In today’s post we answer some reader mailbag questions pertaining to targeting BET/bromodomain inhibitors and what we’ve learned since our original landscape review from early 2016 when they were an emerging new class in the oncology R&D space – how time flies!
Is it time-up for the bromodomain class?
Of course, as usually happens in the targeted therapy space we see a glut of pan inhibitors trying to block everything in sight to a greater or lesser degree… we’ve see this with BRAF, FGFR, PI3K, and even KRAS inhibitors, as well as numerous others, yet these rarely turn out to be the bees knees we’re secretly looking for. Bromodomains, I have long argued, were ripe to fall in this category as well.
Instead, it is better to patiently wait for the next generation molecules where they are much more selective in their actions and matched to the tumour target we are looking to hit.
Think about the BRAFV600E vs. pan BRAF inhibitors or KRASG12C/D vs. pan KRAS inhibitors, for example, or even FGFR2 or FGFR3 vs. pan FGFR inhibitors.
The same evolution may possibly happen in the BET/bromodomain space too.
The first generation of agents seemed to hit everything – BRD1, 2, 3, 4, and often BET as well. They suffered, however, with weak efficacy largely driven by challenges with the on-target, off-tumour effects that necessarily impact the therapeutic window.
Now we are starting to learn from a more focused approach with these agents. Four years on from our original landscape review, what’s hot and what’s not? Who’s in and who’s out? In terms of the magic roundabout of oncology R&D, are there any new gems we should eagerly be watching out for?
The short answer is yes… but what are they and who owns them?
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Part of the next wave of early immuno-oncology agents are focused on addressing the tumour microenvironment and inhibitory factors that dampen down immune responses.
As we look at all the options available, there are a few obvious ones such as physical barriers and inhibitory cytokines or chemokines, but beyond that are a vast array of other potential targets we can aim at therapeutically.
We have covered quite a few of these already, but here’s a new one to add to the list.
One particular advantage is that because it is early in development, few competitors have cottoned on to the concept yet. First mover advantage can have quite a few benefits, after all.
Here’s an important question to consider in terms of oncology R&D – would you rather explore a blue ocean strategy or follow the lemmings off the cliff and be 14th to market in a highly competitive red ocean?
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Checkpoint fight at the Alamo in San Antonio? Say it ain’t so!
This is the $64M question that will be on many people’s mind after seeing two SABCS headlines today:
“Neoadjuvant and Adjuvant Treatment with Pembrolizumab Improves Pathologic Complete Response Rates for Patients with Triple-Negative Breast Cancerwith Lymph Node Involvement.”
“Combining Atezolizumab with Neoadjuvant Chemotherapy Does Not Improve Pathologic Complete Response Rates for Patients with Triple-Negative Breast Cancer.”
In order to answer the question fairly, there are plenty of critical points we can look at in order to address it.
That’s the topic of today’s post in a nutshell… and yes, we do come to a firm conclusion.
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Morning, morning, where’s the strong hot java today?
Barcelona – Here we are on the third day of ESMO 2019 and this is where many presenters and attendees (especially international ones) start to hit the wall with a combination of tiredness, sore feet, late nights, lack of coffee, and jet lag all combine to create a perfect storm of exhaustion.
No matter – the conference schedule marches on!
After the craziness of posting not one, but three, extensive long form posts with commentary and analysis yesterday, I’m delighted to only have to worry about managing the daily highlights today. We’ve also been busy conducting interviews, running round the poster halls and listening to some elegant science talks as well.
If you’ve missed the rest of our ESMO19 coverage, it’s building up nicely so far on this magazine page – do check it out and take your pick of topics to browse.
There are some key phase 3 readouts expected in breast cancer alone, plus a raft of Developmental Therapeutic updates to ponder as well.
As usual, we start off with some known highlights and then move on to updating on oncologic developments that catch our attention through the day.
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One of the expected highlights of the forthcoming European Society for Medical Oncology (Twitter #ESMO19) will be data for breast cancer immunotherapy.
In the first of our pre-ESMO19 previews we are taking a closer look at three breast cancer immunotherapy presentations that we think are noteworthy.
As a reminder, the abstracts are not yet available, so we’re not writing about data that’s not yet been presented, but instead are looking at why the presentations may be of scientific/medical interest, and what the questions we hope they will answer. In cancer biology as we heard from Professor Gerard Evan in a recent expert interview, it’s not about “what” happened, but “why”?
