Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘Bladder’ category

ASCO18 Preview 4 What’s Hot in Urothelial Carcinoma

Downtown Chicago

In our latest ASCO 2018 Preview series we take a look at some of the key highlights from urothelial and bladder cancers and look at how new developments in this space are progressing.

Historically in oncology, we see initial trials begin in advanced stage disease especially in the refractory metastatic setting and move up into earlier lines of therapy later as safety and efficacy become more established.

This situation has been very much the case in urothelial carcinomas, including bladder, penile, renal pelvis, ureter and transitional cell cancers. With the approval of pembrolizumab and atezolizumab in the relapsed setting following cisplatin therapy, much of the focus has now turned to earlier stage disease.

In our latest Preview, we explore some of the key combinations and look at whether or not they are more promising in terms of outcomes than the monotherapy readouts we have seen to date.  There’s a lot to cover and digest…

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AACR18 Preview 4: a look at new developments in a key tumour type

As part of our annual AACR Preview series, we usually explore new developments in at least one tumour type and one new target of interest.

Bladder cancer cells infected with BCG Source: Dr M Glickman, MSK

This year is no different and there were plenty of opportunities to discuss.

We have already covered lung cancer given the intensive interest in the phase 3 trials being presented in the 1L setting, but I also wanted to cover another key tumour type that is generating a lot of keen interest in clinical development for numerous reasons.

Tomorrow we will be exploring a cancer target in detail, but there is much to cover in terms of new preclinical and clinical developments in certain carcinomas.

Without much ado about nothing since there is plenty of important things to discuss, so here’s a look at our second tumour type to watch out for given the sheer numbers of trials, including a variety of different targets to think about.

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The death of PD-L1 in urothelial cancer

Prof Tom Powles GU18 Title SlideAt the 2018 ASCO Genitourinary Cancer Symposium, one of the standout keynote lectures was from Professor Tom Powles, Director of the Bart’s Cancer Cancer Center in London who talked about “Immune checkpoint inhibitors in Urothelial Cancer: which one and why?”

We’ve been following the highs and lows around checkpoint inhibitors in bladder cancer for some time, so it was interesting to hear what Prof Powles had to say in San Francisco.

How does he see the landscape evolving for immune checkpoint inhibitors?

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A potential new IO combination for clinical development

A short, but quite important, post today highlighting an early target we are keen to follow in terms of combination trials in both GI and GU cancers, as well as others.

There’s been a lot of focus this year on the so-called inflamed (hot) and non-inflamed (cold) tumours, but what about the intermediate ones that many refer to as the immune excluded phenotype?

View of Geneva from Cathedral St Pierre, Switzerland

Clearly it makes sense to consider different combination approaches in each category, but what would be appropriate? Before we can set about doing that, we first have to uncover the mechanisms causing the inhibition on the tumour microenvironment and then figure out how best to identify those patients most likely to benefit.

Over the last couple of years, we’ve seen and written a lot about various potential candidates (not all will be useful), including myeloid derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumour associated macrophages (TAMs), chemokines, cytokines, adenosine fog and many others.

There is one target that has started gathering a little bit steam over the last year that we have mentioned a couple of times on BSB and now there is something new to discuss here, at least from a big picture perspective.

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On Kite’s cerebral edema and Genentech’s IMvigor211 miss

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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SITC 2016 Update on the Competitive Urothelial Cancer Market

national-harbor-sunset

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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Beyond PD-L1 Immunotherapy Biomarkers

Crowds of People at ASCO 2016

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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Urothelial Cancer Immunotherapy is a Competitive Landscape

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.

Chicago John Hancock Center View

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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Why didn’t Ipilimumab plus Chemo work in Metastatic Urothelial Cancer?

Streets of San FranciscoOne of the interesting immuno-oncology presentations at the recent ASCO Genitourinary Cancers Symposium held in San Francisco from Jan 7 – 9, 2016 was presented by Dr Matt Galsky (Mount Sinai, New York).

Dr Galsky presented the results of a phase II trial of gemcitabine plus cisplatin plus ipilimumab in patients with metastatic urothelial cancer: HCRN GU-148 (Abstract 357).

The trial failed to reach its primary endpoint of showing a 20% increase in 1 year overall survival by the addition of ipilimumab compared to historical data for Gem + Cis in this patient population.

Many in the media don’t write up what is in essence “negative” data, but this trial is highly informative for those with an interest in urothelial cancer and in the optimal strategy for cancer immunotherapy. The GU16 discussant Dr Elizabeth Plimack (Fox Chase) raised many questions that merit consideration by those in the field.

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Atezolizumab PDL1 Checkpoint Inhibitor will change Bladder Cancer Treatment

LONDON – atezolizumab (Roche/Genentech) is expected to change the standard of care (SOC) for the treatment of metastatic urothelial bladder cancer. That’s the key message I took from a recent interview with Professor Tom Powles (Barts Cancer Institute) on the role checkpoint inhibitors and cancer immunotherapy will play in the treatment of bladder cancer.

Professor Tom Powles BartsReaders will recall the compelling early phase 1 clinical trial data for atezolizumab (formerly MPDL3280A) that Prof Powles (pictured right) presented just over a year ago at the 2014 ASCO annual meeting: “Making a difference in advanced bladder cancer”

Although other checkpoint inhibitors are in bladder cancer trials, and we have written about the pembrolizumab (Merck) data first presented at ESMO 2014 (“Breathing New Life into Bladder Cancer Treatment”), it is expected that atezolizumab will win the race to market in the US and be the first checkpoint inhibitor to gain FDA approval for the second-line treatment of advanced bladder cancer.

Atezolizumab received breakthrough therapy designation (BTD) in May 2014 from the US Food and Drug Administration for PD-L1 positive metastatic urothelial bladder cancer after progression or intolerance of platinum based chemotherapy.

Earlier this summer Genentech announced in a press release that the IMvigor 210 phase 2 study was positive and met it’s primary endpoint, with a greater response rate associated with higher levels of PD-L1 expression.

European Cancer Congress 2015This data will be presented on Sunday Sept 27 as a late-breaker at the forthcoming 2015 European Cancer Congress in Vienna (Twitter #ECC2015), the European equivalent of the ASCO annual meeting organized in alternate years by ECCO and ESMO:

Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): Results from a pivotal multicenter phase II study (IMvigor 210)

Although we won’t know the trial results until they are presented in Vienna by Dr Jonathan Rosenberg (MSKCC), based on the recent press release it’s widely expected that the positive data from this trial will lead to rapid regulatory approval in the United States.

Subscribers can login to read Prof Powles’ opinion on the role checkpoint inhibitors will play in the treatment of bladder cancer, how this may play out in Europe as compared to the United States, and what the future may hold beyond checkpoint monotherapy.

This interview does not discuss the data to be presented at the 2015 European Cancer Congress, the results of which we will have to wait until Vienna to hear.

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