We know from preclinical research that immunosuppressive tumour microenvironments can restrain anti-tumour immunity, thereby making subsequent therapeutic interventions less effective than expected. CD40 activation has been shown to reverse immune suppression and drive antitumor T cell responses, which in turn could lead to potentially better outcomes.
What happens when patients with advanced melanoma are given a checkpoint inhibitor plus an immune agonist such as anti-CD40?
Can we help the non-responding patients to checkpoint blockade improve their outcomes and shift the long tail in survival curves up using this approach?
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After yesterdays post on Gems from the Poster Halls at the American Association for Cancer Research (AACR) in Philadelphia where we took a look at new developments in targeted therapies, several subscribers asked for a repeat, but with a focus on immuno-oncology.
There are a number of elements that many people are interested in, especially given the Merck and BMS clinical data at AACR, where we clearly saw that:
- Anti-PD–1 therapy with pembrolizumab is superior to anti-CTLA4 with ipilimumab in metastatic melanoma (expect nivolumab to show the same thing at ASCO)
- Combined PD–1 plus CTLA4 blockade (with nivolumab plus ipilimumab) was superior to anti-CTLA4 alone, but with higher grade 3/4 toxicities, also in advanced melanoma
Sadly though, we still see that 70-80% of patients don’t respond to these therapies.
- How can we improve on that?
- What happens when we explore other factors, tumour types and different aspects of the immune system?
- What can we learn about novel sequencing or combination approaches?
- Which ones look interesting?
Endless questions can be asked – to which we still have too few answers – although there were some encouraging signs and hints of possibilities at AACR.
The 2015 AACR program was particularly challenging this year with lots of really good symposia and general sessions, making it tough to whizz round the vast poster hall spread out around the exhibits as well. To give you an idea of scale, it was pretty typical to cover 17K to 18K steps a day, approximately 7 to 8 miles. For many people, fitting in a quick lunch and the posters was certainly a challenging feat, depending where you were in the complex. With a morning session ending at 12.30pm, the afternoon session starting at 1pm and 2,000 steps between the Grand and Terrace Ballrooms, you sure had to get your skates on, Beep Beep!
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With the sheer breadth and depth of immuno-oncology data being presented at even the American Association for Cancer Research (AACR), several readers were prompted to write in and ask:
“Is this the end of the road for TKI therapies? Should we even bother to continue working on these agents?”
There was actually quite a bit of interesting data on regular novel targeted therapy to discuss, although I do concede that much of the mass media news focusing on the immuno-oncology tsunami in Philadelphia effectively drowned out targeted therapies and the results coming out in that space.
To maintain the balance between novel targeted agents and immunotherapy, here’s a review of some of the interesting new developments that I came across at AACR, from both the poster halls, as well as some of the thought leaders in this space.
When you stack up the emerging evidence in several tumour subsets, there are quite a few tasty morsels that are worthy of further discussion!
I’d like to take this opportunity to extend a warm welcome to all the new subscribers who took advantage of the AACR Special Offer to continue their education and learning about the exciting new developments in cancer research. Thank you for joining our conference coverage service, we really appreciate it.
To learn more about the hot topics in targeted therapies for cancer research, you can log in or sign up in the box below. Read on…
One of the obvious learnings from the American Association of Clinical Research (AACR) meeting earlier this week was that we are coming to the end of the low hanging fruit opportunities for checkpoint inhibitors as monotherapies.
Speaking with numerous company people in this space, there was wide consensus on that point. As one clinical lead put it succinctly, “From here on out, it’s going to get way more complicated – had a low grade headache develop after the very first science session I attended – and it’s still there after two days!”
How many of us know that feeling all too well? AACR always has the heaviest science load of any cancer conference we attend each year. Sure there’s some nice clinical data, but that is like nibbling on the light appetizers before the 20 course banquet. You need much stamina and fortitude to survive the brain fog at AACR. Then there’s the glee at snagging some key poster handouts at the meeting, only to be rapidly diminished when you try to read the 4pt print post hoc and realise your eyes cannot focus easily.
Looking at the long list of topics I want to cover in the in-depth post meeting analysis for a ‘lighter’ post, especially given that it’s Friday after a very long week, that sinking feeling hit home hard – there are no lightweight topics at AACR.
The other day, we posted about the promising data in triple negative breast cancer (TNBC), following on from the Genentech and Merck presentations at the San Antonio Breast Cancer Symposium (SABCS). These data surprised many folks, mostly because they didn’t consider breast cancer to be an immunogenic tumour – nor is lung cancer in the broader scheme of things for that matter – yet we are seeing some nice durable responses in both tumour types with checkpoint inhibitors.
