Biotech Strategy Blog

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

Posts from the ‘breast’ category

There was a time when it seemed that all the good news emerging in cancer research was on breast cancer, that is clearly no longer true as other tumour types have seen some leaps and bounds with different modalities, including areas previously thought to be a graveyard for big Pharma, such as metastatic melanoma, for example.

new-dawn-houses-of-parliament

New Dawn at the Houses of Parliament

That said, after the excellent developments in hormone-sensitive disease and the identification of the HER2 oncogene, we now have CDK4/6 as a validated target in metastatic breast cancer.

Pfizer’s palbociclib (Ibrance) lead the way, with two approvals in previously untreated and relapsed ER+ HER2- advanced breast cancer. Two other companies in this field are Novartis with ribociclib and Lilly with abemaciclib. Data is being presented on all three therapies at ESMO this year.

In addition, there are some other abstracts of note that are well worth discussing.

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We’ve had a couple of requests come in for a revival of the old conference series… ‘Gems from the poster halls’ because quite a few folks are interested in the up and coming data from small to medium biotechs.

SABCS San Antonio CrowdA bunch of my Post Doc chums in this field were at the San Antonio Breast Cancer Symposium (SABCS) meeting and gleefully highlighted mobbed posters or areas where they thought the data looked potentially interesting.

From these, we selected a few for review in today’s look at the nuggets that can be gleaned from cool and intriguing trials or preclinical research that may influence future trials.

Companies covered in this article include Seattle Genetics, Jounce, Immunomedics, Syndax and MedImmune.

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Today the immunotherapy and related data flooding out of the annual meeting of the San Antonio Breast Cancer Symposium (SABCS) is pretty exciting!

Data was presented on a number of drugs including pembrolizumab, avelumab and atezolizumab, which put together with some recent publications, highlights some potentially exciting opportunities in this fast moving space.

Here, we explore the potential for checkpoint therapy combinations in TNBC, HER2 and even the ER+ subsets.  There’s a lot of new findings to take in and contemplate here.

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One of the obvious learnings from the American Association of Clinical Research (AACR) meeting earlier this week was that we are coming to the end of the low hanging fruit opportunities for checkpoint inhibitors as monotherapies.

Speaking with numerous company people in this space, there was wide consensus on that point. As one clinical lead put it succinctly, “From here on out, it’s going to get way more complicated – had a low grade headache develop after the very first science session I attended – and it’s still there after two days!”

How many of us know that feeling all too well?  AACR always has the heaviest science load of any cancer conference we attend each year. Sure there’s some nice clinical data, but that is like nibbling on the light appetizers before the 20 course banquet. You need much stamina and fortitude to survive the brain fog at AACR. Then there’s the glee at snagging some key poster handouts at the meeting, only to be rapidly diminished when you try to read the 4pt print post hoc and realise your eyes cannot focus easily.

Looking at the long list of topics I want to cover in the in-depth post meeting analysis for a ‘lighter’ post, especially given that it’s Friday after a very long week, that sinking feeling hit home hard – there are no lightweight topics at AACR.

The other day, we posted about the promising data in triple negative breast cancer (TNBC), following on from the Genentech and Merck presentations at the San Antonio Breast Cancer Symposium (SABCS). These data surprised many folks, mostly because they didn’t consider breast cancer to be an immunogenic tumour – nor is lung cancer in the broader scheme of things for that matter – yet we are seeing some nice durable responses in both tumour types with checkpoint inhibitors.

In other words, our definition and perceptions must change as we redefine how we identify and think of possible ‘responsive’ cancers to these agents.

So where are likely heading next?

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Quick Reminder: Today is the last day for the AACR Special – the discount ends at midnight ET tonight. We may not offer this rate again as it’s a limited time only deal!

Philadelphia – at the 2015 annual meeting of the American Association for Cancer Research (AACR), new data was presented that showed checkpoint inhibitors have a greater effect when they work in combination, they may also offer a new effective treatment option in Triple Negative Breast Cancer (TNBC).

Are two checkpoints are better than one?

At AACR 2015, F. Stephen Hodi MD (Dana-Farber Cancer Institute) presented results, published simultaneously in the New England Journal of Medicine, that showed in advanced melanoma, combining two checkpoint inhibitors (nivolumab and ipilimumab) showed better results than with one alone (ipilumumab). The authors in their NEJM paper conclude:

The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile.

What is the potential for checkpoint inhibition in TNBC?

