Biotech Strategy Blog

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

AACR 2016 PostersNew Orleans – Tuesday is the last full day of the 2016 annual meeting of the American Association for Cancer Research (AACR), and the last day of our #AACR16 rolling blog posts.

What struck me at this meeting has been the explosion in cancer immunotherapy research. It’s worth remembering that where we are today is the result of pioneering work done over the last 15 years by researchers, many of whom struggled for funding and recognition as they laid the foundation for where we are today.

Tomorrow, the Vice President of the United States, Joe Biden, will fly in to address the closing plenary session of the meeting. Mr Biden’s remarks will be live streamed by AACR (link to information).

There’s a lot happening at AACR today and tomorrow; and as conference die-hards we’ll be here to the end in order to capture some really interesting data that’s on the program.

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AACR16 RegistrationNew Orleans – it’s Day 3, Monday, at the 2016 annual meeting of the American Association for Cancer Research (AACR). Attending AACR for the first time can be a daunting prospect, with a full program of activities from dawn to dusk.

For those of who don’t regularly go to large medical meetings, it’s all too easy to forget the sheer scale of the event and how mach walking is involved up and down long corridors – it’s easy to clock up 15,000+ steps on your Fitbit!

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New Orleans AACR 2016New Orleans – here at the annual meeting of the American Association for Cancer Research (AACR), the emphasis has shifted from yesterday’s education program to the start of the scientific programme.

If you didn’t make it to the Cell Press/Nanostring, “What’s Next: Bit Topics in Cancer Immunology” event yesterday evening at the Bourbon Orleans hotel in the heart of the French Quarter, you missed a great unofficial AACR16 event that featured a panel of leading experts:

  • Aviv Regev, PhD (Broad Institute of MIT and Harvard)
  • Tom Gajewski, MD, PhD (University of Chicago)
  • Dan Chen, MD, PhD (Genentech)
  • Pam Sharma, MD, PhD (University of Texas MD Anderson Cancer Center)
  • Michel Sadelain, MD, PhD (Memorial Sloan Kettering Cancer Center)
  • Jerome Galon, PhD (INSERM)
  • Ira Mellman, PhD (Genentech)
  • Catherine Wu, MD (Dana Farber Cancer Institute)

Throughout the day, schedule permitting, we’ll be posting top-line commentary from the sessions we’ve been in.

You can also catch up with the commentary from the Day 1 Live Blog, which has several updates from yesterday (Link).

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New Orleans StreetCarNew Orleans – the annual meeting of the American Association for Cancer Research (AACR) starts in earnest today with a full program of educational sessions presented by leading experts in different fields.

There’s a lot going on at AACR, with many sessions in parallel, so always remember the “law of two feet” – if the session you are in isn’t interesting, what you expected or isn’t meeting your needs – get up and go to another one!

Starting today and through Tuesday will be posting a daily blog with commentary around the sessions we attend and the people we speak to. It won’t be real-time, but to the extent possible we’ll be providing updates during the day.

It kills us to do semi-live posts from conferences, but they’re popular with subscribers, many of whom enjoy reading top-line commentary during the meeting, then our in-depth pieces later.

If you’d like to join the club of readers who enjoy access to our content, much of which by definition is exclusive – we don’t think anybody else does what we do or talks to as many thought leaders….

The good news is that a quarterly subscription will also cover you for ASCO 2016 in Chicago.  If you’d like to support our conference coverage, you can purchase access below. Subscribers can login to read more.

European Lung Cancer Conference 2016

European Lung Cancer Conference 2016

Geneva – At the 2016 European Lung Cancer Conference (ELCC) today, one of the highlights to watch out for is the presentation of first-line data for AstraZeneca’s ($AZN) third generation EGFR inhibitor osimertinib (Tagrisso), formerly known as AZD9291.

At 3.30pm in Geneva (9.30am on the East Coast of the United States), Dr Suresh Ramalingam (Winship Cancer Institute, Emory) will present updated data from two expansion cohorts of the AURA phase 1 trial (NCT01802632) with updated results on the use of osimertinib in the first-line setting:

LBA1_PR: Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts. S. Ramalingam, J.C.-H. Yang, C.K. Lee, T. Kurata, D.-W. Kim, T. John, N. Nogami, Y. Ohe, P.A. Jänne

Do follow tweets from the conference (#ELCC16).

