Picture Credit: @gene_antibody
For much of the last two years, one of the hottest topics around has been T cell manipulation, which can happen in many different forms.
This is just one area that we have covered extensively in the immuno-oncology space from Chimeric Antigen Receptor (CAR) T cell therapies to checkpoint inhibitors, as well as various antibodies, including the first bispecific T-cell engager (BiTE) to CD19 that recently approved by the FDA called blinatumomab (Blincyto) from Amgen.
Not all cancer patients respond to all these approaches though.
Why is that and what approaches or novel targets can we explore next to address this vexing issue?
At the SITC and SABCS meetings, I saw some really interesting and unusual presentations, together with some recent publications on topic, that really piqued my interest in this challenge. They are early signs of the new directions some of the research in this field could go. Overcoming resistance and understanding different aspects of immune escape will likely be very instructive in developing the next generation of combination studies that could make a positive impact on patients.
Today’s post touches on some of these exciting developments and includes an in-depth interview with Dr Ira Mellman, the scientist behind Genentech’s immunology research program at gRED.
Interested readers can sign in or sign-up in the box below to read more about the exciting new developments that are happening with different types of antibodies in the immuno-oncology space.
We spend a lot of time in the poster halls at scientific and medical meetings such as European Society for Medical Oncology (ESMO) Congress in Madrid because that’s where the action is in terms of finding nuggets of promising preclinical and early clinical data. You can also spot new trends emerging earlier this way.
At large meetings run by the American Society of Hematology (ASH) and American Association for Research (AACR) there are literally thousands of posters, all of which have passed the grade to merit presentation.
Gaining insights from posters, and in particular, picking those that really matter is often an art rather than a science – a lot of intuition is involved.
This post discusses a few of the posters presented in the developmental therapeutic session at ESMO this year. It focuses on non-immunotherapy topics, i.e. traditional TKIs and monoclonal antibodies to specific mutations or other targets.
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Madrid – it’s Day 3 of ESMO 2014 (#ESMO14), the annual Congress of the European Society for Medical Oncology, and the last day when we will be publishing a live blog from the meeting.
As predicted in our plenary preview, the highlight of the Congress is the overall survival data for the CLEOPATRA trial in HER2+ metastatic breast cancer where the addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) and docetaxel chemotherapy resulted in an additional survival benefit of almost 16 months.
As Dr Sandra Swain noted in her presentation of the data in yesterday’s Presidential Symposium: “the 56.5 month median OS is unprecedented in this indication.”
Note that says MONTHS (almost 5 years) not weeks – it represents the new standard of care that all women with metastatic HER2+ breast cancer should now receive.
The prolonged applause at yesterday’s packed plenary session at ESMO 2014 summed up the feelings felt at hearing this practice changing data; the audience of medical oncologists live for moments like this! It’s truly the sort of stuff that makes you smile and go “Wow.” We will be writing more about the commercial implications of the CLEOPATRA results and the breast cancer treatment landscape in our post-meeting coverage.
One thing that did capture my attention in the poster area at this year’s ESMO meeting was the bank of digital screens (the size of flat screen TVs) on which attendees could view digital copies of posters. What was even more bizarre was to see people taking pictures of an e-poster.
It will be interesting to see whether paper posters survive, or if they are now one of the last vestiges of the pre-digital era, destined to be phased out like paper cheques. I could see them becoming obsolete at scientific meetings in the not too distant future.
Instead we could have posters published online, with investigators interacting via chat or social media to answer questions from around the world during a dedicated interactive “poster viewing session.” I’ll let the social media gurus ponder that thought, but paperless and digital is the inexorable direction we appear to be going in.
My fervent wish is for conference organizers to ditch Flash-based apps that run on a USB key – these are pretty useless with a tablet – why not have a website with simple digital downloads for the PDFs? Thankfully, quite a few of the posters achieved this via QR codes on their posters, making them more accessible and easier to read on the go while sparing trees.
So what’s happening today at ESMO 2014? Subscribers can login to read which sessions we’ll be at and, wifi permitting, read our thoughts as to what catches our attention during the day. Do follow @MaverickNY on Twitter if you don’t already.
