Biotech Strategy Blog

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

Posts from the ‘Bladder’ category

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-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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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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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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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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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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Gumbo Shop New OrleansThe annual meeting of the 2015 American Urological Assoication (AUA) is being held in New Orleans… Yes, we’re on the third and final leg of our Louisiana trip encompassing AAI, ASGCT and now the triumvirate of AUA-SBUR-SUO.

This morning, I attended the Urologic Oncology Research Symposium, “High impact science in urologic oncology and progress in biomedical imaging.”  In particular, I was keen to hear about the latest research in urothelial bladder cancer (UBC) with regards to checkpoint blockade with anti-PDL1 and PD-1 therapies.

In the past, any session on bladder cancer guaranteed the lucky (or hapless) presenters with an audience of a dozen or so people.  Not any more – the room was packed with standing room only very quickly – a nice change for a disease that has seen no new therapies for 30 years.

Part of this renewed enthusiasm is due to the excitement for the checkpoint therapies making a huge impact in this disease, at least in clinical trials to date. While waiting for the session to start, one urologist I spoke to told me he bought the ASCO Virtual Meeting last year just to hear Dr Tom Powles talk on anti-PDL1 therapy with MPDL3280A in advanced urothelial cancer. What did you think of it, I asked?

“Wow, just wow!”

Later this month an update on the more mature data from that phase I trial is due at the American Society of Clinical Oncology (ASCO) from Dr Daniel Petrylak (Yale)… who just happened to be one of the presenters at AUA this morning.

He discussed the checkpoint data with atezolizumab (MPDL3280A) in urothelial bladder cancer, as well as the pembrolizumab data from ESMO last fall and what’s happening with nivolumab. These drugs are quite different in many ways, not just in terms of the efficacy, but also in terms of the biomarker data, as we discovered today.

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ESMO 2014 Bladder CancerCancer immunotherapy, the ability to harness the body’s own immune system to fight cancer, is showing early promise in bladder cancer.

“Breathing new life into bladder cancer treatment” was the title of the excellent discussion by Maria De Dantis (Vienna) of data presented at the recent ESMO Congress in Madrid.

Advanced bladder cancer has a particularly poor prognosis. Once the cancer has spread in the body, according to Cancer Research UK, the average survival time is approximately a year to 18 months.

There is clearly an unmet medical need for effective new treatments, with no major treatment advances for over 30 years. To date, targeted agents in the second-line setting have shown only incremental progression free survival and generally low overall response rates.

Which is why it’s exciting to see hope for patients with urothelial bladder cancer from new inhibitors of the PD-1 immune checkpoint signalling pathway.

At ASCO this year, data for Roche/Genentech’s anti PD-L1 (MPDL3280A) was presented (Abstract 5011) by Thomas Powles (Barts, London). Commenting on the data, in her post “Making a difference in advanced bladder cancer” Sally noted, “it wouldn’t have been out of place in the Plenary session, frankly.”

Recognizing the potential based on the promise of the early clinical data, on May 31st the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) to MPDL3280A in bladder cancer.

ESMO 2014 Bladder Cancer Session ChairsIf you need to catch up on immuno-oncology, we have a growing library of posts on Biotech Strategy Blog, and we’ll be continuing our coverage of the rapid progress in this area at the forthcoming annual meeting of the Society for Immunotherapy of Cancer (SITC), which takes place at National Harbor, MD from Nov 6 -9.

At ESMO 2014, phase 1 clinical trial data in bladder cancer was presented for both Pembrolizumab (Merck) and MPDL3280A (Roche/Genentech).

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One of the most exciting presentations that I heard at ASCO 2014 – the sort that give you goosebumps and elicit a wow from people sitting next to you – was not in the plenary or even a tumour type oral session, but a clinical science symposium.

The subject? Bladder cancer.

The situation? Phase I clinical trial.

The therapy? Anti-PD-L1 therapy with MPDL3280A.

Prof Thomas Powles, Barts Cancer Institute, London

Prof Thomas Powles, Barts Cancer Institute, London

As the presenter, Prof Thomas Powles (Barts), dryly observed to the packed auditorium, it made a welcome change from the ten people who usually show up for bladder cancer sessions! After all, there have been no new approved therapies for this disease for some thirty years.

It wouldn’t have been out of place in the Plenary session, frankly.

By the time the ASCO selection committees cotton on to the fact what many of us know – that immuno-oncology is not only hot, but here to stay and actually changing the way we think about and treat some advanced cancers – some of these new checkpoint inhibitors will already be approved by the FDA.

As one thought leader grumpily said to me:

“It’s not something they understand, nor does it involve the traditional things like breast or prostate cancers, plus it’s all political anyway.”

Ouch. Still, there was a lot to learn from this data, not just in terms of the results in an area of high unmet medical need, but also in our understanding of the immune system and where some future opportunities lie.

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