Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Lapatinib boosts effects of apoptosis-inducing drugs in colorectal cancer

By on June 13, 2011

I’m a subscriber to Science Translational Medicine and one of the things I really like about it is finding little gems like this – shared by Science Magazine on Twitter:

Breast cancer drug lapatinib boosts effects of apoptosis-inducing drugs in colorectal cancer

On clicking the link, I was delighted to see it was from Dr Wafik El Deiry’s group at Penn State, Hersey – you can find him as @weldeiry on Twitter – he tweets interesting snippets from various cancer conferences that he attends, including ones in GI cancers.

Here’s the essence of the paper that caught my eye:

We found that lapatinib improved the proapoptotic effects of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab.

Tumors from mice treated with a combination of lapatinib and TRAIL exhibited more immunostaining for cleaved caspase-8, a marker of the extrinsic cell death pathway, than did tumors from mice treated with lapatinib or TRAIL alone.

Mapatumumab (HGS via Cambridge Antibody Technology) and lexatumumab (HGS) are both monoclonal antibodies that target the TRAIL receptor 1 to induce apoptosis (programmed cell death) as shown in the cartoon below:

Mapatumumab from Human Genome Sciences

Source: Human Genome Sciences

Put simply, death receptors (DR) are cell surface receptors that transmit apoptotic signals initiated by specific ligands such as Fas ligand, TNF alpha and TRAIL. They play an important role in apoptosis and can activate a caspase cascade within seconds of ligand binding. Induction of apoptosis via this mechanism is therefore very rapid.

To date, few of the DR or TRAIL inhibitors have lived up to their promise and lexatumumab also seems to have disappeared from HGS’s pipeline after being returned by GSK in 2008.  Interestingly, there were some data previously published at ASCO in 2007, showing activity in a phase Ib trial in solid tumours due to synergy with gemcitabine, pemetrexed, doxorubicin or FOLFIRI:

Severe adverse events considered at least possibly related to lexatumumab included anemia, fatigue and dehydration. Tumor shrinkage has been observed, including confirmed partial responses (PRs) in the FOLFIRI and doxorubicin arms.

It looks as though mapatumumab is the successor to lexatumumab.  Early studies with mapatumumab have been reported in a phase Ib trial in HCC and phase II in NSCLC although the latter did not support further development in that indication.

What does the current research show?

I was wondering what the possible underlying mechanism for the synergistic effect might be, given that lapatinib (Tykerb) is known to be a HER2/EGFR inhibitor.  It does seem that this main target is not involved here though:

Lapatinib up-regulated the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonists. This activity of lapatinib was independent of EGFR and HER2.

In other words, the effects are off-target and unrelated:

The off-target induction of DR5 by lapatinib resulted from activation of the c-Jun amino-terminal kinase (JNK)/c-Jun signaling axis.

Of course, another EGFR inhibitor, the monoclonal antibody cetuximab (Erbitux) has been shown to work in refractory colorectal cancer and is approved in EGFR+ mutated disease.  Lapatinib, as far as I know, has not shown any clinical activity in colon cancer to date, but is approved for treatment of refractory HER2+ breast cancer in combination with capecitabine.

Sometimes, it can take a while to figure out the logical combinations and tumour types though.  This new research shows that, at least preclinically, there may be value in combining mapatumumab with lapatinib in colorectal cancer:

This activity of lapatinib on TRAIL death receptor expression and signaling may confer therapeutic benefit when increased doses of lapatinib are used in combination with TRAIL receptor–activating agents.

Implications of this research

A quick check of current clinical trials with mapatumumab shows that there aren’t any ongoing in colorectal cancer, but this research may well offer a strong rationale for the novel combination with lapatinib to be considered.

Of course, there is some wry amusement that the original TRAIL inhibitor, lexatumumab, was returned by GSK and lapatinib is marketed by the same company.

