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Posts tagged ‘entinostat’

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

By on December 10, 2011

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

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

Why am I fascinated by these particular studies?

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

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

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

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

BOLERO2

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

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

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

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

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

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

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

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

ENCORE 301

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

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

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

 

Entinostat OS in ENCORE 301

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

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

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

CLEOPATRA

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

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

HER dimerization, source: NEJM

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

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

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

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

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

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

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

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

In summary…

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

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

References:

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

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

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

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Update from AACR Molecular Targets 2011 #1 – Breast Cancer

By on November 21, 2011

Last week I had an enjoyable time at the AACR-EORTC-NCI Molecular Targets meeting but gippy wifi in San Francisco followed by my blog hosting and RSS feed going haywire meant that reviews of the meeting were delayed until now. There are a couple of interesting topics that emerged during the meeting that I’m going to explore in extended posts this week.

Today’s review looks at new breast cancer data from the conference. There were two things that stood out for me:

  • The role of epigenetics in advanced ER/PR+ breast cancer
  • New potential targets for inflammatory breast cancer (IBC)

Let’s take a look at these in turn.

Entinostat in second-line ER/PR+ breast cancer

The other week we discussed the data from a second generation HDAC, entinostat in lung cancer, so it was no surprise to see new data emerge in breast cancer in San Francisco as well.

Syndax reported the initial results from their phase II trial (ENCORE301) in women with hormone-sensitive breast cancer who had relapsed on an aromatase inhibitor. This is the same population recently evaluated in the BOLERO2 trial with everolimus plus exemestane at ECCO in September. In total, 49 patients were included, randomised to receive either exemestane plus entinostat (n=27) or exemestane and placebo (n= 22).

Here’s the schematic for the trial design:

schema

We know that the benefits of hormone therapy decline over time as resistance sets in. One mechanism of resistance is mTOR, and the BOLERO2 data demonstrated nicely how a logical combination of an AI with everolimus can help overcome this, leading to an improvement in progression-free survival (PFS) of 6.5 months. Hopefully, overall survival (OS) data will be available at the San Antonio Breast Cancer Symposium (SABCS) next month. Of course, as with many tumour types, there is usually more than one mode of resistance at play.

There were several key points that emerged from the epigenetics study:

  1. The ENCORE301 study is the first trial to report positive data with epigenetic therapy in breast cancer.
  2. They used a biomarker – acetylation levels – to ascertain response to therapy.
  3. Surprisingly, the clinical response to the therapy could be determined after only one or two doses.

The acetylation biomarker really intrigued me. Essentially, high levels of actylation predicted for better response with entinostat and AI therapy. The concept behind this is that HDAC inhibitors induce hyperactylation of lysines on histones as part of the mechanism of action (MOA). Thus in theory, high acetylation would potentially indicate the level of response.

What did the results actually show?

The good news is that we can see that adding entinostat to exemestane nearly doubled the PFS from 2.3 to 4.3 months, but those women with high acetlyation levels saw another doubling in the response to 8.5 months:

entinostat

Of course, this is a small exploratory study, but… the concept I think, is an excellent one, and well worth testing in a larger phase III trial.

The most obvious question that jumped to my mind after seeing the initail data was what would happen if we used a triple combination of exemestane, everolimus and entinostat or another HDAC in this relapsed population?

I don’t know the answer, but would love to see a phase II study emerge to get a quick readout on the possibilities. Many of you will recall that:

a) The Wyeth mTOR trial with temsirolimus in several thousand women with breast cancer produced a resoundingly negative result, but that that was in the front-line setting and mTOR is activated over time, causing resistance.

b) Merck’s HDAC inhibitor (vorinostat, SAHA) was evaluated in several breast cancer trials and none of those produced a positive result as far as I recall. That begs the question – was it the trial design or the drug – not all HDACs may be equal.

The good news here is that there is both a positive result and also a biomarker of response. Those suggest that it would be worth testing further in the relapsed setting both as a doublet in a large phase III study and in triple combination with everolimus in a smaller phase II trial.

Overall, I was very impressed with these results and Syndax should be congratulated for an excellent study design and also developing a useful biomarker. Neither are easy to do well.

Is ALK a new target in inflammatory breast cancer (IBC)?

This one caught me completely by surprise. IBC is a rare, but rather nasty, form of breast cancer that is often diagnosed late (in stage IIIb/IV). It presents with red, inflamed and thickened skin, rather than with a tumour, like this:

IBC

Sadly, we still have a lot of progress to make in understanding the aetiology of this disease, which often shows an accelerated path to metastasis, although we don’t know why. There aren’t that many new therapies or clinical trials in this area either as a rsult of the paucity of knowledge around the biology.

Dr Fredika Robertson (MD Anderson Cancer Center) presented the initial results of some translational research in a small number (n=12) of women with IBC.

She suggested that the early evidence is that the ALK translocation may be a transforming oncogene in breast cancer.

What did they find?

As a result of earlier work from Perez-Pinera et al., (2007) showing ALK gene expression in several types of breast cancer, they decided to look at this more closely in both pre-clinical animal models and also IBC patients.

These are the initial findings in women with IBC:

ALK

Note that they found an incidence of 75% for the ALK translocation in the dozen patients tested. I personally would be leery of extrapolating the results from such a small sample size to the broader population, but it certainly would be worth investigating further.

There are several questions that come to mind:

  1. Is the effect real or not? See Krishnan et al’s (2009) paper on intravascular ALK-Positive Anaplastic Large-Cell Lymphoma mimicking inflammatory breast carcinoma (reference below).
  2. Is the ALK translocation a key driver of aberrant activity?
  3. If yes, would an ALK inhibitor be effective or not?

In order to answer the last question, there is a multi-centre phase I trial with LDK378 (Novartis) now enrolling patients with ALK+ positive advanced cancer to find out the answer. In addition, Dr Robertson mentioned a single centre trial with crizotinib in ALK+ breast cancer, although I couldn’t find it in the clinical trials database.

Conclusions:

Overall, it was good to see some new progress being made in both translational research and also in the clinic, albeit the results are still early, but rather encouraging I think.

These two concepts, ie epigenetic therapy in ER/PR+ breast cancer and ALK translocations in IBC, will be worth following over the next couple of years to see whether they progress our knowledge and eventually more effective and targeted treatments of different subsets.

In the meantime, a further update of exciting new developments in breast cancer will be posted on this blog next month from the San Antonio Breast Cancer Symposium (SABCS).

References:

ResearchBlogging.org Perez-Pinera, P., Garcia-Suarez, O., Menendez-Rodriguez, P., Mortimer, J., Chang, Y., Astudillo, A., & Deuel, T. (2007). The receptor protein tyrosine phosphatase (RPTP)β/ζ is expressed in different subtypes of human breast cancer Biochemical and Biophysical Research Communications, 362 (1), 5-10 DOI: 10.1016/j.bbrc.2007.06.050

Krishnan, C., Moline, S., Anders, K., & Warnke, R. (2009). Intravascular ALK-Positive Anaplastic Large-Cell Lymphoma Mimicking Inflammatory Breast Carcinoma Journal of Clinical Oncology, 27 (15), 2563-2565 DOI: 10.1200/JCO.2008.20.3984

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Epigenetics – an emerging new potential treatment for lung cancer?

By on November 11, 2011

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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