We’re overdue a roundup and discussion on various key topics of interest to BSB readers, so here goes…
Today’s topics include an in-depth look at the impact of some negative events:
- Kite and the cerebral oedema death with axi-cel
- Genentech’s atezolizumab OS miss in urothelial cancer
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National Harbor, MD
Bladder cancer is the most common of the urothelial cancers and is the 9th most common cancer globally, with over 400,000 new cases each year and around 165,000 deaths. In the US, approximately 76,000 Americans will be diagnosed with bladder cancer in 2016 and ~11% of new diagnoses are made when bladder cancer is in advanced stages.
Unlike tumour types such as ovarian and pancreatic cancers, the majority of bladder and urothelial cancers are diagnosed at an earlier stage. The rates of recurrence and disease progression, however, are high and approx. 78% will recur within 5 years while the 5-year survival for stage IV bladder cancer is pretty dismal at 15%.
Earlier this year, Genentech/Roche’s anti-PDL1 antibody atezolizumab (Tecentriq) was approved by the FDA in the second line setting and was the first such new approval in this disease for 30 years.
Since then, there has been heightened interest in urothelial and bladder cancers in multiple settings, with several companies rushing to play catch up, including Merck and BMS.
We’ve been following the steady progress of checkpoint blockade this year at AACR, ASCO, ESMO and now SITC – amazingly, what was once a graveyard for Pharmaland has now become a hypercompetitive niche in a very short time.
Here, we take a look at the latest data in advanced urothelial cancers and explore the landscape in the context of rapidly increasing competition.
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The ASCO Wall 2016
There has been much frustration on many fronts at the number of trials that do not see a relationship between PD-L1 expression and response. Some do, but many don’t. This has lead to quite a few investigators suggesting that the IHC assay may not be as useful as originally hoped, for predicting response to checkpoint blockade or selecting patients for therapy.
While we often do see a trend for more responders with higher levels of expression, the main issue is that PD-L1-negative patients can also see some responses, albeit at a lower rate.
There are many factors that can affect the measurement:
- Fresh vs. archival tissue
- Heterogeneity within the tumour
- Tumour cells (TC) vs. immune cells (IC)
- Different antibodies used for each assay
- The dynamic nature of the tumour microenvironment – does timing of the biopsy matter?
- Human error – a pathologist has to eyeball the IHC readouts and decide the level of staining intensity
And so on. These are just a few examples of the factors that can potentially affect the results, making it quite a challenging test to undertake. There is also time – does the level of expression vary temporally depending on which prior therapies are administered?
It would be easy to be disheartened by this, but fear not!
There were some impressive new data presented at ASCO that were not only intriguing, but also show us a way forward on how a multi-factorial approach could be used in different tumour types. By this I mean we might end up with different tests used in conjunction for several different cancers in order to a) predict responders and non-responders and b) better select patients for appropriate regimens or clinical trials.
It’s not going to be as easy as one size (or test) fits all. Sometimes a more more sophisticated approach will be needed. New data at ASCO gave us hints on what’s to come in this direction.
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One of the exciting developments in metastatic urothelial carcers of late has been the emergence of checkpoint blockade with some very encouraging signs of durable clinical activity. Urothelial cancers comprise a group of urinary tract tumours including bladder, penile, ureter etc, although most trials tend to enroll bladder cancer patients, where there is a high unmet medical need.
View from the 95th floor of the John Hancock Center, Chicago
This year alone has seen the FDA grant AstraZeneca with breakthrough therapy designation for durvalumab in February, while Genentech/Roche subsequently received approval for atezolizumab (Tecentriq) based on phase 2 data on May 18th.
To put these developments in context, the last FDA approval in metastatic urothelial carcinoma was almost 4 decades ago in 1978 for the chemotherapy cisplatin!
As is often the case in Pharmaland, once one company starts exploring a therapy in a given tumour type, others will quickly follow. Already we have several immunotherapy agents being evaluated in urothelial carcinoma both in early and metastatic disease, so what can we learn from the data presented at ASCO last week and where is the landscape going in the future?
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Biomarkers are a hotly debated topic at the moment within the cancer immunotherapy field.
At the recent Society for Immunotherapy of Cancer annual meeting (SITC 2015), there was even a debate with industry representatives arguing the “pros” and “cons.” Daniel Chen, MD PhD from Genentech (pictured right) argued “pro” and Steven Averbuch MD (pictured left) from BMS argued “con.”
The challenging question for anyone at the moment is if your Parent, Spouse or Best Friend were PD-L1 negative, would you still want them to receive a PD-1/PD-L1 checkpoint inhibitor (presuming it was indicated for the disease) and have a chance of a response, even if their PD-L1 negativity would suggest only a slim chance of responding?
AT SITC 2015 we spoke with an industry expert who offered insights into a leading company’s biomarker strategy and what the future may look like in 5-7 years time.
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Which of these cakes will you choose?
Greetings from Vienna where we are gearing up for our coverage of the European Cancer Congress (Twitter #ECC2015).
We’ll be writing a “highlights” post for subscribers at the end of the day here on Saturday, Sunday and Monday, then will follow- up with more in-depth coverage after we have talked with experts about the data presented.
Checkpoint Inhibitors and Cancer Immunotherapy are not surprisingly hot topics at the meeting.
In case you missed it, this month’s episode of Novel Targets (are we really on show #6 already?!) takes us on a new branch of the journey looking at various aspects of cancer immunotherapy:
Boosting T cell production – Stepping on the Gas
In past shows, we’ve looked at unlocking the brakes (checkpoint inhibitors), immune biomarkers (MDSCs and STING pathway), an inflamed or immunologic tumour type (lung cancer), a non-inflamed tumour type (prostate cancer), adoptive cell therapies and now it’s time for something really different… what happens when we literally step on the gas with immune agonists?
That’s the theme of the latest show – listen to Episode 6 on SoundCloud or iTunes (open access thanks to our sponsors, Genentech).
This article focuses on more detailed background and show notes for BSB subscribers.
It’s an important topic that is both simple in concept to understand and yet highly complex in terms of optimising therapy.
It’s time to take a deeper dive…
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One interesting aspect of the recent American Society of Clinical Oncology (ASCO) meeting was the surprise many people expressed in conversations that chemotherapy might actually be useful in combination with checkpoint inhibitors.
You see, several years ago when we first started writing about this new class of agents, I remember vividly how quite a few analysts grumbled on social media or sent me snarky personal messages when it was even suggested that this — along with combinations with existing targeted therapies — might be a worthwhile and valid approach to explore. Clearly they believed that immunotherapies (as monotherapy) were going to be the ultimate panacea.
Not so fast…
There are a number of scientific reasons for combination strategies, but not everyone thinks rationally when new approches come along and their attititude is often ‘out with the old, in with the new!’ It was actually quite amusing to see some of the very same folks in Chicago now eulogising the combination of checkpoint blockade with… chemotherapy in lung, colorectal or even bladder cancer.
One reason why these traditional therapies may be important is because they can influence the tumour microenvironment in both positive and negative ways. That can be helpful for deciding on rational future combinations, rather than just throwing mud at the wall and hoping based on a limited set of data.
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