Today for the second AACR 2017 Preview, I wanted to switch things up a bit and turn from looking at an important trend to a specific tumour type. One of the reasons for this is that we received questions from readers about recent data presented at medical meetings in this sphere.
It’s also not something that we have covered extensively here on BSB, so looking at something in a different light is often a good idea since insights and intelligence can sometimes jump out afresh.
Given that there are also some important clinical trial results emerging here, this is something we can expect to return to in Washington DC when the data is presented at AACR next month. What can we learn ahead of the event though? It turns out the answer is quite a lot.
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New developments in renal cell carcinoma
Continuing our focus on genitourinary (GU) cancers this week, today we turn our focus from prostate cancer to renal cell carcinoma (RCC).
There were two important announcments on Monday this week relating to renal carcinoma.
Firstly, Exelixis announced positive top line data from a phase 3 pivotal trial of cabozantinib versus everolimus in relapsed metastatic renal cell carcinoma (METEOR). The study met the primary endpoint (i.e. significantly improved progression free survival) and the company revealed the following data:
- Cabozantinib reduced the risk of disease progression or death by 42%; Hazard Ratio = 0.58, (p < 0.0001) compared to everolimus
- Interim Analysis of OS demonstrated a trend in favour of cabozantinib; Hazard Ratio = 0.67, (p = 0.005) compared to everolimus
- Exelixis to complete US and EU regulatory filings in early 2016
Secondly, a press release from BMS highlighted the phase 3 CHECKMATE–025 trial comparing nivolumab to everolimus, also in relapsed metastatic RCC, where the independent Data Monitoring Committee recommended early stoppage on the basis of the primary endpoint (OS) being met. The company likely be seeking discussions with Health Authorities with a view to filing the data with the FDA and EMA.
There are some interesting points that fall out of these releases. To learn more, subscribers can log-in below or you can purchase a subscription in the box below.
At the last count, the renal cell carcinoma (RCC) space is quite competitive with five VEGF inhibitors (sunitinib, sorafenib, axitinib, pazopanib and bevacizumab), two mTOR blockers (temsirolimus and everolimus) and not forgetting IL–2, all approved by the FDA for the treatment of advanced disease.
Much of the recent focus has been on sequencing, exploring combinations (generally too toxic with little added benefit), and evaluating the potential for novel immunotherapies in development such as checkpoint inhibitors. Biomarkers are few and far between, making it hard to rationally decide which therapy each patient should get and in which sequence.
The key question is, why is this tumour type so challenging from a clinical and scientific perspective?
Recently, new data has begun to emerge that may help inform or enable us to switch to new approaches. While the urologists are eagerly watching the live surgery on the EAU cam, we highlight research data presented at the European Association of Urology (EAU) in Madrid and take a look at how the underlying biology of RCC can elevate our knowledge about where the potential future strategies and blueprint might lie, if we want to facilitate exciting new developments in this field.
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Immuno-oncology is one of the hottest topics, if not, the hottest in cancer drug development at the moment, and every conference seems to advance the field forward. The pace of progress is breathtaking as thought leaders and pharma & biotech seek to maximize how to leverage the body’s immune system in the fight against cancer. It’s exciting times!
Coming up next on the calendar are two cancer conferences, the Society for Immunotherapy of Cancer (SITC) held in Maryland later this week, followed swiftly by the EORTC-AACR-NCI Molecular Targets conference (often referred to as the Triple meeting by industry insiders) in Barcelona just before Thanksgiving.
Whoa, that’s a lot of data yet to come, and then in December we have the American Society of Hematology (ASH) and San Antonio Breast Cancer Symposium (SABCS).
Back home in the Blighty, November is often referred to as the ‘month of the drowned dog’ because it rains a lot… at this rate it’s more like raining data – let’s hope not too many agents are headed for dog drug heaven! The good news for subscribers is there’s a lot of conference coverage to come!
So here we are, after nearly two dozen posts, it’s time to close out the 2014 ESMO coverage with a final review of the immuno-oncology posters that piqued our interest.
There were 16 in all that fitted that category. Normally, we highlight three or four gems from the poster halls, so more than a baker’s dozen is quite a feast.
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One of my favourite sessions at any cancer conference is the science symposia, although they go under many different guises and names. At the European Society of Medical Oncology (ESMO) they are known as Special Symposia and conceptually are very similar to Clinical Science Symposia at ASCO.
Here at these sessions, top thought leaders in the space debate and lecture on key issues of the day. They’re usually packed with information and are well worth attending, even in a hectic schedule.
Interestingly, immuno-oncology has a dominant focus on the program for the first time since I’ve been attending ECCO/ESMO events over the last dozen years or so, demonstrating how quickly it is being assimilated into the scientific and clinical consciousness. Years ago, I attended a session on autologous cell therapies (ACT) and there were maybe a handful of us in the room. In Madrid, I doubt if there will be 12 empty seats in the theatre and it will probably be what Pharmaland calls SRO – standing room only.
So what can we learn from the announced sessions this year?
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Yesterday, the European Society of Medical Oncology (ESMO) released the abstracts to the poster and poster discussion sessions. This preview will be quite long by nature of it being the first time we get a look at the topline details behind some of the key sessions and their abstracts for both immunotherapies (especially checkpoint inhibitors) and targeted therapies. This includes posters and their discussion sessions, plus poster late breaking poster titles.
