Biotech Strategy Blog

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

Posts tagged ‘pembrolizumab’

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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The abstracts (apart from the late-breakers) for the 2016 annual meeting of the American Society of Hematology (Twitter #ASH16) went live at 9am ET today. Link to 2016 ASH Abstracts.

ASH16 takes place in San Diego from December 3-6.

View of San Diego from ASH 2011In this initial post, I’m sharing my first impressions of what may be some hotly contested trials at ASH16 in San Diego, as well as a few intriguing abstracts with combination data that caught my attention.

With over 3,000 oral and poster presentations, all typically of a high quality, this by post by definition, is a highly subjective one.

After we’ve had more time to process the data, further ASH16 Previews will roll out over the next few weeks highlighting more key abstracts to watch out for by tumour type or treatment modality.

In-depth commentary and analysis will follow after we’ve heard or seen the data presented at the meeting.

I’ll be flying to ASH from the EORTC-NCI-AACR Molecular Targets meeting. Do say “hello” if you have plans to be in Munich or San Diego.

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One of our popular series from conferences is Gems from the Poster Halls, where we take a look at some of the studies or research data that caught our attention and explain how they may have future significance. In the past, posters have lead to phase 2 or 3 trial designs and subsequent approval. Others have sadly missed signals in small studies that could have prevented an expensive phase 3 faiure. Hence, it is often important to pay attention to posters.

esmo16-poster-hall

The ESMO16 Poster Hall Maze

Posters can also give early warning for what’s developing in pipelines. The BTK inhibitor, ibrutinib, was originally codenamed CRA–032765 (at Celera) and later PCI–32765 (at Pharmacyclics), for example, while the PI3K-delta inhibitor, idelalisib started life as CAL–101 (at Calistoga). We previously followed the progress of these compounds while they were in preclinical and phase 1 and documented progress long before they became active drugs in a race to market in CLL.

My favourite codename is always going to be STI–571 (imatinib). We would start planning ASCO and ASH activities every January and September, so companies should be well in hand in their preparations for ASH and SABCS by now. There’s a tremendous amount of work involved behind the scenes in order to have a great event, and I’m not talking about the fripperies like exhibits and light boxes here.

Last year at ECCO, StemCentRx burst on the scene and were subsequently acquired at a significant premium by AbbVie, taking quite a few people by surprise.

So what can we learn about the data from ESMO this year? What new trends are emerging this time around?

Here, we take a fresh look at FOUR interesting new developments from small and large pharma/biotech companies alike in Part 2 of the Gems series. In the first one [Link], we interviewed an expert and discussed their approach to biomarkers in early small studies to help them better design larger follow-on trials more effectively.

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esmo-poster-hallThis post started out as a look a one of the Gems from the Poster Halls at ESMO, including an interview with a thought leader in biomarkers, then morphed into a broader Op Ed that includes a strategic analysis of where we are, where we are going, and how we could get there more effectively and efficiently.

It’s time to turn tables to start challenging the status quo and slow pace of development if we really want to make a difference in advanced ovarian cancer.  I was recently challenged by a well respected GYN oncologist to delineate how we could do things differently so here are some ideas, along with the scientific rationale in my response to his gauntlet.

Is the ideal situation one where multiple companies randomly throw mud at the wall hoping something sticks the best approach? Or are there more effective ways to make a difference?

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Yesterday saw the FDA approval of atezolizumab (Tecentriq) for the second-line treatment of metastatic non-small cell lung cancer (NSCLC) (link to company press release).  According to Genentech:

“This approval is based on results from the randomized Phase III OAK and Phase II POPLAR studies. The largest study, OAK, showed that TECENTRIQ helped people in the overall study population live a median of 13.8 months, 4.2 months longer than those treated with docetaxel chemotherapy (median overall survival [OS]: 13.8 vs. 9.6 months; HR = 0.74, 95% CI: 0.63, 0.87). The study enrolled people regardless of their PD-L1 status and included both squamous and non-squamous disease types.”

The FDA approval is largely a broad one in 2L and 3L across PD-L1 expression and histologies [Link]:

“TECENTRIQ is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving TECENTRIQ.”

The approval was widely expected in light of the Phase III OAK trial data presented in the Presidential Symposium at ESMO16 meeting in Copenhagen.

Sign adjacent to #ESMO16 in Copenhagen

Sign adjacent to #ESMO16 in Copenhagen

Imagine hearing live about positive first-line data with pembrolizumab, with and without chemotherapy, negative data from nivolumab in the same setting, the 2L data for atezolizumab and two discussants drilling into both the data and broader impact of these studies to a jam packed audience that even included thought leaders from other tumour types who were also eager to hear the news. To say the atmosphere was electric would be a rather British understatement here.

We previously covered our initial impressions from that session [Link], but we also had the pleasure and privilege of interviewing a leading US thought leader in the lung cancer space after the session to garner his impressions of the data and also some perspectives on the key issues that the field is facing.

The pembro plus chemo data is already providing some controversy amongst various protagonists given there are a number of similar combination trials expected to read out over the next year to 18 months, plus much anticipation from analysts regarding the ditching of chemo for IO combos such as anti-PD–1 plus anti-CTLA–4 (BMS and AstraZeneca have keen stakes here), but what do thought leaders really think of that concept? Is that the slam dunk that many analysts seem to think it is?

