to see if a similar (or different) pattern might emerge in BRCA2 breast cancer. Obviously I’m thinking of the recent failed iniparib phase III trial here, as I never understood why BRCA status wasn’t tested and taken into account when balancing the baseline characteristics. We don’t know whether the results reported in ovarian cancer would also be seen in breast cancer, but it would be a critical question to address.

Significance of the results

Ultimately, these kind of findings can help us define and refine specific subsets of women with ovarian cancer who might respond better to certain types of therapies than others. This kind of information is crucial in helping to improve clinical trial design.

What I would really love to see is more logical combinations of targeted therapies or chemotherapy given to patients who have the best chance of responding rather than randomly expose people willy nilly to systemic agents where there is no idea or clue about how they might work. Patients deserve much better than this!

Tak Mak (U Toronto) summed this up beautifully at the recent ECCO meeting, with a most apt quote we could all do well to learn from:

“Doctors pour drugs of which they know little,
to cure diseases of which they know less,
into patients of which they know nothing.”

Moliere, 1622-1673

It is research such as Yang et al., (2011) that may actually help avoid this sorry state and begin to improve the outcomes associated with cancer therapy in the 21st century.

References:

ResearchBlogging.orgYang, D., Khan, S., Sun, Y., Hess, K., Shmulevich, I., Sood, A., & Zhang, W. (2011). Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer JAMA: The Journal of the American Medical Association, 306 (14), 1557-1565 DOI: 10.1001/jama.2011.1456

Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, Ardern-Jones A, Norman A, Kaye SB, & Gore ME (2008). “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 26 (34), 5530-6 PMID: 18955455

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Earlier this year, I announced that there were two people I was hoping to interview next as part of the ongoing Making a Difference series, where thought leaders share their ideas and vision on emerging and important topics in cancer research. Previous discussants have included the following:

Today, I am delighted to announce that one of those identified thought leaders, Gordon Mills (MD Anderson), kindly agreed to be filmed while at last week’s ECCO (European Multidisciplinary Cancer Conference). Dr Mills is Chairman of the Department of Systems Biology, Chief of the Section of Molecular Therapeutics, Professor of Medicine and Immunology, and Anne Rife Cox Chair in Gynecology. He is also one of the best strategic thinkers I’ve come across in cancer research who not only understands the big picture, but also the detailed subtleties.

Originally, we collected audio-visual to ensure an accurate recording for the usual transcript that gets posted here on the blog, but it came out well and the subject was so compelling that we deemed it well worth watching as the first thought leader video interview here on Pharma Strategy Blog.

Dr Mills gave one of the three keynotes in the first Presidential Symposium at the Stockholm meeting, along with Drs José Baselga (MGH) and Tak Mak (U. Toronto) in a fascinating session on Personalized Medicine. This session covered the whole gamut from therapeutics, biomarkers, assays and to metabolism. I took the liberty to include a couple of Dr Mill’s slides to illustrate the points we were discussing in the video below.

We’ve come a long way over the last decade in terms of progress, but hopefully, as technology and our knowledge improve further, the best is yet to come.

This is the fifth interview in the series with thought leaders in the Making a Difference series – it covers a wide range of critical topics including BRAF, mTOR, PI3K, EGFR and RAS – please do check it out:

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A couple of interesting developments have emerged over the last week with AKT and MEK inhibitors, specifically Merck’s MK-2206 and AstraZeneca/Array’s AZD6244, that are well worth discussing.

  1. At the ECCO/EMCC meeting in Stockholm last Tuesday, Johann De Bono discussed the combination data for MK-2206 and AZD6244 in KRAS driven colorectal cancer.
  2. Later the same week, Array Biopharma announced the initial results from a randomized phase II placebo-controlled study that compared the efficacy of selumetinib (AZD6244/ARRY-886) in combination with docetaxel compared to docetaxel alone in the second-line treatment of patients (n=87) with KRAS-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC).

Now, to be clear, I like the concept of AKT and MEK inhibitors, especially in select combinations, but the key thing here is the right combinations in the right context.

Let’s take a look at the lung cancer KRAS data first. One of the challenges I have with this approach, is that we’ve know for a while that BRAF and KRAS driven cancers behave rather differently according to Wee et al., (2009):

“Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response.”

Variable response is not an encouraging phrase when planning clinical trials!

Let’s take a look at the pathway itself:

We can immediately see that MEK is downstream of RAS, meaning that even if we target MEK, unfortunately RAS and KRAS is still largely untouched upstream. This is important to remember when considering the actual results later.