References:

ResearchBlogging.orgDolloff, N., Mayes, P., Hart, L., Dicker, D., Humphreys, R., & El-Deiry, W. (2011). Off-Target Lapatinib Activity Sensitizes Colon Cancer Cells Through TRAIL Death Receptor Up-Regulation Science Translational Medicine, 3 (86), 86-86 DOI: 10.1126/scitranslmed.3001384

European Hematology Association meeting 2011

By on June 8, 2011

Well, after just getting back from the American Society of Clinical Oncology (ASCO) meeting in Chicago, I’m heading off to Europe for the European Hematology Association (EHA) meeting – no rest for the wicked!

ASCO was a rather flat meeting this year – the stars were undoubtedly the imatinib 36 vs 12 month data in adjuvant GIST (clearly superior) and Roche/Plexxikon/Daiichi Sankyo’s vemurafenib in BRAF V600E metastatic melanoma. The ipilimumab data was strangely disappointing in the upfront setting – only 2 months improvement in survival when added to DTIC.

On the Sarcoma front, the catch-all nature of the study came back to haunt Merck with an improvement in PFS but no overall survival benefit for ridaforolimus as maintenance therapy after 1-3 cycles of chemotherapy. That filing will likely result in a highly charged ODAC meeting debating the merits of some awkward results.

Ovarian cancer data was a mixed bag – olaparib continues to look promising in this setting, although the Avastin OCEANS data caught a few people by surprise – yet another PFS endpoint met but no overall benefit in survival and the expected incidence in bowel perforations. I think this will likely be reserved for high risk women, if used.

There was a lot of interesting/promising data in phase II, which are too numerous to mention right now – check back as I will be adding some notes on some of the emerging compounds that I liked.

Meanwhile, I’m aggregating the tweets from the hematology meeting using the #EHA11 hashtag – you can track them in the widget below if interested in following along remotely. Most of the tweets from me will likely be on leukemias, lymphomas and multiple myeloma.

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Continued aggregation of the ASCO 2011 tweets

By on June 4, 2011

This latest widget captures all the tweets and discussion about ASCO data including the week before the meeting – this year the tweets are going at a tremendous velocity, with a much wider variety of people joining in.

Check it out below:

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Aggregating the ASCO 2011 tweets

By on June 3, 2011

It’s that time of year again and boy, does the annual meeting of the American Society of Clinical Oncology (ASCO) come round all too quickly! It’s almost like Battime, Batplace…

As usual, I’ll be aggregating the conference tweets using the official #asco11 hashtag, so that all of you not going to the event can follow along remotely – do feel free to join in the conversation and ask questions or post comments using #asco11 on Twitter:

 

 

This widget will run for the duration of ASCO until close of play on Wednesday, so do check back regularly for new tweets and conversation!

Next Thursday, I’ll be at the European Hematology Association (EHA) meeting in London, so a new tweet aggregator will be added then.

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BMS and Roche join forces in metastatic melanoma

By on June 2, 2011

Two of the most dynamic cancer markets at the moment are prostate cancer and metastatic melanoma, which is great news considering that neither has had much attention over the last decade compared to breast and lung cancers.

My colleague has posted an overview of what’s going on in advanced prostate cancer today, which you may be interested in checking out pre-ASCO.  However, what excited me this morning were announcements from BMS and Roche declaring their intent to pursue combination trials in BRAF metastatic melanoma with their therapies ipilimumab (Yervoy) and vemurafenib (PLX4032).

This is really great news, and a very logical approach that is well worth evaluating.

I’m delighted to see the two companies seeking to work together on this to see if the combination can improve outcomes further than what we have seen for vemurafenib alone, which already showed impressive responses in poor prognosis patients.

How vemurafenib works in BRAF V600E metastatic melanoma

Vemurafenib has been shown to target the BRAF V600E mutation, as you can see in the graphic.

Ipilimumab is an immunotherapy that targets the CTLA-4 antigen and was approved by the FDA in March as a treatment option for newly diagnosed patients with metastatic melanoma.