Yesterday at AACR, Leisha S. Emens MD, PhD (Johns Hopkins) presented the results in TNBC from a phase 1 trial of MPDL3280A (Roche/Genentech), a checkpoint inhibitor that targets the PD-L1/PD-1 signaling pathway.

Dr Emens (right) is shown in the picture below presenting at an AACR media briefing moderated by Louis M. Weiner MD, Dr Hodi is pictured left.

AACR 2015 Press Briefing

The only currently available treatment for TNBC is chemotherapy, but sadly patients often do not live long, and rapidly progress. Progression-free survival (PFS) is estimated to be around 4 months in TNBC. This means there is a real unmet medical need for effective new treatments. The fact that cancer immunotherapy, and in particularly checkpoint inhibitors targeting the PD-L1/PD-1 signaling pathway may have potential in this disease is huge.

Cancer immunotherapy and in particular checkpoint inhibitors are a hot topic at AACR. In this post we look in more detail at the data presented.

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Philadelphia – the 2015 annual meeting of the American Association for Cancer Research (AACR) is in full swing, with over 18,000 attendees, it’s probably the world’s largest meeting dedicated to cancer research. The theme is “Bringing Cancer Discoveries to Patients.”

AACR 2015 Annual Meeting Philadelphia

I challenge anyone not to attend, and come away inspired with new ideas on how the field of cancer research will evolve in coming years.

At this year’s annual meeting, not surprisingly, cancer immunotherapy is one of the hot topics. Yesterday there was the simultaneous publication of two papers in the New England Journal of Medicine (NEJM) to coincide with data presented at the meeting.

Pembrolizumab (Keytruda)  for the Treatment of Non–Small-Cell Lung Cancer

The conclusion of the paper by Edward B. Garon, MD (UCLA) et al was that:

Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non–small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab.

The other paper published in the NEJM was for:

Pembrolizumab (Keytruda) versus Ipilimumab (Opdivo) in advanced Melanoma.

The conclusion of the paper by Caroline Robert, MD PhD, presented at AACR by Antoni Ribas, M.D., Ph.D.(UCLA) was:

The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.

AACR 2015 Press Briefing with Dr Topalian, Dr Ribas, Dr Garon

Dr Ribas (left) and Dr Garon (right) are pictured at an AACR media briefing chaired by Dr Suzanne Topalian (Johns Hopkins).

This year’s AACR annual meeting is to paraphrase Bertrand Tombal, “a Grand Cru year”. Not only in cancer immunotherapy, but in metabolism, epigenetics and advances in drug discovery.

We’re excited about the prospect of another three days at the meeting, but in the meantime in this post there’s some top-line thoughts for subscribers on some of the data that caught our attention over the weekend.

In recognition of AACR, there’s $50 off a quarterly subscription if you wish to purchase access (offer valid only during the week of the meeting – ends this Friday!)  If you’ve been sitting on the fence for a while wanting to try out BSB, now is a good opportunity to dip your toes in the water.

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The DNA in a human cell undergoes thousands damaging events per day, generated by both external (exogenous) and internal metabolic (endogenous) processes. Unfortunately, some of these changes can generate errors in the transcription of DNA and subsequent translation into proteins necessary for signaling and cellular function. Genomic mutations can also be carried over into future generations of cells, if the mutation is not repaired prior to mitosis.

This DNA damage repair from normal cell cycle activity is a field with a large body of research over the last decade or so. Damage to cellular DNA is ultimately involved in mutagenesis and the development of some cancers.

Clinically, there are a number of different ways that can be utilised to help repair the damaged DNA. One approach that is included in this category is the poly ADP ribose polymerase (PARP) inhibitors, which target the enzyme of the same name. I first wrote about PARPs on PSB way back in 2006 – you can check out the short posts for some basic background information on PARPs (here).  Fast forward to 2014, and another post highlights some of the challenges and issues associated with developing targeted agents, including PARPs.

In 2009, the hot buzzword of the AACR Molecular Targets meeting was ‘synthetic lethality’, a term that is highly relevant to understanding DNA mismatch repair and PARP inhibitors. Hilary Calvert gave a detailed talk on synthetic lethality and PARP inhibition at that meeting, where many attendees, myself included, were struggling to understand quite what he meant.

The lead scientist at KuDos, Dr Mark O’Connor, (note: KuDos was subsequently bought by AstraZeneca) had a nice poster on their PARP inhibitor in development at that very same meeting.  I’ll never forget our animated discusson and his simple analogy of a three-legged coffee table, removing one of the legs to cause instability and falling over as a great metaphor for what happens with synthetic lethality.

