Biotech Strategy Blog

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

Posts tagged ‘SCLC’

Time for some additional colour commentary!

There has been some incredibly intense interest surrounding TIGIT as a new therapeutic target in oncology of late, to the point where some observers have been wildly claiming this is the new universal checkpoint everyone has been waiting for.

But is it?

It’s early days yet with little data presented from people with cancer, so at this point it could well be a bit of a stretch to find another anti-PD–1/PD-L1 equivalent, but this doesn’t mean there isn’t utility in seeing clinical activity in some tumour types, far from it.

In our latest post, we take a look at what’s coming up in the TIGIT niche, along with an interview from a company active in this niche.

What do the company have to say and how do they see this panning out?

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In today’s post we answer some reader mailbag questions pertaining to targeting BET/bromodomain inhibitors and what we’ve learned since our original landscape review from early 2016 when they were an emerging new class in the oncology R&D space – how time flies!

Is it time-up for the bromodomain class?

Of course, as usually happens in the targeted therapy space we see a glut of pan inhibitors trying to block everything in sight to a greater or lesser degree… we’ve see this with BRAF, FGFR, PI3K, and even KRAS inhibitors, as well as numerous others, yet these rarely turn out to be the bees knees we’re secretly looking for. Bromodomains, I have long argued, were ripe to fall in this category as well.

Instead, it is better to patiently wait for the next generation molecules where they are much more selective in their actions and matched to the tumour target we are looking to hit.

Think about the BRAFV600E vs. pan BRAF inhibitors or KRASG12C/D vs. pan KRAS inhibitors, for example, or even FGFR2 or FGFR3 vs. pan FGFR inhibitors.

The same evolution may possibly happen in the BET/bromodomain space too.

The first generation of agents seemed to hit everything – BRD1, 2, 3, 4, and often BET as well. They suffered, however, with weak efficacy largely driven by challenges with the on-target, off-tumour effects that necessarily impact the therapeutic window.

Now we are starting to learn from a more focused approach with these agents. Four years on from our original landscape review, what’s hot and what’s not? Who’s in and who’s out? In terms of the magic roundabout of oncology R&D, are there any new gems we should eagerly be watching out for?

The short answer is yes… but what are they and who owns them?

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It’s time for a BSB subscribers Q&A!

We haven’t done a mailbag for a while as things have been pretty hectic, but the end of a week is often a good time to consider this.

Here we take another look at the dismal, if very slowly evolving, SCLC landscape… there are some disturbances in the force here as well as some good and bad news to ponder.

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One of the challenges of the short whirlwind period between AACR and ASCO is that many new research papers get published and largely missed or forgotten about in the data tsunami that drops as people eagerly (and almost exclusively) focus on the new abstracts that are available.

This is a real shame since there were many really good pieces of research that were rich in knowledge that were published around then.  My reading pile heading into AACR was much larger than usual, and after wading through it all, it built up rapidly again heading into ASCO, never mind over 20,000 abstracts to consider between those two meetings!

Contemplating new data…

With this in mind, it’s time for a new Journal Club post – these are surprisingly popular on BSB, although on reflection the selections have tended to highlight either new targets and areas of therapeutic potential or offer explanations for some of the phenomena that we are seeing.

New developments often (but not aways) allow us to step back and see results from clinical trials with greater clarity.

With this in mind, here are our latest selections for the BSB Journal Club, all of which should prove to be a useful read…

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Last October I posted two updates on small cell lung cancer (SCLC). One explored the broad SCLC landscape, while the second was a detailed analysis highlighting the red and green flags to watch out for in the Rova-T TRINITY study.

My sombre conclusion or prediction, if you will, was not particularly well received at that time:

“My sense is that the median PFS and OS in the allcomer ITT population will remain modest and in line with what we might expect from historical chemos in 3L SCLC.”

Dismal happenings are to be expected…

This morning AbbVie announced that they will not be filing for accelerated approval of Rova-T in 3L SCLC based on the interim analysis.  In other words my expectations for this trial were met, although there are many who will be very disappointed at the results.

What matters though is not just how disappointing topline results might be per se, but why they occurred, what we can do about it, and most importantly, where we go next.  There’s a lot more to this than might initially be obvious from the press release.

That’s what this new post is all about… first a post mortem, then the obstacles to be addressed, and finally, what we can look forward to in SCLC…

On a happier note: there may be some surprises ahead!

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Yesterday in part 1 (Link) of our latest mini-series, we looked at the SCLC landscape and some of the key background issues to think about.