A phase I/II trial is planned initially, which is a relatively low risk study – if the results look good we will hopefully see a larger scale phase III trial emerge.  If not, at least we will know a quick answer on the combination.

Meanwhile, these two drugs will be presented in the plenary session at ASCO this weekend comparing either to the current standard of care, dacarbazine (DTIC), in advanced newly diagnosed metastatic melanoma.

I’m really looking forward to writing more on those trials on Monday morning – so do check back then for an update of the phase III data!

 

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Making sense of clinical trial acronymania at ASCO 2011 meeting

By on June 1, 2011

On Sunday, I was delighted to receive an email from a regular Pharma Strategy Blog reader, Dr Al Lalani, a scientist who works at Regeneron.

Like many of us, Al waded through this year’s 5,000 or so abstracts for the upcoming annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago and noticed some interesting trends. He was particularly struck by the number of acronyms in use this year and put together a thoughtful and most amusing summary, which he has agreed to let me post here on PSB as today’s awesome guest post.

Clinical trial acronymania is alive and well at 2011 ASCO

Back in grad school, I recall being amused by the quirky names anointed to freshly cloned Drosophila genes like hedgehog, cactus and lava lamp. Fast-forward fifteen years and now I’m equally tickled about the curious acronyms given to late stage clinical trials.

A quick scan at this year’s ASCO abstracts and you’ll know what I mean.

There’s the MIMOSA trial and the FOxTROT, both of which deserve 10 points for ingenuity since neither study evokes images of Sunday brunch cocktails or ballroom dancing, in my opinion. Then comes the bevy of Avastin studies like AVAGAST, AVANT, AVAglio, AVAPERL, and BEVLiN.  Pure Roche branding genius.

Several gentler, feminine names including MARIANNE, EMILIA and SOFIA appear expectedly for trials in women with breast cancer.

If this is starting to sound a wee bit poetic, well you may want to consider checking out the updates from both POETIC and PROSE in this year’s Trials in Progress Session.

There are also the lofty and inspirational sounding studies like PYRAMID, TRIUMPH and RADIANT-3, or the self-assured ones such as RESILIENCE, PARAMOUNT, EXPERT-C and PREDICT.

Can’t decide on which orientation? Try either the LANDSCAPE or PANORAMA studies.

Feeling like it’s almost beach weather? How about the OCEANS, CALYPSO or TROPIC trials? The SORBET study may help to cleanse the palette after all this nonsensical acronymania.

And finally, leave it to the Spaniards to name an adjuvant lung cancer trial, SCAT.

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What's hot at ASCO 2011?

By on May 31, 2011

This weekend I’m heading off to Chicago for the annual meeting of the American Society of Clinical Oncology (ASCO).  I’ll be writing some in depth pieces and daily highlights from the conference, but in the meantime, many of you will be wondering what might be interesting amongst the 5,000 or so abstracts.

Here’s a quick snapshot of some data I’m looking forward to catching up on – there’s no clapperboard or guy with a teleprompter behind the camera, just a few ideas and some things to watch out for:

http://youtu.be/TNwQvV4aYl8

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Some inspirational reading for the Memorial weekend

By on May 27, 2011

Memorial Day weekend is traditionally the last weekend before the annual American Society of Clinical Oncology (ASCO) meeting and we will be busy working as usual as part of the last preparations for the event.

