One area that is finally seeing a lot more research results of late is neo-adjuvant therapy in breast cancer, i.e. therapeutic intervention prior to surgery.

The main advantages of neo-adjuvant over adjuvant therapy are:

  1. If it works, then the therapy allows the margins to shrink prior to surgery, potentially making the tumour easier to excise
  2. If therapy works prior to surgery, you know what will likely be effective post surgery, whereas in adjuvant treatment after surgery, this is unknown.

One of the leading trials for neoadjuvant breast cancer was the ISPY2 (Investigation of Serial studies to Predict Your therapeutic response with imaging and molecular analysis 2) study.  I wrote about it in more detail at the time it was launched on Pharma Strategy Blog, if you need more information. Basically, the study is based on a complex adaptive conjoint design in neoadjuvant breast cancer, so over time, additional arms were added to the study (there were originally four) while others were removed. In this way, the investigators can find the best therapies for each tumour subtype (HER2+/1, ER+/- or triple negative) based on the responses and biomarkers.

One element of neoadjuvant trials is figuring out what the most valid and meaningful endpoints are. In metastatic breast cancer (MBC), for example, we tend to see the primary and secondary endpoints being focused around the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). These endpoints are rarely used in neoadjuvant trials though, because:

a) the goals of therapy are different and
b) patients are expected to live much longer with earlier stage disease so other outcomes such as DFS or EFS are often used

Given these factors, the FDA recently brought out new guidelines suggesting that pCR improvement would be a useful surrogate marker and predictor of survival endpoints. One example they used was HER2 disease and the ISPY2 model where drugs ‘graduate’ based on their performance over time. This is why the current ISPY2 trial is recruiting different arms than the original study setup. The first two therapies were considered to have ‘graduated’ from the trial with data (triggered 60–120 patients are enrolled) late 2013, i.e. AbbVie’s veliparib, a PARP inhibitor, and Puma’s neratinib, a pan-HER/ErbB inhibitor.

Veliparib was considered to have graduated in the triple negative signature. Initial veliparib data was presented at SABCS in December (see our analysis, commentary and update of this study data here). The neratinib data has yet to be presented at a medical conference, although the company have announced an oral presentation at AACR in 3 weeks time.

That said, neratinib and neoadjuvant therapy, in general, was discussed by several participants at last week’s Miami Breast Cancer Conference (MBCC).

For those interested in my thoughts and analysis, you can sign in or sign up below:

 On neratinib in neoadjuvant breast cancer

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