September 1st… as the hot summer floats away from London town and cooler autumn days draw in, it’s time to think about the upcoming fall cancer conference season – it’s quite a busy one this year!
In the coming weeks, I will be rolling out our series on the ESMO 2016 Previews (Twitter #ESMO16) and taking a more in-depth look at various topics of interest. The Copenhagen meeting is later than usual and also more compressed, with numerous sessions now held simultaneously. It used to be that you could take a break between key sessions, but not any more – there’s a lot going on this year.
One of the things that jumped out to me from a preliminary review of this year’s hectic ESMO program is an interesting novel target that had some early preclinical data at AACR, but that sadly got lost in the tsunami of data there.
It is good to have that reminder and be able to return to it in the context of broader data because overcoming barriers to drug resistance with targeted therapies is still an important issue that is worth researching.
You likely won’t see it in many analyst reports or previews, however, although it’s a hidden gem of great interest and well worth exploring in terms of what we know so far. This means that readers will be both prepared and intrigued – don’t be surprised to hear about some BD&L deals in this niche in the future.
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SITC Day 3 Highlights
There were a couple of late breakers presented in the oral session yesterday that are worth discussing for several reasons, not least the controversy surrounding the stock action afterwards.
Dr Tara Gangadhar (U Penn) presented epacadostat, Incyte’s IDO1 inhibitor, in combination with pembrolizumab, Merck’s anti-PD1 inhibitor in a phase 1/2 trial with selected solid tumours.
Will combining these agents lead to better responses and outcomes than with pembrolizumab alone?
Dr Naiyer Rizvi (Moffitt) presented the combination data of AstraZeneca’s anti-PDL1 (durvalumab) plus anti-CTLA4 (tremelimumab) in patients with non-small cell lung cancer (NSCLC).
Neither of these agents have yet been approved in any indication, so the only relative comparators we have here are nivolumab and pembrolizumab as single agents in NSCLC and ipilimumab plus nivolumab in metastatic melanoma. There are no data approved for the BMS combo in lung cancer.
This review looks at both trials, in terms of the controversial data presented, and also in a broader context of the ever-changing landscape.
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Beyond the late breaking abstracts and plenary sessions at the European Cancer Conference being held in Vienna, Austria later this month, what other important topics can we expect to hear about?
We covered the former in the last article on Biotech Strategy Blog, today we turn our attention to the proffered (oral) sessions and what we can learn from those sessions and the expected data that is due to be presented.
There are a number of interesting topics and new data slated for presentation that are worthy of review and highlighting in a What To Watch out For (W2W4) format.
Here’s our take on the potential highlights at the meeting.
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At the recent American Association of Immunology (AAI) and American Society of Gene & Cell Therapy (ASGCT) meetings in New Orleans, we had the good fortune to interview a number of leading cancer immunologists about their work. Some of these have already been published either here on Biotech Strategy Blog, or on the Novel Targets podcast.
In the meantime, the huge tsunami of data from the annual meeting of the American Society of Clinical Oncology (ASCO) hit and we have been a bit backlogged! Time to address that and focus on some more thoughtful reflections about where the cancer immunotherapy field is going.
Already, we are seeing another round of new collaborations and deals hit the newswires with AstraZeneca announcing two collaborations, one with Inovio on the INO–3112 HPV cancer vaccine and another with Heptares, where they acquired the exclusive global rights to develop, manufacture and commercialise the adenosine A2A receptor antagonist, HTL–1071. The first involves a cancer vaccine and the second immune escape mechanisms. Not to be outdone, their rivals Clovis also announced a collaboration with Genentech to explore rociletinib (EGFR T790M) with atezoliumab (anti-PD-L1) in EGFR mutation-positive lung cancer.
Cancer vaccines have not, however, been a very successful or fertile area of R&D for Pharmaland to date, with only one such therapy approved by the FDA (sipuleucel-T or Provenge) and literally hundreds of other such compounds consigned to dog drug heaven. This illustrates the sheer enormity of the task we need to undertake in stimulating the body’s immune system to successfully attack the cancer in a sustained and robust way.
Dr Rosenberg, NCI
Despite this setback, there is still notable interest in exploring the innate immune system and finding effective ways to target and stimulate the T cells or T lymphocytes to attack the cancer.
One man who has accomplished an incredible body of work over the last two to three decades is Dr Steven Rosenberg from the NCI’s Surgery Branch (right).
No one who attended any of the cancer conferences where he spoke at over the last year is ever going to forget the dramatic before and after slides of remarkable transformation in his patient case history examples using Tumour Infiltrating Lymphocytes (TILs) as this example illustrates:
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With the news hot off the press at the 2015 annual meeting of the American Association for Cancer Research (AACR) that Merck’s pembrolizumab (Keytruda) beat out BMS’s ipilimumab (Yervoy) in advanced melanoma, quite a few readers wrote in asking whether this signals the end for ipilimumab?