Today, I’d to share some interesting blogs that you may not have come across to broaden your reading:

  1. Jody Schoger, a breast cancer survivor wrote a superb post about ‘Anchored activism’ in Oncology Times. She will be writing a regular blog there later this year, she’s a thoughtful and provocative read.
  2. David Sampson, is the Director for Medical & Scientific Communications at the ACS.  He wrote an absolutely fabulous post ‘A Call to Honesty’ explaining why Jody’s thoughts were highly welcomed.
  3. Rich Meyer of World of DTC Marketing posted his weekly round up opinion piece that draws attention to the end of life issues being discussed in Oregon. Now, I don’t always agree with Rich’s opinions, but on this one we both agree we would rather end our lives than suffer chronic unbearable pain from advanced cancer. The story reminded me that I really should think about having a legal document with my own wishes in it.
  4. Dr Matthew Mintz recently wrote a nice overview on the spiralling costs of health care.  This is particularly relevant in cancer, where new high priced treatments offering a few extra months of life seem sadly to be de rigeur these days.

Last, but by no means least, since it is a Holiday weekend – for all of you with iPads do check out what fun you can have with them – not recommended during conference sessions during the odd boring talk ;).  Hat Tip to one of my favourite non medical/pharma/biotech bloggers, Chris Penn, for this one:

Hope you all have a wonderful weekend and see you all on Tuesday after the break!

Crossing the blood brain barrier with drug development

By on May 26, 2011

The beauty of social media is that sometimes someone shares something monumental before you even pick it up yourself in a journal you’re subscribed to. I love that – it’s a great way to see how others find things with what I call ‘interestingness’.  This morning, John Carroll of Fierce Biotech tweeted something that gave me goosebumps.

What was hot this morning you may all be wondering?

Crossing the blood-brain barrier (BBB)?

Wow, now that is something that really grabs my attention!  Normally, when you try to target drugs to the brain, you find that the endothelium acts as an impenetrable and largely impervious layer that forces you to keep adding more and more drug in an effort to get a small amount through.  This approach obviously increases side effects and the reality is so little drug actually gets through that efficacy is severely limited.

It also explains why we haven’t made much progress with brain related diseases such as Alzheimer’s, Parkinson’s and Glioblastoma (a malignant brain cancer).

We’ve talked a bit about nanotechnology on this blog and it’s companion, Biotech Strategy Blog, as a way to make things small enough to potentially cross the BBB, but I was keen to see what this was all about.  Enthusiastically, I checked out the original article in Science and Translational Medicine myself (see references below).  The editorial commentary associated with it began:

“As impenetrable as the walls of ancient Troy, the tight endothelial cell layer of the blood-brain barrier (BBB) allows only a few select molecules to enter the brain. Unfortunately, this highly effective fortress blocks passage of therapeutic antibodies, limiting their usefulness for treating diseases of the brain and central nervous system.”

Oof, a tad dramatic perhaps, but what did the Genentech scientists do that was different?

Well, the research team were looking at using a BACE-1 antibody to block the enzyme involved in amyloid production, but the BBB prevented little drug from getting through, despite higher doses.

The engineers then developed a new antibody to take advantage of the fact that cells need iron by creating an antibody with two arms:

  • One arm held anti-BACE1 drug
  • The other arm hosted a receptor called transferrin that carries iron to brain cells, providing a ferry across the barrier

In other words, they made use of the body’s natural transport system in much the same way the Trojan horse carried men.  Perhaps the analogy wasn’t so dramatic after all…

This novel approach allowed the scientists to use lower concentrations of the new drug to get the active therapy through.  This should limit side effects and hopefully, increase efficacy.  According to the authors:

“BACE1 can be targeted in a highly selective manner through passive immunization with anti-BACE1, providing a potential approach for treating Alzheimer’s disease. Nevertheless, therapeutic success with anti-BACE1 will depend on improving antibody uptake into the brain.”

Note my emphasis… I can just see the anti-immunisation crowd up in arms before we even get started on this.

Implications of this research

The obvious potential benefits from this novel approach are in Alzheimer’s Disease research, although I caution that we still need to see results from human trials.

However, what piques my interest is how the technological approach of the iron receptor could be used for other brain diseases such as Parkinson’s Disease and brain tumours such as glioblastoma (GBM), which is a nasty malignant cancer limited by how much drug we can get inside the tumour cells. It crossed my mind that it might not take long for Genentech scientists and engineers to use the iron transport concept to bolt together a new monoclonal antibody combining the transferrin receptor and bevacizumab (Avastin), which is already approved as a treatment for GBM. Who knows how that might pan out, but the idea is very appealing indeed.

