Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘News’ category

A lot of people have asked me over the last year how I keep up with so much information in cancer research.  I thought it would be a nice idea to illustrate one way I consume information on a daily basis.

Since getting an iPad2, my life has changed for the better.  There are a number of really useful apps that let you browse information in a more user-friendly way.  Four of these include:

  1. Flipboard
  2. Zite
  3. Reeder
  4. Feedly

After trying them all over time, I found that for me, the one that resonated most for me was Flipboard.

What you get starts out like this:

Oh dear, that wasn’t welcome news this morning, bearing in mind I’m flying to ASCO in Chicago and then to London for the European Hematology Association meeting back to back in a few weeks.  The return of #ashcloud tweets on Twitter looks imminent!

Here’s how Flipboard works…

  1. Select your Twitter lists
  2. Other people’s curated Twitter lists you follow
  3. RSS feeds for blogs, journals, pubmed searches, etc

And the inside of the magazine becomes organised into recognisable categories:

You can then flip through the categories and see what’s interesting to you for further reading.  It also enables you to see broad trends much more easily.

Here’s an example from my journal and Pubmed feeds, since I have searches for all the key pathways that are associated with cancer.  Some are more active than others, but over time, you get a mix of new articles whenever you browse them.

This is much easier to browse than reading lists and lists of things in Google Reader – Flipboard brings them life:

Now you can sort the chaff from the wheat – we know that the BRAF V600E mutation is important in melanoma, but not colon cancer for example, but I sure didn’t know it might have a role to play in thyroid cancer!

Reading the abstracts this way is much more impactful and user-friendly.

Another thing that is useful is browsing one’s Twitter lists on topics such as Cancer, Medicine etc.  In the latter, I spotted an interesting tweet about how an app could be used to record your ECG on an iPhone – how cool is that?


You can see the play button for the video on the iPad (it obviously won’t work on the photo though, in case you just clicked on it ;)) – you just click and listen while travelling or sitting in the comfort of your office.

The way technology has evolved over the last couple of years is simply amazing, but best of all, it makes processing information you have selected as relevant to your personal interests much more user-friendly and digestible.

That’s a big win for busy people on the go!

What apps do you like?  Do share them in the comments below.

 

 

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It’s the end of a long week and today I thought it would be nice to highlight some people who write about cancer in the blogosphere since some people have emailed asking me what blogs do I read.

Here are a few cancer news sources I enjoy each week – some are writers, some survivors, some physicians, some analysts and not all have blogs, but some use other social media tools creatively to aggregate useful cancer information.

I heartily suggest you check them all out – their linked names take you to their Twitter stream and the other link to their blog or social media resource:

  1. Jody Schoger: Women with Cancer
  2. Alicia Stales: Awesome Cancer Survivor Blog
  3. Dr. Jack West: GRACE – expert mediated discussions on cancer esp. lung cancer
  4. Matthew Herper: Forbes Health
  5. Adam Feuerstein: The Street
  6. Dr. Len Lichtenfeld (ACS): Dr Len’s Blog
  7. Dr. Elaine Schattner: Medical Lessons blog
  8. Dr. Anas Younes: Curates an awesome Facebook page with regular cancer news
  9. Dr. Wafik El Diery: Has a superb cancer daily on Paper.li that I read each morning on my Flipboard
  10. Dr. Ray DuBois and Dr Naoto Ueno from MD Anderson and Dr Robert Miller from Johns Hopkins also share lots of interesting cancer news in their Twitter streams

There are many others, but I’ll stop there for this week and add a few more in the next update.

Disclosure: I am an unpaid member of the GRACE board.

Who do you enjoy reading and why?  If you have any other suggestions, please do include them in the comments below.

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I was delighted to see, amongst all the big news this morning on President Obama and Osama Bin Laden, that there was a little gem for Biotech – Seattle Genetics announced that the FDA have accepted their BLA filings for antibody drug conjugate (ADC), brentuximab vedotin, and awarded Priority status.  The company stated that the Prescription Drug User Fee Act (PDUFA) date is now set for August 30th, based on the Feb 28th filing date.

Two BLA filings were submitted, one for relapsed Hodgkin Lymphoma (HL) and another for relapsed or refractory systemic anaplastic large cell lymphoma (ALCL).  These two hematologic cancers share a commonality, ie CD30, which is the defining marker of the disease and the target for the ADC therapy.

Based on the data we saw at the recent American Society of Hematology meeting in December, the recent NEJM publication, this is very good news indeed for patients.

New treatment options in rare or difficult to treat diseases are always most welcome. With the American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) meetings both coming up in June, I’m really looking forward to an update of the data and to see how this exciting new concept (antibody drug conjugates) are progressing.

This is an area where I think we will see many more developments in the very near future, with Genentech’s T-DM1 also likely to have data at ASCO in breast cancer.