The other key factor to consider is what are the adaptive resistance pathways that might evolve as a result of treatment with a MEK inhibitor? In an ideal world, logical combinations would be tested that target both the primary driving mutation or aberration, as well as the adaptive resistance, to try and shut down the pathway more completely than targeting either alone. Another key question that needs to be addressed is what is driving the KRAS aberrant activity in the first place?

We’ve discussed MEK numerous times here on PSB, but the Wee et al., (2009) MEK paper stands out in particular. They identified a critical resistance pathway to MEK inhibition, namely PI3K. Although we discussed this originally in the context of BRAF driven tumours such as melanoma, it is well worth discussing again here in regards to KRAS driven tumours given a MEK inhibitor is being tested.

They observed that:

“Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance.”

It isn’t clear from the Array press release whether any of the patients with NSCLC exhibited PIK3CA mutations or loss of PTEN, but they definiely do occur in this disease. It will be interesting to see of more meta data is available at the forthcoming AACR Molecular Targets meeting next month.

I’m not a big fan of chemotherapy plus a single targeted agent, because as you can see from the evidence above, the pathway is not being shut down by one targeted agent and resistance is not being addressed at all. The chances of such a combination working (by that I mean increasing overall survival), I think would be fairly low.

According to the press release, the study did not see a significant improvement in overall survival (OS) but did show an encouraging response in the form of progression free survival (PFS):

“The key secondary endpoints of progression-free survival, objective response rate, and alive and progression-free at 6 months were all demonstrated with statistical significance, showing improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.”

Indeed, at the recent AACR and ASCO meetings, there was also some encouraging early signs from Genentech’s PI3K inhibitor, GDC-0941, as a single targeted agent with chemotherapy in NSCLC (a very small early trial), albeit not KRAS specific, but defined more broadly by squamous and non-squamous histology. Thus, all is not lost with the MEK agent yet – if we combined MEK and PI3K inhibitors in NSCLC patients previously treated with chemotherapy, we might have a better chance of succeeding and shutting down the pathway, based on evidence offered from Wee et al’s preclinical research:

“At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death.”

As a result, they went onto to suggest a logical treatment approach:

“Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.”

Of course, clinical trials like this always progress incrementally, such that we test a MEK or a PI3K inhibitor alone to determine safety and efficacy activity, then perhaps in combination, which requires another phase I dose finding study to determine the ideal dosages and whether they are too toxic or not combined.

So while either single agent targeted therapy with chemotherapy in and of itself is not a win, there are signs that combining the two may be more appropriate. I would still want to know what is driving the KRAS activity though, given MEK and PI3K are downstream of it. It is entirely possible that a third agent would be needed to shut down the pathway more completely in that patient subset.

At ECCO, De Bono (Royal Marsden) discussed the combination of AstraZeneca’s MEK inhibitor (AZD6244) and Merck’s AKT inhibitor (MK-2206) in RAS mutant colorectal (CRC) and lung (NSCLC) cancers. The results here were not a big win in the former, with 8/15 patients showing no antitumour activity to date.

There are several things we can conclude from the initial data:

  • If we have the right combination for the right target in the right patient subset, then the therapeutic index of the agents is lacking and we need better drugs
  • Are the targets (AKT and MEK) critical?
  • Is something else driving the KRAS activity (see below)*?
  • Are we shutting down the adaptive resistance pathways (escape routes?)
  • Which patient subsets are most likely to respond and how do we best characterise them (ie need more biomarker data)?

And so on… there are always more questions than answers sometimes.

    * Note: This situation could well be similar to BRAF in malignant melanoma, where it is the V600E mutation that is driving the BRAF activity, thus specifically targeting ithe mutation rather than the kinase will have a greater clinical effect than targeting BRAF broadly. In this case, if we really believe KRAS is critical to the lung or colorectal tumour’s survival, then we need to figure out what is driving it before progress is made. Frank McCormick’s elegantly simple wac-a-mole concept for pathway inhibition is very apt here!

No doubt we will see more detailed data and an update soon, perhaps even at the forthcoming AACR Molecular Targets meeting next month.

References:

ResearchBlogging.orgWee, S., Jagani, Z., Xiang, K., Loo, A., Dorsch, M., Yao, Y., Sellers, W., Lengauer, C., & Stegmeier, F. (2009). PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers Cancer Research, 69 (10), 4286-4293 DOI: 10.1158/0008-5472.CAN-08-4765

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This year I decided to write some longer posts from the ECCO/EMCC meeting owing to the amount of potentially paradigm changing data coming out. These in depth op eds will roll out over the next few days.