To this day, every time the leading British researchers in this field, Profs Hilary Calvert or Alan Ashworth, mention ‘synthetic lethality’, I immediately think of the unstable and wobbly coffee table visual!

Incidentally, the KuDos PARP compound in preclinical development back in 2009 subsequently became olaparib… is now Lynparza, marketed by AstraZeneca, and available on both the US and EU markets for refractory ovarian cancer with germline BRCA mutations. The EU approval is specifically in platinum-sensitive disease.

The Alamo San Antonio TexasSince then, we’ve seen iniparib (Sanofi) fail badly in phase 3 in a poorly designed catch-all study that didn’t screen or test patients with triple negative breast cancer (TNBC) for BRCA mutations (doh!) and three new promising next generation PARP inhibitors emerge – veliparib (AbbVie), rucaparib (Clovis) and talazoparib / BMN 673 (Biomarin).  All three of these have received attention on this blog in the past (check the links).

In this article, we discuss what’s happening with Biomarin’s PARP program based on their latest update at the recent San Antonio Breast Cancer Symposium (SABCS) last month.

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Picture Credit: @gene_antibody

Picture Credit: @gene_antibody

For much of the last two years, one of the hottest topics around has been T cell manipulation, which can happen in many different forms.

This is just one area that we have covered extensively in the immuno-oncology space from Chimeric Antigen Receptor (CAR) T cell therapies to checkpoint inhibitors, as well as various antibodies, including the first bispecific T-cell engager (BiTE) to CD19 that recently approved by the FDA called blinatumomab (Blincyto) from Amgen.

Not all cancer patients respond to all these approaches though.

Why is that and what approaches or novel targets can we explore next to address this vexing issue?

At the SITC and SABCS meetings, I saw some really interesting and unusual presentations, together with some recent publications on topic, that really piqued my interest in this challenge. They are early signs of the new directions some of the research in this field could go. Overcoming resistance and understanding different aspects of immune escape will likely be very instructive in developing the next generation of combination studies that could make a positive impact on patients.

Today’s post touches on some of these exciting developments and includes an in-depth interview with Dr Ira Mellman, the scientist behind Genentech’s immunology research program at gRED.

Interested readers can sign in or sign-up in the box below to read more about the exciting new developments that are happening with different types of antibodies in the immuno-oncology space.

A lot has happened this month with San Antonio Breast Cancer Symposium (SABCS) and other data emerging that it could be subtitled:

A brief tale of two breast cancer drugs

SABCS San Antonio CrowdAt SABCS a couple of things looked pretty intriguing indeed. One we will cover in the New Year, along with an in-depth expert interview on the topic, while the other is the main focus of today’s note.

In the last post of 2014, it’s time to address some pertinent questions on triple negative breast cancer (TNBC) from subscribers – there is good news to report here, unlike the surprising MARIANNE results for Kadcyla and Perjeta in frontline HER2+ disease that were announced early this morning.

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A big thank you to all who have supported Biotech Strategy Blog Conference Coverage this past year. Wishing you good health, happiness and prosperity in 2015. See you on the other side!

SABCS BannerSan Antonio – The San Antonio Breast Cancer Symposium (Twitter #SABCS14) is underway, and one of the key questions everyone is asking is do checkpoint inhibitors work in Triple Negative Breast Cancer (TNBC)?

TNBC is defined as the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 protein expression. This means that treatments aimed at these targets such as aromatase inhibitors and Herceptin are unlikely to work in TNBC.

TNBC represents approximately 15% of breast cancer patients in the U.S, and to put this number into perspective, around 200,000 women have the disease, with 40,000 deaths each year. Globally, there are an estimated 1 million cases of breast cancer, of which 170,000 are triple-negative (ER-/PR-/HER2-).

The only currently available treatment for TNBC is chemotherapy, but sadly patients often do not live long, and rapidly progress. Progression-free survival (PFS) is estimated to be around 4 months in TNBC. This means there is a real unmet medical need for effective new treatments.

Checkpoint inhibition of the programmed-death 1 receptor (PD-1) such as pembrolizumab (Merck) and the ligand (PD-L1) e.g. MPDL3280A (Genentech/Roche) can increase the effectiveness of a body’s T cells to fight cancer. Are checkpoint inhibitors the future in TNBC and will they offer hope to patients?

Some early preliminary clinical data is being presented this week at SABCS. Subscribers can login below or you can purchase access to read more about what this data signals about the potential of checkpoint inhibition in TNBC.

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