As Dr Ramalingam noted in a press release issued by the European Society for Medical Oncology (ESMO):

“The overall response rate was among the best reported for first-line therapy of EGFR mutated NSCLC. The PFS results are exciting, well exceeding the historical control rates of 10 to 13 months with first or second generation drugs. Many of the patients have not had disease progression on the study and are still benefitting from treatment.”

Readers will recall osimertinib was approved by the FDA last November (link to press release) for the treatment of advanced non-small cell lung cancer (NSCLC) in patients who test positive for an epidermal growth factor receptor (EGFR) T790M mutation following prior treatment with an EGFR tyrosine kinase inhibitor (TKI).

Nearly two-thirds of patients who receive an EGFR-TKI develop a T790M mutation, and until the approval of osimertinib, there were no approved treatment options.

I vividly remember being in the audience at the European Cancer Congress in Amsterdam back in September 2013 and listening to Professor Malcolm Ranson (Christie, Manchester) present the first clinical data from the phase 1 study, which at that time was only a single center. See post: ECCO 2013: AZD9291 shows early promise in NSCLC.

Dr Ross Camidge (Denver), who was the discussant in Amsterdam, concluded his discussion with a picture of the first step on the moon. Cancer metaphors around the moon and moonshots have since become overused, but I think this one was justified at the time:

“By addressing acquired resistance at the molecular level potentially creating one small step in the EGFR treatment paradigm, third-generation inhibitors like 9291 are likely to represent one giant leap forward in the treatment of EGFR mutant disease.”

~ Dr Ross Camidge at ECC 2013.

Whatever the role we play in cancer drug development, and most of us are but bit players, we live for moments like that. Dr Camidge’s visual metaphor remains etched on my memory as a landmark moment when all in the audience saw the first glimpse of a drug that could make a difference.

We’ve been following the development of osimertinib over the past 3 years and the race to market with Clovis Oncology’s rociletinib (formerly known as CO-1686). See e.g. AstraZeneca ramps up AZD9291 lung cancer clinical development, AstraZeneca leaps over Clovis with AZD9291 data at World Lung Conference.

Looking back, when you compare the development of osimertinib to rociletinib, it is a “Tale of Two Cities,” to paraphrase the title of a novel by Charles Dickens.

In a recent article (open access) published in Annals of Oncology, Dr Antoine Yver, Senior VP at AstraZeneca described how fast the development of osimertinib was:

“The development programme for osimertinib is the most rapid to date, taking just 24 months from filing the FDA Investigational New Drug Application to submitting the FDA New Drug Application and just 2 years 8 months and 1 week from the first patient dosed to the first approval.”

To put this in context, the speed of the osimertinib development rivals – and perhaps even just beats – the accelerated development of imatinib (Gleevec) by Novartis from Feb 1998, when the first patient was dosed, to approval in May 2001, a tremendous achievement.

Key to AstraZeneca’s success was the company’s previous experience in bringing gefitinib (IRESSA) to market in EGFR lung cancer.

The development of osimertinib by AstraZeneca offers a new case study to other companies in how to bring a drug to market.

Sadly, the drug development by Clovis Oncology offers the exact opposite, as evidenced by the recent meeting of the FDA Oncology Drugs Advisory Committee, which recommended (12 to 1) against accelerated approval of rociletinib for the same indication as osimertinib. See FDA ODAC meeting briefing documents (link).

So what do we learn from the first-line osimertinib data presented at European Lung?

Dr Pasi Jänne at ASCO 2014

Dr Pasi Jänne, Dana-Farber Cancer Institute pictured at ASCO 2014

I spoke with the senior author of the LBA_1 PR abstract at European Lung, Dr Pasi Jänne, who is Director, Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute (DFCI) and Professor of Medicine, Harvard Medical School about the significance of the data presented at European Lung.

During the interview, excerpts of which I’ve posted for subscribers, we touched on acquired resistance to osimertinib and whether rociletinib has any future in the treatment of EGFR positive NSCLC.