The short answer is no, and here’s why…
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To round off our series of post AACR reviews this week (there will be more coming next week as well, don’t worry), I wanted to look at some interesting non-immunotherapeutic agents that I found compelling and worth watching out for in the future.
A couple of things to remember or understand is that AACR is a very different conference from ASH and ASCO, aside from the presence of noticeably more science:
a) Much of the data presented at this meeting is either preclinical or phase I-II cinical data
b) Most of these studies are usually exploratory or preliminary in nature
Phase I trials are usually designed to evaluate dose finding in either a single agent or with an untested and untried combination. Investigators are interested in a number of key things here, which might include:
- Maximum tolerated dose (MTD)
- Dose limiting toxicities (DLT)
- A recomemmended phase II dose (RP2D)
- PK and PD
- General tolerability assessment.
Sometimes a different formulation is tested, in which case bioavailabity is also important. To be expressly clear though – any efficacy signals seen are a bonus. That’s the main purpose of phase II trials.
That said, one of the things I most like about AACR is the early phase I data in new targets or data that explains why resistance develops as an adaptive response to therapy. With these in mind, here are three excellent examples from well put together research from the meeting that we can learn a lot from.
To read more about our analysis of up and coming compounds including:
DEDN6526A, a novel ADC in melanoma; AG–221 in IDH2 mutant AML and MDS; a PI3K-α isomer-specific inhitor, BYL719, and the impact of PTEN alterations
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For the third part of the series on the AACR Previews, I wanted to switch directions and take a broad look at five completely different approaches in cancer research that we haven’t discussed on Biotech Strategy before and look at how they are doing and which ones might be promising going forward. Some of these scientific developments could potentially impact existing compounds in development.
Companies mentioned: Exelixis, Roche/Genentech, GSK, Clovis, AstraZeneca, Oncoethix
Compounds discussed: cobimetinib, DEDN6526A, ipatasertib, dabrafenib, trametinib, OTX015, JQ1, CO–1686, AZD9291
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Every year at AACR meetings there seems to be a new update on how researchers are doing with their work on overcoming resistance in metastatic melanoma. We’ve seen some stunning photos where targeting the BRAF V600E mutation with a specific kinase inhibitor such as vemurafenib (Zelboraf) or dabrafenib (Tafinlar) results in dramatic reduction, and sometimes even complete disappearance of the lesions, only for resistance to set in and the melanoma sadly comes back with a vengeance. Adding a MEK inhibitor such as trametinib (Mekinist) was originally thought to be a rather promising strategy, until it became clear that this only gave a few extra months with exactly the same result.
Over on Pharma Strategy Blog, I’ve written a lot about the fascinating research on various mechanisms of resistance in this disease. They range from specific mutations emerging to activation of COT or MEK and others in response to therapy. There are a number of questions we can ask that need to be addressed:
- Do we need a better/more potent BRAF inhibitor?
- Do we need a better/more potent MEK inhibitor?
- What other combinations and targets can be explored?
- Is timing and dosing important? (e.g. continuous vs. intermittent dosing)
- And many others…
At the recent AACR Molecular Targets meeting in Boston I chatted with Dr Bill Sellers, who is the Global Head of Oncology Research at the Novartis Institutes for Biomedical Research (NIBR) and oversees the drug discovery efforts in this space for Novartis.
Yesterday we highlighted NIBR’s work with CDK4/6 inhibition in breast cancer, but this compound may have surprising utility in metastatic melanoma.
Novartis also have several other melanoma agents in their pipeline in the clinic, including a BRAF inhibitor (LGX818), a MEK inhibitor (MEK162) and more recently, an Mdm2 inhibitor (CGM097) in preclinical development.
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Following on from yesterday’s post about learnings from the Boston AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.
We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?
Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.
As cancer becomes increasing complex with adaptive responses to therapeutic intervention, so our knowledge and strategies for overcoming it must also adapt and improve. Immunotherapy – in several forms – is probably the hottest topic on the landscape at the moment with both checkpoint inhibitors and chimeric antigen receptor technology (CART) vying for air time and attention but where are these approaches going and how can we harness the immune system more effectively?
One of the things I like most about AACR meetings is that there are nearly always some strategic gems emerging from the scientist-physician thought leaders if only you stop to think about how the field can rapidly change by looking at the early patterns that are emerging.
Here’s the first part of a synopsis of what I learned at the recent Molecular Targets meeting in Boston, some of these findings may well have a major impact on cancer research over the next few years…