This time around in part 2 we drill down focus more specifically on Rova-T, including physician and patient sentiments and in particular, what to watch out for with the upcoming phase 2 TRINITY readout.   There’s a lot to consider here so we’ve broken the analysis down to five key areas.

Mystic Meg is also back with her canny predictions – what does the crystal ball portend for Rova-T and the TRINITY trial?  Caveat: she’s been on a tear of late; this situation will not continue forever.

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Many of the questions we received from BSB readers this month was a plea from several folks to answer numerous queries about small cell lung cancer (SCLC) and the anti-DLL3 ADC, Rova-T, in particular.

Of course I’m happy to oblige, but this was way too big a topic for inclusion in Friday’s mailbag.

Cornish Tin Mine

What makes a lot more sense here is a short two-part mini series where we look at the dismal landscape of the disease and then consider the red and green flags that arise from the Rova-T development.

With the interim results expected from the phase 2 TRINITY trial in 2H17, this is a timely moment to sit down and reflect on what to expect.

In the first part of the series, we walk through SCLC as a disease, including what is known and what to consider when contemplating a new therapy here.

In the second part tomorrow we will focus more specifically on Rova-T and what to watch out for.

So let’s rock and roll with a look at the SCLC landscape…

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This week certainly turned out to be a defining tale of two drugs with a chequered history…

Lion DancersFirst off, the FDA approved AbbVie/Genentech’s venetoclax, now known as Venclexta, in a subset of CLL patients with 17p deletions. These patients have a historically poor prognosis and the approval goes some way to addressing the high unmet medical need.

Secondly, another biotech company, Clovis Oncology, got slammed by ODAC with a 12-1 vote to wait for phase 3 data from the TIGER-3 trial for rociletinib to better determine the efficacy:safety benefit profile.

For a long while it seemed that AbbVie had nothing but toil and trouble over the tumour lysis syndrome (TLS) issues giving them some significant challenges to overcome, while Clovis were one of the new darlings of Wall Street.

In the final dash to the market, the tables were turned almost at the 11th hour and fortunes stunningly reversed.  Yet a mere eighteen months ago, few industry watchers would have predicted the difference in outcomes.

In our latest AACR Preview series, we take a look at Bcl2 inhibition and where some of the emerging opportunities might lie based on new preclinical research that is being presented here in New Orleans this weekend.  It makes for interesting reading.

While one tiger is licking its wounds, another is smacking it chops at what the future might hold for new combination approaches; how the tails have literally turned.

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Over the last decade we have seen some real progress with some subsets of lung cancer, particularly in EGFR mutated and ALK translocated tumours.  Indeed, an incredible amount of translational work has emanated from just a few groups based in Boston, New York and Hong Kong.

Dr Jeff Engelman Source: MGH

Dr Jeff Engelman Source: MGH

At AACR earlier this year, Dr Jeffrey Engelman (MGH, Boston) gave a fantastic talk not just about heterogeneity, resistance mechanisms, but also on how lung cancer can transform. Included in his review was the role of biospies and how he sees those evolving.

I’ve been meaning to write up this important talk since April, but decided to wait until the key publications that were in press at the time were actually published – it was a longer wait than expected!

In general, it is our policy to write up published, rather than unpublished data, out of respect to researchers.  It also makes it more useful to readers when the translational and clinical data is publicly available for those interested in reading the in-depth research articles.  We also gathered commentary from other though leaders in the lung cancer space for some additional insights.

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Anyone who has been regularly to the American Society of Clinical Oncology (ASCO) over the last decade or two will have have sat through quite a lot of trials with doublets and triplets in numerous advanced solid tumours and seen an impressive graveyard of failed cytotoxics and targeted therapies build up… Too toxic, lack of efficacy, futile even. This is especially true for some of the more difficult to treat cancers such as pancreatic, small cell lung cancer, melanoma, glioblastoma and soft tissue sarcomas.

Chicago Riverwalk

ASCO 2015

There is hope though, after all, things have changed quite dramatically in the metastatic melanoma landscape over the last five years that it is now quite unrecognisable compared to a decade or even five years ago. This is very good news indeed.

What about the other tumour types in that list, though? How are we making progress with those?

In the latest series here on BSB, we’re going to focus on the new developments happening on the fringes of cancer research out of the main spotlight and look in more depth at what’s looking promising in some of these areas. Today, we’re going to start with small cell lung cancer (SCLC), a truly devastating disease with a horribly dismal prognosis.

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