It is the development and spreading of novel and creative ideas like these that really excites me as a scientist and reminds me what I loved about it as kid.

Crazy Deranged Fools

This idea is so creative, so simple, so brilliant that I’m giving the Genentech scientists my Crazy Deranged Fool (CDF) award of the month for having the temerity to try something so boldly different – check out Hugh’s cartoon at Gaping Void to find out what that is!

References:

ResearchBlogging.orgAtwal, J., Chen, Y., Chiu, C., Mortensen, D., Meilandt, W., Liu, Y., Heise, C., Hoyte, K., Luk, W., Lu, Y., Peng, K., Wu, P., Rouge, L., Zhang, Y., Lazarus, R., Scearce-Levie, K., Wang, W., Wu, Y., Tessier-Lavigne, M., & Watts, R. (2011). A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-  Production in Vivo Science Translational Medicine, 3 (84), 84-84 DOI: 10.1126/scitranslmed.3002254

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Antibody Drug Conjugates (ADCs) in cancer research: what are they?

By on May 25, 2011

Quite a few questions have hit my inbox recently from people wanting to know more about Antibody Drug Conjugates (ADCs) and how they work.

They basically consist of three things:

  1. Monoclonal antibody
  2. Linker
  3. Cytotoxic agent

Antibody Drug Conjugate (ADC)

Source: Roche

The goal is to create a new molecule that essentially is greater than the sum of its parts by making it more targeted, like a guided missile against the cancer cells.

With normal monoclonal antibodies, they bind to atarget antigen that is a tumor-specific antigen on the surface of a tumour cell. With an ADC, the monoclonal antibody part of the molecule still latches onto the target antigen in the same way, but in this case it now has a powerful cytotoxic attached to potentiate the effect.

As Emeril would say, “Bam!”

You can see a video of how the ADC technology works HERE.

Unfortunately, the site only allows you to watch it there or download the video; it’s not easily sharable with others, short of emailing it.  Sadly, I couldn’t embed it here on the blog post for easy consumption either.

A nicer way would have been to put the educational videos on a company YouTube channel and allow it to be shared through social media via Facebook, Twitter etc. Imagine clicking on a link in Twitter and being taken to YouTube on your iPad, iPhone or Android smartphone?  Or watching an embedded video on someone’s blog post?

That’s a much more fun and immediate way to communicate ideas and technology from a medical or scientific learning perspective than a old fashioned static website.

It is good to see Pharma and Biotech companies active on social media, but they have a long way to go yet in terms of how they can help improve learning about the science behind new cancer research and development in an integrated way that helps the end users, ie the scientists, healthcare professionals, patients in clinical trials and analysts who might be interested.

We really do need to get away from the old web 1.0 world into the 21st century of sharing ideas, tools and medical or scientific information using social media in the web 2.0 era.

That said, there are some advanced ADC’s in clinical development at the moment.  The three leading compounds I’ve come across so far are:

  • Brentuximab vedotin (Seattle Genetics) in Hodgkin Lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL) targets CD30 and now has a brand name, Adcetris.
  • T-DM1 (Roche/Genentech) in HER2+ breast cancer
  • SGN-75 (Seattle Genetics) in RCC and NHL

Overall though, Roche/Genentech probably have the largest active research in this area, with a large portfolio of agents in development across a multitude of different tumour types.  You can check out this full ADC pipeline here.

Seattle Genetics have a couple of abstracts on their ADCs at ASCO this year and Roche have an abstract on the phase III EMILIA trial comparing T-DM1 with lapatinib plus capecitabine in metastatic breast cancer, all on Monday 6th that I hope to check out, that is if the sessions don’t clash!

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