Abiraterone (Zytiga)This afternoon the FDA approved Ortho Biotech’s abiraterone acetate (Zytiga) in combination with prednisone for the treatment of castrate resistant prostate cancer in patients who have received prior chemotherapy with docetaxel.

Abiraterone was filed on December 20th, 2010 and received fast track designation, so the FDA approval comes 2 months ahead of the expected PDUFA date of June 20th.

It represents another exciting advance for this disease after what Dr Bernard Tombal described as a “Grand Cru” year for prostate cancer in 2010 following the successive launches of cabazitaxel (Jevtana), sipuleucel-T (Provenge) and denosumab (Xgeva), the first since docetaxel (Taxotere) was approved back in 2006 for chemotherapy naive metastatic disease.

I’ve written much about the clinical data from various oncology meetings over the last nine months such as ESMO last September and EAU in Vienna last month.  You can check out the data in the related posts below.

The big question on everyone’s mind, though, has been price.  Docetaxel is now generically available, Sanofi-Aventis’s cabazitaxel is around $6K per cycle (assumes ~$48K if 6 cycles are completed), Dendreon’s sipuleucel-T is $93K for three infusions.

Ruth Coxeter of CNBC Health Sciences was the first to tweet the confirmed abiraterone price of $5K per month, with a median of eight months of therapy.  This gives a treatment price of  ~$40K, which I think is very fair, although some patients will obviously take it for longer than that.

Ruth Coxeter, CNBC Pharma's Market

For those interested in the press release, you can read more here.

What does this approval mean?

abiraterone acetate (Zytiga)

For men with castrate resistant prostate cancer (CRPC) who have previously received chemotherapy, there is now a new treatment option for them to choose other than more chemotherapy with cabazitaxel in the form of easy to take pills (four per day).

The data from the 302 trial in the pre-chemo setting is expected later this year and is expected to be better than the 3.9 months overall survival benefit seen in the post chemotherapy setting reported at EAU last month.

In the analysis for the FDA approval, the overall survival benefit had increased further according to Ortho Biotech:

“In an updated analysis, results were consistent with those from the interim analysis with a 4.6 month difference between the two arms in median survival (15.8 months vs. 11.2 months [HR = 0.74]).”

At the European Association of Urology meeting earlier this year, Dr Johann De Bono (Royal Marsden) told a packed audience that the data for the circulating tumour cells (CTCs) would finally be available at the ASCO annual meeting in June.  It will be interesting to see whether this is a better surrogate measure of response than PSA. With the American Urology Association meeting coming up in a few weeks in DC, not doubt there will be more to discuss then.

All in all, it is good to see new treatment options emerge for the treatment of castrate resistant prostate cancer.

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Hormone replacement therapy (HRT) is one of those subjects where many have a strong opinion either way and I suspect even if we have another dozen trials evaluating at the pros and cons, those opinions won’t change very much.

That said, the latest large randomised, double blind, placebo controlled study from the Women’s Health Initiative (WHI) in postmenopausal women with a prior hysterectomy (n=10,739) taking conjugated equine estrogens (CEE) such as Premarin has just reported their health outcomes analysis.

The original goal of the trial was to examine health outcomes after a mean of 10.7 years of follow-up.  The study was stopped, however, after a mean of 7.1 years of follow-up because there was an increased risk of stroke. LaCroix et al., (2011) provided some context:

“The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.”

The baseline characteristics looked well balanced between the two arms, so I took a quick look at the hazard ratio plots to see which factors favoured placebo and noted not only stroke, but also deep vein vein thrombosis (DVT) and pulmonary embolism.  It was easy to see why the trial was stopped early based on those results, especially as there were no significant differences in statin or aspirin use between the two groups.

Interestingly, looking at the topline hazard ratios on the cancer side, invasive breast cancer was lower on the treatment side, but colorectal cancer was more favourable in the placebo arm.  Previous trials have shown an increase in treatment related breast cancers. Part of this reason may lie in the type of hormone treatments given (estrogens only versus combination therapy) and variations in the patient groups.  Of course, the news media instantly picked up on the cancer issue rather than the cardiovascular effects.

Things started to get interesting, however, as I noticed that in the abstract, LaCroix et al., (2011) clearly stated:

“Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.  A decreased risk of breast cancer persisted.”

Eh?  That’s not what you see in the hazard ratio plots, so I went back to re-read the paper and discussion in more detail.

The differences can be explained in the long term follow-up after treatment:

“Among postmenopausal women with prior hysterectomy who stopped taking CEE after a median of 5.9 years of use, several patterns of health risks and benefits seen during the intervention period were not maintained during the postintervention period, while other trends persisted.”

In other words, you often lose an effect post treatment, which can be a good or bad thing depending upon the parameter itself.

With the stroke and cardiovascular events seen in the intervention period on treatment, for example, in the post intervention period those effects “rapidly dissipated” during the postintervention period.

