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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Today, I’m going to summarise some of my notes on what we learned about lung cancer and immunotherapy at AACR. The burgeoning immuno-oncology topic is way too big to do justice in one single post, so over the next couple of days, you’ll find a mini series evolving here on BSB to cover many of the points relating to checkpoint inhibitors from AACR. It was the first time in 15 years I’ve seen immunotherapy dominate a basic scientific meeting and it was good to see it happen. It is definitely very much the focus – and excitement – of many major cancer centres in the US.
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Sometimes you get lucky before a conference and catch an interview with a thought leader ahead of time when it’s more relaxed and less fraught with all the demands of meetings etc while there.
Dr R Young, Source: WI
That good fortune happened to me on the Friday before the recent AACR conference in San Diego, when I recorded an interview with Dr Richard Young, (Whitehead Institute & MIT and scientific co-founder of Syros), who was giving a plenary talk on the Sunday at AACR entitled, “Transcriptional and Epigenetic Control of Tumor Cells.”
Epigenetics and transcriptional changes are fascinating concepts to me because they get right to the heart of what’s going on deep in the oncogenes and how they control processes in cancer. Clearly, in simplistic terms, if we can understand how things change and evolve, then we can potentially devise better strategies to overcome them. Instead of targeting a protein kinase with a small molecule or a cell surface antigen with a monocloncal antibody, this is an altogether different approach. Protein-protein interactions such as MYC, RUNX1, p53/TP53 etc have long been the bugbear and frustration of many good researchers, precisely because they are challenging to target with conventional approaches.
So what’s new and why am I really excited about these new developments?
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Dr Richard Finn Source: UCLA
At AACR this weekend, Dr Richard Finn (UCLA) presented the much anticipated front-line phase II data for Pfizer’s CDK4/6 inhibitor, palbociclib (palbo) plus letrozole versus letrozole alone in ER+ HER2- breast cancer.
The PALOMA series of trials are designed to show that adding a specific CDK inhibitor to an aromatase inhibitor enhances efficacy and improves outcomes.
There are three metastatic breast cancer trials in all, with PALOMA–1 being the phase II study while PALOMA–2 and –3 are phase III randomised controlled registration studies aimed at confirming the initial phase II results in combination with letrozole and fulvestrant, respectively. In addition, palbociclib is also being evaluated in combination with standard endocrine therapy (PENELOPE-B) for certain early-stage breast cancers.
In short, an analysis demonstrated that the primary endpoint of progression free survival (PFS) was met, but the overall survival (OS) data was not significant at the time of the analysis.
What does this does this data mean and in what context should we look at the results?
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In the past, I’ve sometimes been accused of being a bit of an immunotherapy bear for my dislike of cancer vaccines as a single agent therapy in advanced disease where the tumour burden is very high. That particular field has undoubtedly been a huge graveyard for many companies, much in the same way that metastatic melanoma was, until novel therapeutics and immunotherapeutics emerged to push through the envelope.
To be clear, I am though, a big fan of targeted immunotherapies such as checkpoint inhibitors and chimeric antigen receptor (CAR) T cell therapies, which have been very much to the forefront in immuno-oncology over the last two years and rightly so, with some initial trials showing some very promising results.
Both of those approaches are squarely part of the adaptive immune system and seek, in different ways, to retrain the bodies immune system to fight the tumour. More recently, the innate immune system has seen new advances as reearchers moved beyond simple vaccines to develop more thoughtful and innovative approaches that seek to outwit the very masking the cancer is trying to fool the immune system with. It’s no less exciting, just a different way of looking at the science and improving out understanding of the biology of the many diseases that cancer makes up.
In this AACR preview, I take a broad look at some innovative and novel scientific approaches, including targeting anti-CD47 and SIRPα (Stanford and Stem Cell Therapeutics), KIR and MICA (Innate Pharma) and neutrophils (Biothera).
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“You may say I’m a dreamer
But I’m not the only one.”
John Lennon, Imagine
As part of our ongoing series on the AACR Previews, today I want to take a closer look at some interesting scientific and clinical data in triple negative breast cancer (TNBC). One reason for this is that we need to remember that the disease, as currently defined, is essentially what’s left after taking out the ER+, HER2+ and inflammatory breast cancer subsets. In other words, it’s a very heterogeneous catch-all population, making clinical trials rather challenging at best. It also means that the chances of success in general all-comer trials is rather low.
It is my hope that as we learn more about the biology of this disease, we may see further subsets be defined by molecular peculiarities, much in the same way that gastrointestinal stromal tumours (GIST) were defined by KIT expression and CD117. Once we have more homogenous subsets, it will be easier to conduct trials just looking at those specific patients, thereby improving the chances of clinical success with therapeutic intervention.
There’s been a lot of work focused on this area over the last few years, so it seems a good point to find out where the progress has got to.
Without much further ado, what can we learn about the biology of TNBC from AACR this year and which potential new targets might emerge?
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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.