With the advent of single agent checkpoint blockade and success in melanoma, lung and urothelial carcinomas has come the realisation that the majority of patients do not respond and even some that do have a response of short duration. Immune escape and adaptive resistance are not an uncommon occurrence.
There has been much focus of late in looking at ways to address this by uncovering the relevant mechanisms underlying the biology of the disease and this is an avenue we can expect to see more research evolve. We already know that JAK1/2 upregulation and PTEN loss have lead to resistance with checkpoint blockade – what about other possible mechanisms?
Indeed, at the ASCO-SITC meeting in Orlando last week, another such target emerged and clinical evaluation is already underway, making it a worthwhile area to explore.
Here we take a look at the science and biology, as well as the emerging clinical landscape to see which companies are involved and may get a jumpstart on the combination niche.
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One of the frequently cited conceptual frameworks in Cancer Immunotherapy is the Cancer Immunity Cycle developed by Drs Dan Chen and Ira Mellman from Genentech.
Ira Mellman and Dan Chen
As we heard Dan and Ira tell us on the Novel Targets Podcast recorded last year at #AACR16, the cancer immunity cycle doesn’t include all the elements that we now know impact the immune system and whether someone will have an immune response. The microbiome is one example that readily comes to mind.
To address this, Chen and Mellman have now published the next installment in the series in Nature:
“Elements of Cancer Immunity and the cancer-immune setpoint.”
The review paper published last month incorporates the latest research into a different framework that looks at the factors that influence what they call the ‘cancer-immune setpoint.’
Anyone involved with cancer immunotherapy knows how fast moving and dynamic the field is, something they draw attention to:
“The pace of cancer immunotherapy clinical studies is such that they have outstripped our progress in understanding the underlying science. However, this situation has created the opportunity to combine emerging scientific and clinical insights in a synergistic fashion that… will also provide guidance for the identification of new targets… and the crafting of a framework for making decisions on a personalized basis.”
Conceptual frameworks such as those proposed by Chen and Mellman will be of increasing importance as we try to make sense of the tsunami of cancer immunotherapy clinical trial data, including combinations, that is coming our way over the next 18 months.
During my recent visit to San Francisco for ASCO GI, I had the great pleasure to catch up with Daniel S. Chen, MD PhD, (Global Head of Cancer Immunotherapy Development, Genentech/Roche) and talk about his latest thoughts on how we should think about cancer immunotherapy.
In writing these review papers he told me:
“We look at this as an opportunity to really think about the field, and try to conceptualize what is happening.”
We also discussed their collaboration with Kite Pharma, something of relevance to conferences this week as we head off to BMT Tandem and the ASCO-SITC meeting.
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After several years in the wastelands of cancer research due to lack of significant results and only one product on the market, therapeutic cancer vaccines now look to be back in fashion and are seeing a revival with their inclusion in clinical trials.
One of the reasons behind the resurgence of interest is the advent of checkpoints, and the potential of vaccines in the immuno-oncology space to boost or enhance the immune response.
Their use could not only increase the response to checkpoint inhibitors in people who might otherwise not respond, but in those who obtain some initial response such as a partial response, they could also potentially help achieve a more durable long-term response.
As we continue to ride the wave of cancer immunotherapy on BSB, the cancer vaccine field is suddenly an exciting area to watch.
I’ve long been known as a cancer vaccine sceptic, although recently several approaches in this niche have begun to look rather promising indeed. Here, we highlight and discuss one such company in the field, including an interview with the CEO.
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At the recent 2016 San Antonio Breast Cancer Symposium (SABCS16), Cascadian Therapeutics (NASDAQ: CASC) presented a poster (Abstract #P4–21–01) on:
“Efficacy Results of a Phase 1b Study of Tucatinib (ONT–380), an Oral HER2-Specific Inhibitor, in Combination With Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases.”
Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for HER2.
Cascadian’s tucatinib poster at #SABCS16
We’ve seen several new treatments approved for HER2 positive breast cancers in recent years including four targeted treatments: trastuzumab, pertuzumab, lapatinib and T-DM1.
Other companies such as Puma Biotech (NASDAQ: PBYI) also have oral TKIs in development. Puma’s drug, neratinib has, however been shown to have a high incidence of grade 3+ diarrhea, raising questions about its tolerance.
At SABCS16 (Abstract P02–11–03), the company presented the interim analysis of an open-label, multicenter phase 2 trial, which explored their compound:
“Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC).”
There has been a lot of interest and controversy in this space, so it’s time to take a look at the latest events in HER2+ breast cancer and consider the ramifications since there are a number of new developments that are well worth following, including neratinib (Puma Biotech) and pertuzumab (Genentech).
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San Francisco: In the final post of the week, it’s time to focus on some of the interesting concepts and early ideas being explored in GI tumours such as pancreatic and colorectal carcinomas.
Gems from the Poster Hall or what Dog Drug Heaven really looks like?
Despite the image implied by the used poster bins (right), there were actually several encouraging signs from emerging IO approaches as well as some surprising results that lead to some compounds – or at least some indications – going off to dog drug heaven.