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This week certainly turned out to be a defining tale of two drugs with a chequered history…

Lion DancersFirst off, the FDA approved AbbVie/Genentech’s venetoclax, now known as Venclexta, in a subset of CLL patients with 17p deletions. These patients have a historically poor prognosis and the approval goes some way to addressing the high unmet medical need.

Secondly, another biotech company, Clovis Oncology, got slammed by ODAC with a 12-1 vote to wait for phase 3 data from the TIGER-3 trial for rociletinib to better determine the efficacy:safety benefit profile.

For a long while it seemed that AbbVie had nothing but toil and trouble over the tumour lysis syndrome (TLS) issues giving them some significant challenges to overcome, while Clovis were one of the new darlings of Wall Street.

In the final dash to the market, the tables were turned almost at the 11th hour and fortunes stunningly reversed.  Yet a mere eighteen months ago, few industry watchers would have predicted the difference in outcomes.

In our latest AACR Preview series, we take a look at Bcl2 inhibition and where some of the emerging opportunities might lie based on new preclinical research that is being presented here in New Orleans this weekend.  It makes for interesting reading.

While one tiger is licking its wounds, another is smacking it chops at what the future might hold for new combination approaches; how the tails have literally turned.

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Dawlish TrainspottingIt’s Day 7 of our 12 day Countdown to AACR 2016 in New Orleans.  After exploring GITR and OX40, we’re now looking at another stimulatory target for cancer immunotherapy: CD40.

We’ve been writing about CD40 as a cancer immunotherapy target for some time. See posts: “CD40 as a Cancer Immunotherapy Target” and “Targeting CD40 in Cancer Immunotherapy.

Anti-CD40 antibodies are agonists that act on stimulatory signalling receptors on T cells and antigen presenting cells (APCs). Targeting CD40 effectively acts to “put the foot on the gas” and may help generate a better immune response. This could be important in cancers that have fewer natural T cells present.

CD40 is an attractive target because it’s expressed in more than 50% of carcinomas and melanomas and almost all hematological B cell malignancies.  Of particular interest is the potential to combine a CD40 agonist with a PD-1/PD-L1 checkpoint inhibitor.

Multiple companies have CD40 agonists in clinical development including Roche, Apexigen, Alligator Biosciences and Seattle Genetics.  There are others coming too.

In this preview of AACR 2016, we’re looking at the CD40 landscape. New products and companies have entered the scene, so we’re highlighting them and some of the CD40 presentations to look out for at AACR 2016 (and why they matter).

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British Javelin TrainIt’s Day 6 of our Countdown to the AACR 2016 annual meeting in New Orleans. We’re at the halfway, 6 posts written and 6 more to go!  Then it will be daily Live blogs from the meeting.

There’s a lot of cancer immunotherapy at AACR this year, so after yesterday’s post on GITR we’re continuing our mini-series with a look at another immune agonist.

Today, we’re moving onto OX40 (CD134) as a novel immuno-target. Regular readers will know that we’ve been following this target for some time.

Immune agonists such as GITR, OX40, CD40, CD27 and 4-1BB help to rev up T cells. As Dr Tom Gajewski (Chicago) told us last year, in an interview published on the blog and excerpted in Episode 6 of the Novel Targets Podcast: Stepping on the Gas:

…there are inhibitory receptors on activated T cells that are involved with shutting immune responses down. There are also activating receptors that help to rev up those T cells. You might question whether you can push an activator and block an inhibitor, and maybe get a good anti-tumor response going as well.

When we drive a car, we both lift our foot off the break and we step on the accelerator. We have really beautiful data in animals that that this is exactly the case, that if you hit one of those strong positive regulators, and block just one of the negative regulators, you can have complete disappearance of the tumors in mice.

Several of those positive agonistic antibodies against costimulatory receptors are in the clinic. One of them is anti-OX40 that a couple of groups have in the clinic. We’re working with Genentech, that has one of those agents in phase I.

What does the OX40 competitive landscape look like?

In those post we’ve provided commentary on some of the new products in development from companies and highlighted a surprising number of abstracts that you’ll want to watch out for at AACR 2016 if you’re on the cancer immunotherapy track.

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Macarons in shop windowWe’re all familiar by now with the idea of checkpoints that can be inhibitory (release the brake) or stimulatory (put the foot on the gas) on the immune system.

