Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘neratinib’

If there’s one topic that has generated a LOT of questions from BSB readers this month it is Puma Biotech’s neratinib in adjuvant breast cancer.

The FDA briefing documents came out yesterday and that started another flurry of ‘what do you think of them?’ style questions so here goes.  I will say that while many are eulogizing ‘benign’ or ‘friendly’ on close reading and studying them, I’d say caveat emptor.

Things are not always what they seem.

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At the recent 2016 San Antonio Breast Cancer Symposium (SABCS16), Cascadian Therapeutics (NASDAQ: CASC) presented a poster (Abstract #P4–21–01) on:

“Efficacy Results of a Phase 1b Study of Tucatinib (ONT–380), an Oral HER2-Specific Inhibitor, in Combination With Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases.”

Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for HER2.

Cascadian’s tucatinib poster at #SABCS16

We’ve seen several new treatments approved for HER2 positive breast cancers in recent years including four targeted treatments: trastuzumab, pertuzumab, lapatinib and T-DM1.

Other companies such as Puma Biotech (NASDAQ: PBYI) also have oral TKIs in development. Puma’s drug, neratinib has, however been shown to have a high incidence of grade 3+ diarrhea, raising questions about its tolerance.

At SABCS16 (Abstract P02–11–03), the company presented the interim analysis of an open-label, multicenter phase 2 trial, which explored their compound:

“Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC).”

There has been a lot of interest and controversy in this space, so it’s time to take a look at the latest events in HER2+ breast cancer and consider the ramifications since there are a number of new developments that are well worth following, including neratinib (Puma Biotech) and pertuzumab (Genentech).

This is our final expert interview from SABCS – if you missed it you can catch up with the rest of the conference coverage and thought leader sentiments here.

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In today’s post, it’s time to address a bunch of questions we’ve received over the last few weeks from subscribers about the latest and – not so greatest – in cancer research.

Chicago City View

ASCO 2015 Chicago

Sometimes these queries are fairly straightforward to answer, other times requires some sleuthing and hunting down thought leaders for some additional context and insights… For obvious reasons, these folks are best caught in person at cancer conferences such as AACR and ASCO.  The feedback isn’t always sparkly and positive though, it can also be gloom and doom, just like the inclement weather!

So here goes, questions on the following are covered in the article below:

  • Neratinib
  • Bavituximab
  • Gilead
  • Enzalutamide
  • MDSCs

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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).

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