There were also some salutory lessons to be learned in terms of understanding biomarkers and useful these can be.
After years of incremental improvements with targeted therapies, it’s time to look at whether some immunotherapy combinations can make an impact in what is known as cold tumours.
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San Diego – after “Flying Friday” where I flew from Munich to San Diego, Biotech Strategy Blog coverage of the 2016 annual meeting of the American Society of Hematology (ASH) is now done for another year.
With over 27,000 attendees – it’s the largest ASH annual meeting I’ve seen in 20 years of coming here! ASH is definitely the pre-eminent global meeting for hematology and blood cancers.
As you might expect, the thought leaders at this event are super-busy, but we’ve already managed to catch up with a few, and we’ll be rolling out interviews in the “post-game show.”
Subscribers have been asking what’s really hot at ASH this weekend, so reflecting my interests and the sessions I went to, here are my seven highlights/learnings of ASH 2016 (so far). There’s a lot more data to come!
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National Harbor, MD
Despite remarkable results with cancer immunotherapy to date, we do need to keep out feet on the ground and remember that response rates are relatively low to modest (10–30%) and the majority of patients do not respond or see a benefit with these approaches.
As we start moving beyond checkpoint monotherapy, the realisation has fast hit many researchers and companies that we really don’t know as much about the tumour microenvironment (TME) as we would like.
No doubt we will learn a lot more about it from the combinatory approaches, but be aware that this also means higher risk associated with such developments – we will likely see a lot of failures – and hopefully, some successes too.
This is where the little biotech companies have an opportunity to shine… they may have some intriguing IO compounds in development but not an anti-PD1/L1 backbone, meaning they can collaborate with a big pharma company to explore novel combinations in small phase 1/2 trials to determine what works or not. This is much lower risk (and R&D costs) for both parties and we get to see more quickly where things shake out.
At the annual Society for Immunotherapy of Cancer (SITC) meeting last week, there was a whole day devoted to New Immunotherapy Drug Development.
Some of these agents look worthy of watching out for and following their progress. A variety of data in different targets and MOA were presented from big and small companies alike. We selected a few of the promising ones for further review and discussion.
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Post 2016 US Election, we move on and get back to business with an in-depth review of some new science and clinical data.
Yes, it’s time for another Bushidō – “Way of the Warrior” – guide to the key ASH abstracts!
Here we focus on acute myeloid leukemia (AML), a difficult and challenging disease to treat with a high unmet medical need for new effective therapies.
In this Preview we look at key companies in the AML space, as well as a look at what’s happening in classic targets and also some new ones that are receiving notable attention, both preclinically and also in the clinic.
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There was a time when it seemed that all the good news emerging in cancer research was on breast cancer, that is clearly no longer true as other tumour types have seen some leaps and bounds with different modalities, including areas previously thought to be a graveyard for big Pharma, such as metastatic melanoma, for example.
New Dawn at the Houses of Parliament
That said, after the excellent developments in hormone-sensitive disease and the identification of the HER2 oncogene, we now have CDK4/6 as a validated target in metastatic breast cancer.
Pfizer’s palbociclib (Ibrance) lead the way, with two approvals in previously untreated and relapsed ER+ HER2- advanced breast cancer. Two other companies in this field are Novartis with ribociclib and Lilly with abemaciclib. Data is being presented on all three therapies at ESMO this year.
In addition, there are some other abstracts of note that are well worth discussing.
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In our ECCO Preview series last year (note: ESMO and ECCO have alternated the EU major cancer conference in the Fall for years), we highlighted several promising novel agents in development including the following:
- StemCentRx’s anti-DLL3 inhibitor: rovalpituzumab tesirine (ROVA-T)
- Ignyta’s Pan Trk, ROS1 and ALK inhibitor: entrectinib
- Pfizer’s anti-NOTCH3 inhibitor: PF–06650808
- Pfizer’s PTK7 ADC in TNBC: PF–06647020
What happened to them all? Were they good selections or not?
Well, AbbVie acquired StemCentRx in a $10.2B deal, Ignyta are busy advertising their new clinical trial enrollment for entrectinib as a non-chemotherapy and non-placebo controlled study on social media, suggesting that compound’s clinical development is still very much alive, while both the Pfizer compounds are also still active, as far as I know.
None have yet been consigned to dog drug heaven, which is quite something considering the failure rate in oncology drug pipelines!
Indeed, last year the Pfizer PTK7 ADC data was focused on triple negative breast cancer, where there is a solid rationale. This time around, the same research group explore the latest activity in advanced solid tumours, including ovarian cancer, as mentioned in the earlier Preview (See: 9 key abstracts in Ovarian Cancer).
So it’s time to sit down and chew the fat on one of my favourite topics at conferences – Development Therapeutics.
Here we consider which other compounds – other than the Pfizer ADC – that are worthy of highlighting and watching out for this year?
There are certainly some curious and quite different (i.e. novel) approaches to look at.
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