Pharma Strategy Blog

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:

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:

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:

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:

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:

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