This, my friends, is where things start to get a lot more complicated, akin to 3D chess in Star Trek.

What is happening now in advanced NSCLC is not how the market will look in a year or two. In many ways, the rate of approvals are outstripping the pace of science right now, but once the low hanging fruit is gone, competition will need to evolve in much more sophisticated and elegant levels.

With these questions in mind, we have a double header for you today – you can read on to find out more details from our latest though leader interview, supported by some insightful perspectives from a medical oncologist who treats lung cancer patients in private practice. Today’s post therefore covers some wide ranging discussions across the key issues in advanced NSCLC and it’s future direction.

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Please note that subscription prices will increase on Monday 24th, so if you’ve been on the fence about our upcoming coverage of #SITC2016, #ENA2016 (EORTC/NCI/AACR Mol Targets), #ASH16, #SABCS16 and #JPM17 then now is a good time to lock in at the current rates!

The 2016 Congress of the European Society for Medical Oncology (ESMO) is fast approaching. It takes place next month from October 7th to 11th and we will be on site covering the meeting for Biotech Strategy Blog. We’re looking forward to a great meeting!

ESMO 2016 CongressIf you are sitting on the fence as to whether you should go to Copenhagen, then hopefully our series of Previews will help you decide.

Be warned that accommodation is in already in short supply and ESMO are now putting people up across the Oresund bridge in Malmo, Sweden.

The Congress App has a lot of useful information and is well worth downloading, if you haven’t done so already.

Last week many of the late breaking abstract (LBA) titles were announced, although there are still some placeholders. While we won’t know the actual late-breaking data until the meeting, the LBA titles offer insights into what will be presented in Copenhagen.

In the second in our ESMO 2016 Preview series, we’re highlighting the lung cancer late breakers that we’re looking forward to hearing, providing some background on why they may be of interest, and a look at how some of subset landscapes may be a-changing in the future.

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BioTwitter is all a-flutter today with the announcement from BMS that the CheckMate–026 trial in first line non-small cell lung cancer (NSCLC) comparing nivolumab (Opdivo) to chemotherapy did NOT meet its primary endpoint of progression-free survival (PFS).

The news was not entirely a surprise to us at BSB, here’s why…

Figurative statute representing Science on Holborn Viaduct in City of London.

Figurative statute representing Science on Holborn Viaduct in City of London.

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The Shard from River ThamesMuch has been written about the impact of cancer immunotherapies, particularly the twin pillars of checkpoint blockade and CAR T cell therapies, but beyond that lies a huge wealth of alternative approaches that may come in very useful indeed.

Just as we have seen oncogenic escape witth targeted therapies, there is also a related phenomenon called immune escape. Likewise, this can occur as either primary or secondary resistance.

It’s very important to consider this issue, because, after all, the vast majority of cancer patients with solid tumours do NOT see durable clinical benefit with immunotherapies when given as single agents. Some don’t respond at all (primary resistance), while others may see an initial response, then relapse (secondary resistance).

Understanding the mechanisms involved in resistance may help us design better combination trials to address the underlying biology as well as develop biomarkers to help select appropriate patients for each regimen. Clearly resistance can vary, not only by tumour type, but also by lesion and patient, making it a very complex situation to research.

Some interesting new information has recently come to light that is worthy of futher discussion and analysis, particularly in the context of other published data in this niche.

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It’s been very clear for over four years now that combinations were going to be necessary if we want to a larger number of deeper and more durable responses than can attained with monotherapy.  Gradually, we are starting to see early and very preliminary readouts with some of the trials in progress.

We are also learning very quickly that it’s going to be a case of #notalltumours and #notallsubsets.

ASCO 2016 Posters 2

Another very busy poster session at #ASCO16!

By this, I mean we obviously can’t take a one-combination-fits-all approach for all tumour types.

We need to be able to classify patients into more homogenous subsets and then devise different combinations or even sequences that address the underlying biology of both the cancer itself and also the tumour microenvironment.  That’s going to take a while to sort out, perhaps even years.

Let’s not forget though that in the meantime, we can gather information quite a few clues both preclinically, as well as from initial clinical studies.  Sometimes, after all, we even learn more from negative trials than positive ones. This is an area that is ripe for combinations with traditional targeted therapies, the question is which ones are promising and why?

We took a look at the landscape in SCCH&N and how this might evolve over time in the medium term, with future opportunities, that can be explored in rational combination approaches.

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Tesaro’s niraparib is a highly selective poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor that can induce synthetic lethality in tumor cells with homologous recombination DNA repair deficiencies (HRD), including germline BRCA-mutated tumours.  It received a lot of attention yesterday following the company’s announcement that the phase 3 trial successfully met its primary endpoint.  The trial was expected to readout this month, so it was bang on schedule.

ASCO 2016 Posters 5

Braving the scrum in the ASCO 2016 poster hall

The results generated a lot of discussion and also a bunch (half a dozen!) of questions from readers, since there was a lot noise around the top-line data in the press release, but very little real analysis or context.

I was planning on rolling out the draft posts we have been working on Gems from the Poster Halls, which included one focused on ovarian cancer.  It therefore makes sense to combine the poster analysis with a reader Q&A on ovarian cancer, including a detailed look at Tesaro’s niraparib as there are some important subtleties that many have missed.

Inevitably this ended up as a rather meaty analysis rather than the quick review I originally intended!

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