Quite a few people have been asking what my picks of the conference are, so here goes, in order of Wow factor (purely from my perspective):

  1. Everolimus BOLERO-2 data in ER/PR+ HER2- breast cancer
  2. Alpharadin in advanced prostate cancer
  3. T-DM1 in HER2+ breast cancer
  4. Vismodegib phase III data in basal cell carcinoma

You can read more about the Alpharadin data on the companion Biotech Strategy Blog, but I will put up a post in the pros and cons of this therapeutic later in the week. It’s going to be very interesting indeed to see how this pans out.

Why did I pick the everolimus (Afinitor) data first over the others?

Well, regular readers here on PSB will know that I’m a great believer in

a) targeted therapies and
b) identifying mechanisms of resistance to determine logical combinations

We know that the PI3K-mTOR pathway is dysregulated in hormonal sensitive breast cancer leading to resistance, so a logical approach would be to treat women whose initial AI therapy has failed with another, but add in an mTOR or PI3K inhibitor. That’s exactly the case here.

The results? Simply stunning!

Jose Baselga presented the BOLERO-2 data to a packed audience. When he showed the slide for PFS, there were gasps in the audience around me – a shift in favour of the treatment arm (everolimus plus exemestane) over control (placebo + exemestane) not of the usual 1-2 months, but 6.5 months:

BOLERO-2 data at ECCO 2011

The side effect profile was consistent with what we know about mTOR and Aromatase inhibitors. One thing I would very much like to see is some subset analysis to see what factors separated the super responders from the average responders. This trial tested the combination in a general unselected population, but it would be nice to see if any factors can be derived from the data that suggests what might be predictive of response.

While these results are a major paradigm shift in women with hormonally sensitive breast cancer, the big question is can we do even better?

We also know from basic science that mTOR upregulates AKT, so eventually adaptive resistance will occur through that route too, but you can see where the next round of logical therapies might emerge in future. The current batch of AKT inhibitor have some challenging side effects when used in combination, but next generation of inhibitors might have a more tolerable and improved side effect profile.

All in all, I thought the BOLERO-2 data were my pick of the conference for major practice changing data and I hope to see this data submitted for approval to the Health Authorities very soon. This development is very good news indeed for women with ER/PR+ breast cancer.

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After a wild day yesterday once we realised Continental had mysteriously and unaccountably changed our flights to Stockholm from Weds to Weds to Thurs to Tues, it seems that Cinderella will be going to the ball after all.

European Multidisciplinary Cancer Conference (EMCC) here we come, whew!

There are a couple of sessions I’m particularly looking forward to this year:

    1. Presidential Symposium on Sat 25th with talks from some of the leading lights in translational research:
      • Tak Mak (U Toronto) on metabolism and cancer
      • Jose Baselga (MGH) on the challenges of personalised medicine
      • Gordon Mills (MDACC) on the future of personalised medicine

 

    1. Various abstract highlights include:
      • Update on phase II ERIVANCE data for the Hedgehog inhibitor, vismodegib, in basal cell carcinoma (see phase I data from AACR)
      • Biomarkers, including VEGF-A in the bevacizumab trials and an update on KRAS
      • Phase II T-DM1 (trastuzumab emtansine) data in breast cancer
      • Reversing drug resistance in breast cancer (Mon 27th)
      • Updated data from the phase I and III (BRIM3) studies of vemurafenib (Zelboraf) in BRAF V600E-mutation positive metastatic melanoma (will be interesting to see how this compares to the ASCO data
      • Update on therapies in prostate cancer, including new phase III Alpharadin data (see Biotech Strategy Blog)

 

  1. Scientific symposia on PARP inhibitors and PI3K inhibitors (both on Tues 28th). I’m gutted these two important sessions clash, as they are both key events I’d love to attend 🙁

All in all, it promises to be a fun and interesting meeting. For those interested, here’s the link to the full details of the EMCC programme.

Social media comes to ECCO

 

The official Twitter hashtag of the meeting is #emcc2011, a bit long I know, and I would much rather have the shorter, more descriptive and well known #ECCO or #ESMO, but it is a three organisation event afterall, with ECCO, ESMO and ESTRO all involved. You can also follow the EMCC conference organisers on Twitter (@EuropeanCancer).

This inevitably creates branding issues given it seems everyone in the industry has been seemingly asking me over the last two weeks if I’m going to ECCO or ESMO in equal measures! None outside of Twitter have mentioned EMCC at all. Ah well.

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“The problem at the moment is that it takes $1bn [£600m] to get a drug to market and 15 years or more. That is the justification for the pharmaceutical industry charging high prices.

If on the other hand by the time you get to phase 2 you know exactly which patients it is going to work on, you only put those patients through and instead of 10% you get an 80% response rate.

