Biotech Strategy Blog

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

Posts tagged ‘acquired resistance’

Old Dog New Tricks

As often happens in cancer research, a new class of compounds emerges every so often, fades out with various tricky clinical challenges then roars back again anew with target variations on a similar theme, as new data become available.

Most cancer signalling pathways veer towards the complex rather than simple, so can we learn from the past and try again by aiming at different compartments and cells?

Some recent translational data relating to IO and cancer immunotherapy can offer us fresh hope for potential novel combinations, especially with immunotherapies rather than chemotherapies.

The molecule designs have also moved on too thus offering additional opportunities and possibilities, which may not have the same difficulties with the therapeutic window limitations seen a decade ago.

There’s always something new to be hopeful about, so let’s take a look at what new ideas are emerging from the doldrums…

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A hidden gem in the KRAS niche

Attention on small molecule inhibitors – after being in the doldrums for a while – seem to be making a comeback over the last year with much attention focused on a few companies developing new selective agents in specialised niches.

Time for a KRAS spring clean!

One such space is KRAS inhibition. Not just in terms of direct or indirect inhibition, but also with regards to tackling acquired resistance mechanisms such as SHP2.  While there has been quite the frenzy over what Amgen, Mirati, Revolution Medicine and a few others are all doing, other companies are quietly getting on with the business of producing some nice work and will soon be ready for the off.

In our latest review we explore some of the factors involved, which companies will need to be concerned about going forward, especially in the context of future combination strategies.

In solid tumours, with targeted therapies the winners are not always the ones who reached the market first, but rather the crafty ones who optimise the combination strategies and become ingrained in protocols across multiple situations.

Here we look at one of the hidden gems in the KRAS space and explore what it does, why it’s important and how it might fit in.  We also include a company interview with a scientist who gets the broader implications…

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Update on the KRAS Runners and Riders

In Pharmaland it is frequently the case that once a target has been validated there’s always new developments in the form of novel agents that emerge, as well as emerging new related targets to consider.

Standing from the KRAS crowd

Here we combine an update on some new market entrants in the KRAS niche with an expert interview discussing how to address a known area of acquired resistance that has recently been highlighted.  Naturally, that also brings with it yet more novel targets and potential combination strategies that may need to be considered by players in this space.

Yes, KRAS G12C is now a rapidly evolving area with multiple players and many moving parts, whereas even just back in January this year many observers saw it as a three horse race – think again, it’s much deeper and broader than that somewhat naive hypothesis already!

As usual, we follow these races longitudinally with regular updates and explain why new scientific findings need to be considered if we are to make a difference in the clinic with future combination strategies.

Are you ready for the latest game of 3D chess?

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What can genomics and tumours teach us about cancer drug development?

Non-small cell lung cancer (NSCLC) is big news this morning with the announcement from Genentech/Roche that the IMpower150 trial exploring whether adding atezolizumab to the standard of care Avastin plus chemotherapy hit it’s first co-primary endpoint of PFS. The data will be presented at European Society for Medical Oncology (ESMO) Immuno Oncology Congress in Geneva, Switzerland next month. The other co-primary endpoint, overall survival, is expected in a couple of months.

I’m delighted that this trial hit a positive note, especially after a few folks were surprised at our emphatic positive prediction for both the PFS and OS outcomes in reviews this year when we looked at it in the summer and again in the fall – see: predictions in 1L NSCLC trials followed by red and green flags.

In the meantime, recently there was some very important news in the lung cancer niche relating to the field of genomics and our understanding of how tumours develop and evolve.

It’s easy for many folks to forget that even in a tumour type that is considered to be a hot/inflamed one due to the high tumour mutation burden (TMB), not all patients respond to checkpoint therapy upfront and not all will achieve lasting durable responses that go out five years. Resistance (primary and acquired), as well as immune escape, will inevitably have a large impact on many patients.

Understanding the underlying biology of the disease will not only help us figure out the causes of non-response and relapse, but also explore rational combination approaches that might improve outcomes.

Just as the triplet of atezo/bevacizumab/chemo has now been show to be superior to the control doublet, we may well see other approaches evolve in the near to medium term future.