For reference, you can find the ESMO 2014 poster and poster discussion abstracts can be found here.
In addition, there appears to be some pretty cool presentations in the Special Symposia, which are rather like ASCO scientific symposia and contain a lot of useful information and often strategic ideas about where thought leaders see hot topics going in the future. This can be very helpful in learning about possibilities for new clinical trials ahead of time. As we focus on the poster highlights today, do check back tomorrow for a detailed look at the scientific symposia.
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Our latest European Society of Medical Oncology (ESMO) 2014 conference preview takes a look at some of the key immunotherapy sessions and presentations that look interesting in Madrid.
Based on a detailed look at the online program, some abstracts are clearly a re-hash of the ASCO data for a European audience, yet there are clearly some new topics and data being presented too.
As companies begin to ramp up development with data emerging from phase I to III trials across a gamut of different tumour types, things start to get very interesting indeed. Let’s not also forget the importance of science and translational work, particularly in understanding the tumour microenvironment and how the immune system can impact that in many ways.
Companies mentioned: BMS, Merck, Roche/Genentech, Biothera
Drugs mentioned: ipilimumab, nivolumab, pembrolizumab, MPDL3280A, Imprime PGG
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Our ASCO 2014 conference coverage continues with more gems from the poster sessions; it’s where we believe you find the promising gems that offer hints of future promise (or not) as the case maybe.
Sometimes a failure with one agent can help another company design a more optimal trial for their own new product in development, thus moving the field on. Other times, a surprising result can emerge that teaches us something new about the science and increasing our body of knowledge about pathways or biomarkers.
The other thing to understand about phase I trials is that they are generally conducted in the salvage situation where patients are refractory to most current treatments. The disease burden is high and the patients much sicker than when they were newly diagnosed. What companies are looking for is to characterise the side effect and PK profiles while looking for possible hints of where the agent might be efficacious. Given that most cancer therapies are given in combination, it’s very rare to see a home run in phase I, especially in solid tumours.
Here are a triplet of interesting posters from small companies looking at moving the needle in solid tumours with early phase I studies:
Companies mentioned: Nucana, OncoMed, Celldex
Agents mentioned: Acelarin, OMP–59R5, varlilumab
Over the last few days, we’ve covered data from the leading checkpoint inhibitors from BMS, Merck and Roche, but what about other agents in development in immuno-oncology? One of the companies that burst on the scene in Chicago at ASCO 2014 with solid data was AstraZeneca with their anti-PD-L1, MEDI4736.
To put progress in context, last year Merck had one single abstract for MK–3475 (pembrolizumab), whereas this year MEDI4736 debuted with 7 abstracts, including several Trials in Progress posters in combination with their anti-CTLA4, tremelimumab, plus some important oral presentations too.
The last morning of the final day of the ASCO conference has not exactly been well attended in past years, especially in Developmental Therapeutics. This year was different – the large hall was jam packed and it was standing room only. I was lucky to get one of the last seats in the front row a good 15–20 mins early!
As we were waiting for the proceedings to start, the Japanese doctor sitting next to me turned and said:
“What do you think of this compound? I’m not expecting much, and they are behind the others already!”
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In her ASCO Gastrointestinal Cancer symposium (ASCO GI) keynote presentation earlier this year, Elizabeth M. Jaffee MD described the future of immunotherapy as being in combinations.
Overcoming or delaying resistance mechanisms or hitting multiple targets to greater effect will be achieved through combinations of drugs rather than single agent therapy. Combination strategies are the accepted future, whether drug companies like it or not.
In her keynote, Dr Jaffee also likened the revolution in immunotherapy to the same excitement the Beatles brought to music or the same magnitude of technology advances made by Apple. We agree completely.
Thought leaders at ASCO expressed similar sentiments. Steven O’Day (UCLA) said,
“This is truly a brave new world of immunotherapy. I think the message is that the revolution is here, it’s ongoing, and it’s bursting out of melanoma into solid tumors.”
Interestingly, no immunotherapy data was considered to be of worthy of presentation in the plenary session at ASCO this year for the second year running, a decision that may reflect either an unwillingness to showcase early data, however good it may appear to be, or the influence of politics on the selection committee.
One potential combination is to target more than one checkpoint pathway to see if you can obtain a synergistic response. This is the rational for combining the monoclonal antibody ipilimumab and nivolumab. Ipilimumab (Yervoy) targets the CTLA-4 checkpoint protein that prevents dendritic cells from priming T cells to recognize tumors while nivolumab targets the PD-1 checkpoint protein that prevents T cells from attacking cancer cells. Yervoy is an FDA approved therapy for the treatment of metastatic melanoma.
Data published last year in The New England Journal of Medicine by Wolchok et al, showed that combining ‘ipi’ with ‘nivo’ gave more frequent and deeper responses in melanoma, but at the expense of much greater toxicity. Some 53% of patients receiving concurrent treatment had a grade 3-4 adverse event (see Table S-1B in the article).
Does it make sense to combine two immune pathway modulating agents? Does the enormous potential for synergy outweigh the additional toxicity?
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