You get a licence on the basis of the data and don’t have to go to phase 3 (a trial involving thousands of people). That saves vast sums of money and years of development. What that does to the business model is it means you can justify charging lower prices because it cost a lot less in the first place.

If we get this right, it changes the entire dynamics of the business model of the pharmaceutical industry.”

Source Harpal Kumar, the chief executive of Cancer Research UK (CRUK) via The Guardian

A UK friend kindly sent me this article today and provocatively asked me what I thought. Hmmm, a very interesting, meaty and relevant topic indeed.  Here goes…

Will this change the way we do business in cancer research?

The theory behind this statement by CRUK is that if we develop more targeted drugs to fewer patients and generate higher response rates e.g. 70-80% in a specific biologic subset, instead of say, 10% in a broader population, then the costs of development will come down and thus the treatment cost of the disease will ultimately lower.

Not so fast!

The reality might actually be different, and here’s why:

  1. For this to happen you need more translational research, biomarkers and companion diagnostics.
  2. The cost of researching and developing the targets is quite high.
  3. While clinical development costs might be lower with fewer large scale trials, the costs of iterative phase II trials will go up and the available pool of patients for commercialization is now much lower e.g. 5% of patients with the ALK translocation in lung cancer not 100% of all available relapsed patients.
  4. In order to maintain revenues, it is basic economics 101 that smaller patient niches will equal higher costs.

If you are not convinced of the last point, take a look at the costs of treating rare diseases or small subsets of patients.

Some good examples exist in the hematology space include:

  1. Alexion’s Soliris (eculizumab),which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This is a rare hematologic disorder that affects approx. 8,000 to 10,000 people in North America and Europe. The cost is something like $400K per annum.
  2. Genzyme’s Fabrazyme (agalsidase beta) for the treatment of Fabry Disease, another rare hematologic condition, this time an inherited metabolic defect that affects 1 in every 40-50,000 people in the US. Fabrazyme lowers the amount of a substance called globotriaosylceramide (GL-3), which builds up in cells lining the blood vessels of the kidney and certain other cells. It’s very effective, but certainly not inexpensive at around $160K per annum.

What is the likely impact of the changing research paradigm?

Both of the above patient pool sizes are not out of the realm of reality for a comparison with oncology.

In the old model, clinical trials tended to involve more allcomer trials, i.e. patients with a particular tumor type (e.g. non-small cell lung cancer), stage of disease (metastatic) and line of therapy (frontline, relapsed or refractory).

In the new world order, things are changing in clinical trials already:

  1. Roche’s Zelboraf (vemurafenib) was recently approved in metastatic melanoma in patients with the BRAF V600E mutation, reducing the available pool who might respond by 50%. It was launched last week with a price tag of around $56.4K for an average of 6 months treatment.
  2. Crizotinib (Xalkori) is being evaluated in patients with NSCLC who have the ALK translocation and have failed prior therapy. That’s a tiny subset of patients. Patients with this aberration make up maybe 4-7% of the total NSCLC pool. Imagine how small the target population will be for other ALK inhibitors in crizotinib refractory disease?!
  3. The cost of funding and finding biomarkers that predict response is a huge undertaking.  Genentech have no doubt spent many millions looking for a predictive biomarker for Avastin, so far to little avail.

Of course, there are plenty of other exciting targets with small subsets being evaluated in the clinic, but there are several factors to consider:

  1. Small subsets = fewer patients = higher cost.
  2. Will combination strategies be affected by the cumulative costs that will inevitably result? e.g. Yervoy + Zelboraf in metastatic melanoma potential treatment cost = $170-180K if the studies are successful in showing that survival is improved.
  3. Since Dendreon’s Provenge ($93K) was recently given the green light by the CMS, the costs of new targeted entrants is creeping up over the $100K watershed marknot down, viz Yervoy ($120K) and Adcetris (~108K), for example.

In conclusion…

I admire the chutzpah of CRUK, but disagree with some of their conclusions, which I think are rather naive.

Today, I will go on record here and declare that I believe specialised treatment based on the underlying biology will ultimately cost more, not less, in the long run in terms of research and development, diagnostics/biomarkers and treatment costs of ever smaller subsets.

However, I have no doubt we will ultimately see better results clinically with this more scientific approach but this will come at a cost.  While that’s great news for patients and caregivers, it is not so great for the payers, Government or investors, because higher risks and R&D costs will inevitably equate to more failures and this drives higher costs in a spiral fashion.  Ultimately, those costs will trickle down to all of us in the form of higher co-pays and more expensive medical plans to cover the payers margins.  Success has to be paid for somewhere down the line.

And the constant refrain from everyone in Pharma of “let’s do more with less” will increase.

It’s a vicious cycle of unsustainability, with no end in sight.

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