Biotech Strategy Blog

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

Posts tagged ‘colorectal cancer’

This week in our colorectal cancer mini-series we have covered the validation of Immunoscore as a tool for determining which patients have high T cells in their tuours and are therefore candidates for single agent immunotherapy (Link), as well as microsatellite instability (MSI) and mismatch-repair deficient tumours and how they can respond immunotherapy (Link).

What happens in the majority (95%) of patients, the microsatellite stable (MSS) disease who are mismatch-repair proficient though?  They don’t respond well to checkpoint blockade so how can we help them?

Dr Johanna Bendell ASCO 2016In Chicago, BSB interviewed Dr Johanna Bendell from the Sarah Cannon Research Institute in Nashville, Tennessee to find out more about what she and her colleagues have been doing and where they plan to go next.

You can learn about her perspectives from ASCO by logging in below or if you’re new then you can sign up for a BSB subscription via the blue box…

ASCO 2016 Collective WisdomContinuing part two of our mini-series on colorectal cancer, today we move from the big scale Immunoscore study to small subsets of disease that are looking interesting in several ways.

For years, advanced colorectal cancer has been dominated by chemotherapy (FOLFOX or FOLFIRI) with and without targeted therapies (VEGF and EGFR antibodies), with very little new to talk about. Part of the challenge here is how do you add something the existing standard of care and move the needle significantly. In front-line, for example, the OS is already out 2-plus years, so these are long and risky trials to undertake. Not surpisingly, many companies have sought to evaluate their agents in tumour types where they consider the risk of development to be lower.

Unless… we can find creative approaches that turn the paradigm on its head and identify a clearly defined niche that can be carved out separately from allcomers.

This is where we’re at now – identifying subsets that might respond exquisitely to novel approaches based on a rational understanding of the underlying biology.  One obvious subset might be BRAF, which can be treated with a BRAF inhibitor with or without other targeted therapies as Dr Pietrantonio and colleagues (2016) literally just showed for example, but what about others of potential interest?

Colorectal cancer with microsatellite stable (MSS) disease represents 95% of metastatic patients. These are people whose mismatched repair system is proficient and actively functional in fixing the DNA strand breaks that occur during the course of life.

In contrast, those with microsatellite instability (MSI) are the minority of people with colon cancer (and some other cancers too) whose mismatched repair system is deficient and unable to adequately repair the DNA strand breaks. Ironically, this leads to thousands of mutations that can be recognised by the immune system to help detect the presence of cancer. It also tends to occur in hereditary cancers such as Lynch Syndrome.

We’ve been following the MSI vs MSS story for a while now, but at ASCO this year there was more data available and things appear to be getting clearer on the commercial front too.

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We have selected five key strategic trends that are emerging that will be critical to follow, understand, and even implement if you are on the coal-face of clinical research and new product development.

ASCO16 Chicago 5We aren’t talking about financial things such as cost toxicity, or even how doctors should be paid, but meaty scientific aspects that we need to watch out for. If we are going to improve on cancer research and R&D in the future, these issues will be important.

For companies and academic researchers alike, there is much to learn from the tsunami of data that hit this week if you have a keen interest in the field and a bent for making sense of patterns out of an amorphous mass of data.

Not paying attention to evolution in clinical development can mean the difference between being in the winners circle, on the outside looking in, or falling way behind your competitors. Playing catch up is never anyone’s idea of fun in this market – oncology moves at a lightning fast pace compared to many other therapy areas.

Intrigued? To find out what these strategic trends are, subscribers can log-in to read the analysis or you can sign-up by clicking on the Blue Box below.

For years we’ve followed the trials and tribulations of targeted therapies seeing many approved and quite a few disappear forlornly (and officially) off to dog drug heaven. Many more sit in no-man’s land as companies eagerly wait in a holding pattern for other trial readouts in different tumour types. Sadly, sometimes these studies don’t generate enough compelling data either. With so much competition about, there are no shortcuts or low-hanging fruit in biotech or cancer drug development any more.

ASCO16 Chicago 1

En route to Chicago and ASCO!

Then along came antibody drug conjugates (ADCs), with some encouraging results in a range of cancers in both solid tumours and hematologic malignancies that lead to the approval of several new therapies.