We have “boots on the ground” in Barcelona from Sept 27th to October 1st providing daily posts for BSB subscribers with our unique blend of data, analysis and commentary.
Do download the ESMO19 app if you want to check out what already looks like it will be a busy, informative and interesting congress in Barcelona. Hopefully the rain that struck the recent World Lung meeting in Barcelona will have gone away, leaving us with a sunny and dry spell one normally associates with Spain!
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In the enlightened realm of phase 1 oncology trials there generally more unknown unknowns than there are known unknowns, especially with new target approaches.
Who knew it was so beautiful outside of the cold dark halls?!
You could say that makes for a more interesting world, but it also makes for more caution, especially when the FDA is considering agonists that induce stimulatory effects. What it means is that you start off very low – in this latest example it was 50µg and going up to 1600µg to determine the safety profile of a combination.
We have covered the STING pathway quite extensively over the last four or five years now, so it’s time for a new update and a look at some of the much awaited combination data. What can we learn?
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Before we move on to the Society for Immunotherapy of Cancer (SITC) meeting later this week, it’s time to wrap up the exciting AACR-NCI-EORTC molecular targets conference, which along with the CRI-CIMT-EATI-AACR international cancer immunotherapy conference in Mainz, have been my two favourite oncology meetings of the year so far.
Who would have predicted that back in January?
A scoot around the narrow #Targets17 poster hall…
It would be hard not to close out coverage without a popular Gems from the Poster Halls post.
Typically, we have focused this theme from cancer conferences around the following:
- A new target
- An interesting molecule
- Intriguing basic or translational science of note
- A particular tumour type
- Insightful sentiments from thought leaders
In this latest version, we have examples of each. We also have my favourite quote and discussion from the meeting, which perhaps not surprisingly, comes from a CAR T cell therapy discussion.
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The ASCO Wall 2016
There has been much frustration on many fronts at the number of trials that do not see a relationship between PD-L1 expression and response. Some do, but many don’t. This has lead to quite a few investigators suggesting that the IHC assay may not be as useful as originally hoped, for predicting response to checkpoint blockade or selecting patients for therapy.
While we often do see a trend for more responders with higher levels of expression, the main issue is that PD-L1-negative patients can also see some responses, albeit at a lower rate.
There are many factors that can affect the measurement:
- Fresh vs. archival tissue
- Heterogeneity within the tumour
- Tumour cells (TC) vs. immune cells (IC)
- Different antibodies used for each assay
- The dynamic nature of the tumour microenvironment – does timing of the biopsy matter?
- Human error – a pathologist has to eyeball the IHC readouts and decide the level of staining intensity
And so on. These are just a few examples of the factors that can potentially affect the results, making it quite a challenging test to undertake. There is also time – does the level of expression vary temporally depending on which prior therapies are administered?
It would be easy to be disheartened by this, but fear not!
There were some impressive new data presented at ASCO that were not only intriguing, but also show us a way forward on how a multi-factorial approach could be used in different tumour types. By this I mean we might end up with different tests used in conjunction for several different cancers in order to a) predict responders and non-responders and b) better select patients for appropriate regimens or clinical trials.
It’s not going to be as easy as one size (or test) fits all. Sometimes a more more sophisticated approach will be needed. New data at ASCO gave us hints on what’s to come in this direction.
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At the European Cancer Conference (ECC 2015) held in Vienna recently, a number of promising targets emerged along with new drugs in development in several different tumour types. Not all of them were from big Pharma – some were from up and coming young biotechs that will be worth watching out for.
In this first part of our ‘New Drugs on the Horizon’ mini series, we chose four interesting and largely positive studies to highlight and discuss in-depth.
In the past, there were many negative trials to pick over and ponder why they didn’t quite pan out. After all, it’s relatively easy to be an armchair critic and hindsight is a wonderful thing.
Picking only four from the many promising choices of trials presented this year available turned out to be quite hard given there were many that caught our attention – a bit like choosing only one of four out of the many schnaps to sample locally!
Today’s review looks at four very different drugs and approaches in early development from Pfizer, Stemcentrx and Ignyta – they include encouraging early data on both small molecule tyrosine kinase inhibitors (TKIs), as well as antibody drug conjugates (ADCs).
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San 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.