Pharma Strategy Blog

Yesterday evening brought a flurry of news around the New England Journal of Medicine articles for the BOLERO2 and CLEOPATRA trials, but out of respect to the presenters, I hate talking about the actual data before its being presented. Call me old fashioned if you like, but it seems odd moving up deadlines for the publication ahead of the presentations instead of releasing them on the day and is a little disrespectful of the journal towards the presenter and attendees.

I will therefore discuss the data for BOLERO2 and CLEOPATRA studies in detail after they have been presented today and tomorrow, respectively. For those of you interested in the study designs and their potential implications, you can check out my brief video highlights in the meantime.

Yesterday at the San Antonio Breast Cancer Symposium (SABCS) brought some really intriguing biology data that are well worth discussing:

• Notch inhibition to reduce AI resistance
• HER2 mutants
• Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

Notch inhibition

Perhaps one of the most intriguing presentations (to me) yesterday at SABCS looked at combining a Notch inhibitor plus an AI to reduce breast cancer resistance in preclinical models.

This is an interesting idea that is worth exploring because resistance to oral therapies, including AIs, is a common problem. Understanding the potential mechanisms of resistance should therefore lead to new trial designs and logical combinations.

In this research, the presentation focused on early data on combining MK-0752 (notch) plus hormone therapy. Interestingly, it also finally mentioned the magic word, biomarkers! I think this is a combination we will here much more about going forward.

In his award lecture, Dr Carlos Arteaga correctly observed that the medical community has not done a good job with ER+ drug-resistant disease. This situation is slowly changing as the BOLERO2 data has shown and other mechanisms of resistance will no doubt follow now that more attention is being focused on it.

HER2 mutants

Dr Boulbes from MD Anderson presented the results of some elegant research identifying three mutants to HER2, namely:

• D808N
• V794M
• L726F

All three phenotypes displayed aggressive tendencies. Both the V and L phenotypes showed a dramatic lack of phosphorylation and the latter may be related to the development of HER2 resistance. Data was shown in relation to lapatinib, a HER2 small molecule TKI, which is known to develop resistance to treatment over time.

This is the first time I think HER mutant phenotypes have been reported to my knowledge and if validated clinically, they will represent a breakthrough in our understanding of how HER2 resistance develops, but more importantly, suggest directions for potential therapeutic strategies to overcome it.

Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

HER3 has not received a lot of attention relative to its more popular HER2 cousin, largely because it is tricky to target. However, at this meeting, Dr Garner et al., showed that an anti-HER3 antibody (Novartis) nicely shrank breast cancer tumours in immunocompromised mice.

The presenter observed that the alpha-HER3 mAB recognizes and stabilizes HER3 in the inactive conformation. I was left wondering whether HER2 and 3 pairing / dimerization was shut off or something else was going on?

Dr Cook subsequently showed some clear data whereby HER3 is required for HER2 cancer growth in genetic engineering animal model. This was a very nice piece of research.

What was interesting was that Dr Garner also showed that alpha-HER3 can combine w/ trastuzumab plus a PI3K inhibitor to improve efficacy in trastuzumab-resistant settings. This caught my attention because earlier this year at the AACR PI3K special meeting, Neal Rosen (MSKCC) noted that targeting PI3K activated HER3 as one mechanism of resistance in the breast cancer model they were using and thus speculated that combined inhibition of HER3 and PI3K would lead to reduced resistance. Looks like his hypothesis was correct 🙂

And that was just the first full day of presentations with much more to come!

In the meantime, you can follow the conversations remotely using our tracking tool, accessible here on the blog.

Check back tomorrow for more updates on cancer biology and clinical trials from SABCS.