The Dynamic Duo at #TARGETS17

Up on deck today is a timely yet rare joint interview that explores the science behind how cancers (including lung cancers) evolve and adapt to try and evade not only detection, but also being destroyed, by anti-cancer therapeutics.

Professor Charles Swanton (Crick and UCL) and Dr James Gulley (NCI) make for a thoughtful and compelling double act.

It was an absolute delight and a privilege to conduct our latest BSB fireside chat with them together. What they had to say was fascinating.

Often we have jested about putting researchers in the BSB hotseat, but frankly when it comes to people of this calibre, the tables are usually turned and the interviewer is the one in the hotseat with some selective pressure to keep up and maintain a flow of intelligent questions!

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Can entinostat overcome resistance to pembrolizumab?

SITC 2017

Treatment with checkpoint blockade has undoubtedly improved the lives of some people with advanced cancers such as melanoma and lung cancer, however the number who do achieve complete remission with single agent therapy is low (typically <20%).

In addition, not all people will respond up front while others achieve an objective response then relapse as acquired resistance or immune escape hits.

One challenge facing the field is identifying these mechanisms of resistance and finding the optimal combination approaches that lead to improved outcomes.

This weekend at the Society for Immunotherapy of Cancer (SITC) annual meeting, there were quite a few interesting new combination developments with early data.

Here, we take a look at one such combination to explore the data, the biomarker research that is ongoing and also some of the challenges associated with finding needles in the proverbial haystack…

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Can this novel combination overcome resistance to checkpoint blockade?

As we demonstrated in the recent Novel Targets podcast that opened Season 3, one topic that is a key focus for many in the IO space is addressing mechanisms of immune escape and acquired resistance to single agent treatment with immunotherapy.

We’ve seen several oncogenic escape mechanisms reported, included activation of the JAK/STAT pathways in some patients and loss of existing immunity when the tumour suddenly becomes cold or an immune dessert.

The good news is that there are a number of ideas that can be pursued, including activating the innate immune system in various combinations.

As we see more companies invest in the innate immunity space in order to have a rational partner with which to combine with their checkpoint inhibitor, it will be important to maintain focus on trial designs and synergistic mechanism of actions to improve efficacy while reducing the potential for overlapping or severe toxicities.

Here’s one intriguing and promising new approach that caught our eye this month that is worthy of researching and following over time…

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EACR17 Cancer Genomics Day 3

Churchill College, Cambridge: Yesterday heralded the 4th and final day of the EACR Cancer Genomics conference with some invited speakers and proffered papers based on research from several groups and labs.

Churchill College, Cambridge

We got to see through the keyhole on several important areas of research that highlight both challenges and opportunities faced by the field.

The good news is that the opportunities provide insights into how we can learn from ongoing and optimise future clinical trials.

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A promising IO combo approach to watch out for

As we start to see early readouts from new IO combos and also new trials emerge to begin enrolling patients, it’s going to be intriguing to see how the new cancer immunotherapy landscape evolves.

ASCO17

Some of these trials will be random in that the drugs are what the company has, others will be based on existing or new collaborations, while others will be based on rationally based science… not all will be successful, though.

Of course, it’s easy for all of us to be an armchair critic and grumble about the flaws, the problems, and even the weaknesses in clinical trials, but what about rational approaches that attempt to scientifically address the acquired resistance that develops on montherapies?

Here’s one approach I really like – we’ve written about the underlying biology behind it previously, but what about the clinical trials, and what does the company evaluating the combos think?

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Gems from the EBCC10 Poster Hall

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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Overcoming acquired resistance to BRAF in colorectal cancer

After the recent raft of posts on immunotherapy, it’s time to turn our attention back to oncogenic addiction.  A couple of key topics have dominated colorectal cancer over the years, namely what causes EGFR resistance and why don’t patients with the BRAF V600 mutation do as well with RAF monotherapy compared to melanoma patients?

In today’s post, we take a more detailed look at BRAF mutant colon cancer in terms of what we’ve learned so far and what the potential therapeutic solutions are, which could influence patient outcomes in a positive way.

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