There are multiple checkpoint modulators in development, it’s becoming a bit like buying a macaron – which flavour do you want?

As the late Holbrook Kohrt said on the Novel Targets Podcast last year:

There are two types of checkpoint inhibitors, one checkpoint inhibitor are these series of markers that each of them when you target them, they will slow down the function of that cell. Now that’s a good thing if that cell is a suppressor cell, such as a regulatory T cell. Anti-CTLA-4, ipilimumab, the first approved immunotherapeutic monoclonal antibody targets these regulatory T cells. Essentially is this concept as you said of taking off the brake .

Now if you want to press on the gas pedal, you want to find a target that is essentially that actually increases the function of a cell you want to make work better…….

…. these ideas of the different checkpoint inhibitors, essentially we should really call them, checkpoint modulation, because the checkpoints can either be gas pedals or they can be brakes.

And ultimately, it’s a question about how do you combine them in a rational way so that way you’re not either pushing the car too hard or taking the brake off at a time when the car is rolling in the wrong direction.

So essentially, you need to do checkpoint modulation in a setting where you still have the steering wheel on your car to ensure it’s directed against the right cells, otherwise you’re going to get significant toxicity.”

Which is a good introduction to Day 5 of our Road to AACR 2016 mini-series.

Over the course of 12 days in the run up to the 2016 annual meeting of the American Association for Cancer Research (AACR), we’re taking a look at some of the areas we expect to hear more about in New Orleans.

In today’s post, which continues our look at some of novel cancer immunotherapy targets, we’re look at the modulation of GITR (glucocorticoid-induced tumor necrosis factor receptor related gene) and companies that are targeting this.

GITR was named as the 12th most promising cancer immunotherapy target by the National Cancer Institute (NCI) back in 2006.  Interestingly, high GITR expression can be found on both T cells and NK cells.

There are now several agonist antibodies in development and entering the clinic that seek to activate GITR, and new data is expected at AACR 2016.

What GITR pathway data is worth looking out for at AACR 2016?

If you want to know more about why GITR matters, and where it fits into the cancer immunotherapy landscape then do read more. 

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St Charles Streetcar New OrleansIt’s Day 4 of our Road to AACR 2016 mini-series

In the run up to the start of the annual meeting of the American Association for Cancer Research (AACR) that takes place in New Orleans from April 16 -20, we’re highlighting some of the hot topics and interesting targets with data to be presented at the meeting (Twitter #AACR16).

We’ll be providing conference coverage from AACR both during and after the meeting. The program this year offers a veritable smorgasbord of choices, particularly in cancer immunotherapy. It’s going to be hard to cover every session we want to attend!

AACR will be webcasting many presentations, however, much of the work presented and discussed at AACR is unpublished and/or still a work in progress, so do check if a talk you are interested in will be webcast or not. The online meeting calendar indicates whether permission has been given and if all the slides will be included. If you really want to hear something do get to meeting rooms early; we expect the cancer immunotherapy sessions will be especially popular!

In today’s post we’re looking at what’s new at AACR 2016 for cancer immunotherapies that target IDO1 and TDO and their downstream effectors.

Tumor cells and myeloid cells in the microenvironment express high levels of indoleamine-2,3-dioxygenase 1 (IDO1). IDO1 is a rate-limiting enzyme in the degradation of the amino acid tryptophan (TRP). Depletion of tryptophan inhibits T cell responses.

Another route by which the tryptophan metabolic pathway can lead to immunosuppression is via the enzyme TRP-2,3-dioxygenase 2 (TDO), which may be an additional target for cancer immunotherapy. Some IDO1 inhibitors also inhibit TDO, others don’t, which makes for an interesting question as to whether you need a dual-targeted approach or not?

In this post we’re looking at:

  • Some of the companies who have IDO1/TDO inhibitors in development – there is a surprising amount of activity!
  • What is the right combination partner?
  • Who is most likely to benefit from IDO1/TDO cancer immunotherapy?

Data at AACR 2016 may help us answer some of the above questions, and we’ve showcased a few of the relevant sessions and presentations for your AACR “dance card” if this is an area of interest.

Subscribers can login to read more or you can purchase access below. This post is Day 4 of our Road to AACR 2016 mini-series.

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