After that, the next big advance was immunotherapies, specifically checkpoint blockade, with encouraging single agent activity in melanoma, lung, and even urothelial bladder cancer. We’ve also seen the promise fo combining two different checkpoints such as nivolumab and ipilimumab together in metastatic melanoma, albeit with an increase in toxicities.

This is all very well and good, although the challenge remains that the majority of patients either respond to therapy and relapse, or do not respond at all, depending on the circumstances, the tumour type and the regimen. We still have a long way to go in moving the needle and creating a new paradigm shift on a broad scale.

So what happens when we start to combine modalities – such as targeted therapies with immunotherapies?

Uh-oh, I hear the distant cries of disagreement erupt…

  • Remember vemurafenib plus ipilimumab in metastatic melanoma was scuppered by severe hepatitis?
  • What about osimertinib plus durvalumab in NSCLC and the increased incidence of ILD?

Both of these statements are true, and yet… we should not assume that all mixed therapy combination approaches are doomed on the basis of a mere n of 2. What happens if some are synergistic or additive? What happens of there are hidden gems that teach us new ways of doing things rather than doing the same old thing just because it’s always been done that way?

With this in mind, I’d like to open the door on our first ASCO 2016 Preview series with a look at novel combination approaches in development that caught my eye.

What are the early hints and signals that we can learn from the data? Which companies are evaluating imaginative new ideas that may turn the tables on traditional thinking?  The ideas discussed here may well surprise a few people.

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One thing has become very clear in the oncology space over the last year… checkpoint inhibitors are insufficient on their own for the vast majority of tumour types and patients that they have been explored in to date.  There are a number of reasons for this, but the main one is lack of T cells in the tumour, which enable an effective immune response to be mounted.

This begs the question – how can we address that issue and manipulate the tumour microenvironment in our favour, thereby making subsequent checkpoint blockade more effective?

There are a number of different ways to do this.

In the past, we’ve discussed several methods including innate immunotherapies such as Aduro’s STING or Biothera’s immunotherapeutic, Imprime PGG.  Other approaches include vaccines, which we have discussed in detail, t-cell receptors (TCR) or even monoclonal antibodies, such as AdaptImmune’s approach with their ImmTac technology.

There are other novel strategies currently being investigated by numerous companies too.

In this article – and also the second part of the latest miniseries – which will post tomorrow, we straddle our final reviews of interesting data from the European Cancer Conference (ECC) in Vienna with the upcoming one from the Society of Immunotherapy for Cancer (SITC) being held in National Harbor, Maryland.

Today’s post explores the concept of immunocytokines, engineered antibodies that are designed to boost the immune system, so that subsequent therapies will be more effective.

Subscribers can log-in or you can sign up in the box below to learn more about this exciting new development in cancer immunotherapy…

It’s time for the August mailbag where we answer questions about cancer research and R&D from subscribers.

After the recent queries about immuno-oncology, it’s time to focus a little on targeted therapies again. Neither chemotherapies nor targeted therapies are going to go away – they are still the bedrock of many treatment approaches in the clinic today. Sadly though, much of the new data for the latter trials were easily swamped by the sheer tsunami of immunotherapy data in Philadelphia (AACR) and Chicago (ASCO).

One important area that we have been discussing on both blogs for some time is the value of well designed basket trials.  It’s time to revisit this concept in the light of new data relating to the BRAF V600 mutation outside of metastatic melanoma.

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One interesting aspect of the recent American Society of Clinical Oncology (ASCO) meeting was the surprise many people expressed in conversations that chemotherapy might actually be useful in combination with checkpoint inhibitors.

You see, several years ago when we first started writing about this new class of agents, I remember vividly how quite a few analysts grumbled on social media or sent me snarky personal messages when it was even suggested that this — along with combinations with existing targeted therapies — might be a worthwhile and valid approach to explore. Clearly they believed that immunotherapies (as monotherapy) were going to be the ultimate panacea.

Not so fast…

There are a number of scientific reasons for combination strategies, but not everyone thinks rationally when new approches come along and their attititude is often ‘out with the old, in with the new!’ It was actually quite amusing to see some of the very same folks in Chicago now eulogising the combination of checkpoint blockade with… chemotherapy in lung, colorectal or even bladder cancer.

One reason why these traditional therapies may be important is because they can influence the tumour microenvironment in both positive and negative ways. That can be helpful for deciding on rational future combinations, rather than just throwing mud at the wall and hoping based on a limited set of data.

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