One of the most exciting presentations that I heard at ASCO 2014 – the sort that give you goosebumps and elicit a wow from people sitting next to you – was not in the plenary or even a tumour type oral session, but a clinical science symposium.
The subject? Bladder cancer.
The situation? Phase I clinical trial.
The therapy? Anti-PD-L1 therapy with MPDL3280A.
Prof Thomas Powles, Barts Cancer Institute, London
As the presenter, Prof Thomas Powles (Barts), dryly observed to the packed auditorium, it made a welcome change from the ten people who usually show up for bladder cancer sessions! After all, there have been no new approved therapies for this disease for some thirty years.
It wouldn’t have been out of place in the Plenary session, frankly.
By the time the ASCO selection committees cotton on to the fact what many of us know – that immuno-oncology is not only hot, but here to stay and actually changing the way we think about and treat some advanced cancers – some of these new checkpoint inhibitors will already be approved by the FDA. As one thought leader grumpily said to me:
“It’s not something they understand, nor does it involve the traditional things like breast or prostate cancers, plus it’s all political anyway.”
Ouch. Still, there was a lot to learn from this data, not just in terms of the results in an area of high unmet medical need, but also in our understanding of the immune system and where some future opportunities lie.
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“Nothing lasts forever, because nothing ever has.”
James Shelley, The Caesura Letters
This year’s annual AACR meeting was so good, we could probably write another 50 posts and still not be done! With ASCO fast approaching, however, it’s almost time to draw it to a close and the final post conference note will be published on Monday.
Today is the penultimate report and focuses on the key highlights that caught my attention in immuno-oncology, which covers the gamut from checkpoint inhibitors, co-stimulants, innate immunotherapy and CAR T cell therapy to bispecific antibody TCRs.
To learn more about our insights on the highlights and lowlights, you can sign in or sign up below.
One of the interesting new developments at AACR was the return of FGFR inhibitors with more enthusiasm and encouraging data compared to the past. Recall that previous small molecule inhibitors such as brivanib (BMS) and dovitinib (Novartis) didn’t fare particularly well, despite a multitude of clinical trials in different tumour types where FGFR was thought to matter.
This begs several key questions:
- Does the target matter to the tumour?
- Do we have enough therapeutic index to shut down the pathway?
- Is it better to be a specific or a pan-FGFR inhibitor?
- Does having multi-kinase effects offer off-target adverse events to the detriment of efficacy?
- Do we need an antibody or an ADC rather than a small molecule to improve potency?
And many other questions that cannot be addressed or answered on the basis of two chemical entities.
Interestingly, and perhaps even surprisingly, new data emerged in San Diego that might help us answer some of these questions.
In this review, a number of anti-FGFR compounds are mentioned including brivanib (BMS), dovitinib (Novartis), lenvatinib (Eisai), ponatinib (Ariad), BGJ398 (Novartis) and BAY 1179470 (Bayer).
Here, we take a particular focus on promising new FGFR compounds with new data at AACR from Novartis (BGJ398) and Bayer (BAY 1179470, BAY 1163877, FGFR2-ADC).
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Following on from yesterday’s post on the potential for small basket trials in ER+ breast cancer with the ESR1 mutation, I wanted to highlight another area where these type of highly focused and rational studies appear to be not only useful but also potentially produce stunning responses.
Some of you will recall the fascinating and widely told story of a single bladder cancer patient at Memorial Sloan Kettering who was resistant to multiple lines of therapies. The team sequenced the genome and found a rare TSC1 mutation. Importantly, this is known from pediatric astrocytoma studies, to be sensitive to an mTOR inhibitor, everolimus (Afinitor). The refractory patient was given the drug and responded well. The rest is history, as they say.
Can we learn more from these type of appraches, i.e. genomic sequencing of patients who have relapsed after initial therapy?
Can we also learn more from the few exceptional responders in clinical trials – what was unique about their response that elicited such a stunning effect?
The short answer is a resounding yes – to learn more about some stunning new genomic approaches to research and the lessons we can learn for future drug development, sign in or sign up below.