In other words, our definition and perceptions must change as we redefine how we identify and think of possible ‘responsive’ cancers to these agents.
So where are likely heading next?
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Quick Reminder: Today is the last day for the AACR Special – the discount ends at midnight ET tonight. We may not offer this rate again as it’s a limited time only deal!
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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Much has been written about the success of checkpoint blockade in solid tumours over the last couple of years with the advent of anti-CTLA4 therapy (ipilimumab/Yervoy) for metastatic melanoma followed by the more recent approval of the anti-PD-1 antibodies in advanced melanoma (pembrolizumab/Keytruda and nivolumab/Opdivo) and lung cancer (nivolumab).
What about hematologic malignancies though?
At the recent American Society of Hematology (ASH) conference, we heard about the first clinical data for anti-PD1 antibodies in patients with refractory classic Hodgkins Lymphomas (cHL) and saw some impressive results. Interestingly, though, the early preclinical work was conducted in mice looking at CTLA4 blockade in a variety of tumours, both solid and liquid.
Is there a rationale for targeting CTLA4 in leukemias, lymphomas and even myeloma? New data presented at a medical meeting in patients with heavily pre-treated and relapsed disease post stem cell transplantation suggests that this might be feasible.
Check out to today’s article to learn more about this clinical opportunity in more detail – you can log in or subscribe in the box below.
Recently, Merck have been on a roll in the immuno-oncology space, with the announcement that their anti-PD–1 antibody, pembrolizumab (Keytruda), beat out BMS’s anti-CTLA4 antibody, ipilimumab (Yervoy) in a Phase 3 head-to-head frontline trial in metastatic melanoma. The two primary endpoints of OS and PFS were met and the trial will therefore be stopped early based on the IDMC recommendation. No further details are available until the presentation.
The data from the KEYNOTE–006 study is being presented at the annual American Association for Cancer Research (AACR) next month in the opening plenary session by Dr Antoni Ribas (UCLA).
While it’s nice to see evidence that one checkpoint inhibitor is potentially superior to another, in the long run, combinations are likely to be the best way forward. This approach is more likely to yield improved responses in immunogenic tumours, but also to make non-immunogenic tumours more responsive, thereby improving patient outcomes further.
This begs the all important question – what hints from new emerging data can we glean that will help us figure out novel combination approaches with checkpoint inhibitors?
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Some really intriguing news was announced this morning, with Aduro Biotech issuing a press release on their new global collaboration with Novartis for their “immuno-oncology products derived from its proprietary STING-targeted CDN platform technology.”
Many readers will recall Aduro for its program that inserts genetically engineered lysteria into therapeutics aka the LADD regimen. The lead program, CRS–207, in combination with GVAX Pancreas in pancreatic cancer previously received Breakthrough Therapy designation from the FDA. Their scientific advisers include Drew Pardoll and Frank McCormick, who are immunotherapy and protein pathway specialists, respectively.
The collaboration with Novartis is for a completely different platform based on cyclic dinucleotides (CDNs), which are small molecules that are naturally expressed by bacteria and immune cells and have been recently shown to activate the STING (Stimulator of Interferon Genes) signaling pathway in immune cells.
So what’s the significance of this exciting deal and why does it matter?
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Today I’m answering recent questions from readers, in this case on checkpoint inhibition and where this field is going in the near future.
No doubt we can expect to hear a lot of new data and research being presented at the upcoming AACR and ASCO conferences, so this is a timely point to reflect on a few topics of relevance.
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As we’re coming to the end of our European Association Urology (EAU) coverage for 2015, I wanted to discuss at a rather more quirky, off-the-wall topic and look at one of the gems from the poster halls at this conference.
This year, it’s the turn of urothelial bladder cancer (UBC), a topic that doesn’t usually get much coverage or respect when it comes to new product development. Part of the challenge is the need for new targets to aim at because the particular patient population doesn’t tolerate high dose chemotherapy very well.
At ASCO last year, perhaps the surprise (and most stunning) data of the meeting was the anti-PDL1 checkpoint data (Genentech’s MPDL3280A) in refractory UBC, a disease where there are a lot of elderly and frail patients who are challenging to treat in many ways. This certainly put more attention on the disease and raised awareness to the potential opportunities for new, targeted and altogether more benign approaches to treatment. Subsequently at ESMO last fall, we also saw early data for an anti-PD1 antibody (Merck’s pembrolizumab) in advanced urothelial cancer.
Checkpoint blockade is not the only potential way to treat UBC though, so what other novel therapeutics are in development in this space?
To learn more about this evolving landscape, check out our quick review in the article below by signing up or logging in via the box below.