Biotech Strategy Blog

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

Posts tagged ‘mTOR’

EBCC10

EBCC-10 Cancer Conference

Amsterdam: The 2016 European Breast Cancer Conference organised by the European CanCer Organization (ECCO) is underway (Twitter: #EBCC10 – it’s the 10th official one they have organised).

We thought it would be a good opportunity to take a break from our coverage of #BMTTandem16 to look at some of the posters that are of interest at the meeting.

As regular readers know, we spend a lot of time reading posters – it’s where we pick up new trends and early data. Most go unnoticed or unpublicised in press releases.

For this post, I’ve highlighted four posters that I’m quite interested in and that merit further discussion.

They range from basic and translational research to clinical new product development. By chance, they are evenly split between immunotherapy (PD-L1 and TILs) and acquired drug resistance to different targeted therapies.

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New developments in renal cell carcinoma

Continuing our focus on genitourinary (GU) cancers this week, today we turn our focus from prostate cancer to renal cell carcinoma (RCC).

There were two important announcments on Monday this week relating to renal carcinoma.

Firstly, Exelixis announced positive top line data from a phase 3 pivotal trial of cabozantinib versus everolimus in relapsed metastatic renal cell carcinoma (METEOR).  The study met the primary endpoint (i.e. significantly improved progression free survival) and the company revealed the following data:

  • Cabozantinib reduced the risk of disease progression or death by 42%; Hazard Ratio = 0.58, (p < 0.0001) compared to everolimus
  • Interim Analysis of OS demonstrated a trend in favour of cabozantinib; Hazard Ratio = 0.67, (p = 0.005) compared to everolimus
  • Exelixis to complete US and EU regulatory filings in early 2016

Secondly, a press release from BMS highlighted the phase 3 CHECKMATE–025 trial comparing nivolumab to everolimus, also in relapsed metastatic RCC, where the independent Data Monitoring Committee recommended early stoppage on the basis of the primary endpoint (OS) being met. The company likely be seeking discussions with Health Authorities with a view to filing the data with the FDA and EMA.

There are some interesting points that fall out of these releases. To learn more, subscribers can log-in below or you can purchase a subscription in the box below.

At the last count, the renal cell carcinoma (RCC) space is quite competitive with five VEGF inhibitors (sunitinib, sorafenib, axitinib, pazopanib and bevacizumab), two mTOR blockers (temsirolimus and everolimus) and not forgetting IL–2, all approved by the FDA for the treatment of advanced disease.

Much of the recent focus has been on sequencing, exploring combinations (generally too toxic with little added benefit), and evaluating the potential for novel immunotherapies in development such as checkpoint inhibitors. Biomarkers are few and far between, making it hard to rationally decide which therapy each patient should get and in which sequence.

The key question is, why is this tumour type so challenging from a clinical and scientific perspective?

Screenshot 2015-03-23 12.44.32Recently, new data has begun to emerge that may help inform or enable us to switch to new approaches.  While the urologists are eagerly watching the live surgery on the EAU cam, we highlight research data presented at the European Association of Urology (EAU) in Madrid and take a look at how the underlying biology of RCC can elevate our knowledge about where the potential future strategies and blueprint might lie, if we want to facilitate exciting new developments in this field.

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We hope that everyone had a relaxing holiday break and now it’s time to get back to work.  Tomorrow I will review some more of my thoughts in the immuno-oncology space, since that area had a tremendous amount of progress in San Diego with lots of new ideas to process and summarise.

In the meantime, a few people have written in and asked about what was happening with overcoming resistance in various tumour types, was there anything new to say in that space that was in addition to the the detailed previews we covered before the conference?

Actually, there was a quite a few posters and presentations that caught my eye, so I thought this would be a good idea to review them here:

Lung Cancer: HER2, VEGF, T790M, EGFR, erlotinib, gefitinib, trastuzumab, bevacizumab, CO-1686, AZD9291

Prostate Cancer: mTOR, PI3K, Androgen Receptor, enzalutamide, abiraterone, CC214–2, ARN–509, BET Bromodomian inhibition, ODM–201, GDC–0980, GDC-0068, PF–04691502, BKM120, BEZ235

“You may say I’m a dreamer

But I’m not the only one.”

John Lennon, Imagine

As part of our ongoing series on the AACR Previews, today I want to take a closer look at some interesting scientific and clinical data in triple negative breast cancer (TNBC).  One reason for this is that we need to remember that the disease, as currently defined, is essentially what’s left after taking out the ER+, HER2+ and inflammatory breast cancer subsets. In other words, it’s a very heterogeneous catch-all population, making clinical trials rather challenging at best. It also means that the chances of success in general all-comer trials is rather low.

It is my hope that as we learn more about the biology of this disease, we may see further subsets be defined by molecular peculiarities, much in the same way that gastrointestinal stromal tumours (GIST) were defined by KIT expression and CD117. Once we have more homogenous subsets, it will be easier to conduct trials just looking at those specific patients, thereby improving the chances of clinical success with therapeutic intervention.

There’s been a lot of work focused on this area over the last few years, so it seems a good point to find out where the progress has got to.

Without much further ado, what can we learn about the biology of TNBC from AACR this year and which potential new targets might emerge?

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Following on from yesterday’s post on the potential for small basket trials in ER+ breast cancer with the ESR1 mutation, I wanted to highlight another area where these type of highly focused and rational studies appear to be not only useful but also potentially produce stunning responses.

Some of you will recall the fascinating and widely told story of a single bladder cancer patient at Memorial Sloan Kettering who was resistant to multiple lines of therapies. The team sequenced the genome and found a rare TSC1 mutation. Importantly, this is known from pediatric astrocytoma studies, to be sensitive to an mTOR inhibitor, everolimus (Afinitor). The refractory patient was given the drug and responded well. The rest is history, as they say.

Can we learn more from these type of appraches, i.e. genomic sequencing of patients who have relapsed after initial therapy?

Can we also learn more from the few exceptional responders in clinical trials – what was unique about their response that elicited such a stunning effect?

The short answer is a resounding yes – to learn more about some stunning new genomic approaches to research and the lessons we can learn for future drug development, sign in or sign up below.

Some interesting early drugs in development were presented in a packed session this morning, across a wide variety of targets and tumour types. The four that stood out from the pack to me were:

1) MEDI4736 (anti-PD-L1)

2) GDC-0980 (dual PI3K/mTOR)

3) BKM120 (buparlisib) + GSK112 (trametinib) (PI3K + MEK)

4) alectinib (ALK)

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