No doubt we will see future subgroup analyses emerge from this trial, it would be interesting to see, for example, whether mammogram screening was higher in either group and whether that impacted the findings or not.  Certainly that has been suggested in the past as one reason for the higher incidence of breast cancer in HRT users in other studies – in other words if you got looking for it more often you may well find it.

That said, the HRT story is likely to run and run as will emotions and opinions.

For some different perspectives, I can highly recommend checking out blog posts on the subject from Medical Lessons for a physician’s take and Flash Free for a science writer’s thoughts.  There was also an insightful commentary (open access) in Cancer Prevention Research from Craig Jordan and Leslie Ford (see references), who noted:

“Administration of estrogen replacement therapy (ERT) to hysterectomized postmenopausal women decreases the incidences of breast cancer.  Though paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances.”

Personally?  I wouldn’t take it and I’m too young anyway, but I would like to see more granular research on which subpopulations are most likely to benefit, something that is not really that clear even now.  I’ll leave you with a striking insight from Jordan and Ford:

“The important issue for the decision of breast cancer cells to survive or die in response to estradiol depends entirely on the cell populations present in an estrogenized environment or following estrogen deprivation.”

Maybe we need more cowbell.

References:

This post was chosen as an Editor's Selection for ResearchBlogging.orgLaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J, & WHI Investigators (2011). Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA : the journal of the American Medical Association, 305 (13), 1305-14 PMID: 21467283

Jungheim ES, & Colditz GA (2011). Short-term use of unopposed estrogen: a balance of inferred risks and benefits. JAMA : the journal of the American Medical Association, 305 (13), 1354-5 PMID: 21467291

Jordan, V., & Ford, L. (2011). Paradoxical Clinical Effect of Estrogen on Breast Cancer Risk: A “New” Biology of Estrogen-Induced Apoptosis Cancer Prevention Research DOI: 10.1158/1940-6207.CAPR-11-0185

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This weekend I’m at the annual meeting of the European Association of Urology (EAU), which takes place here in Vienna, Austria.  It promises to be an interesting meeting, with new developments in the areas of bladder/urothelial, prostate and renal cancers being discussed.

For those of you interested in following remotely, here are the links to the scientific programme and the podcasts.  You can also browse the abstracts online.

According to the EAU:

“For the 2011 edition, more than 3,700 abstracts were submitted and reviewed by the EAU Scientific Congress Office. As a result, 1,111 abstracts and 50 video abstracts were accepted, and will be presented at 92 poster sessions and 8 video sessions.”

While not as big as it’s American cousin, the AUA, that’s still an impressive number of abstracts submitted for the meeting.  They have an active presence on Twitter, you follow them via @uroweb.

I’m going to try and aggregate my thoughts and tweets from the sessions, depending upon the availability of wifi access.  Most of the sessions I’m interested in will be from Saturday to Monday.  Unfortunately, my iPad didn’t arrive in time so the iPhone and wifi will sadly have to suffice, although coverage may be spotty with thousands of people also trying to access the network.

Check back over the weekend for any live tweeting for the hashtag #EAU11 (#EAU is unfortunately used for other things, including water tweets), but you can follow the #EAU11 coverage in the widget below:

If any one has any questions or observations, please do add them in the comments below.

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Ohayo gozaimasu!  Like many people this weekend, I have been following the twin earthquake and tsunami disaster in Northern Japan with a great sense of sadness after hearing that thousnads of people have died.  If you haven’t already seen it, pictures of Japan before and after the tsunami devastation are an astonishing testament to the power of nature.  Coming so soon after the harrowing pictures of the massacres in Libya, it certainly feels like a violent world at the moment.

It is interesting to follow the news on Twitter in real time, generally much more useful (bar some hype and silliness from some people) than CNN and other News outlets who struggled to get to grips with timely information.  I was, however, disheartened to see that the engineers at Fukushima had no choice but to resort to venting the gases and also pumping in borax and sea water into the reactor chamber.  They needed to do this to try and cool the reactors down, reducing pressure, thus try to prevent explosions (and noxious radioactivity escaping into the atmosphere) or even worse, a core meltdown.

One source of accurate information was the Nuclear Energy Institute, who provided regular, factual updates on their website and pictures to explain what was going on with the Fukushima Boiling Water Reactors or BWR in short (you can see where the NY Times and others got their pictures from, for example):

Source: Nuclear Energy Institute

Social Media is useful for collating information from local people in Japan, such as this brief but alarming video from Fukushima courtesy of Japanese tv of one of the explosions at the nuclear plant:

There was some great commentary on Twitter from nuclear professionals such as Arclight, who spent most of his weekend monitoring the situation and answering anxious people’s questions about what was going on.  In times like these, accurate information rather than speculation is more more helpful and reassuring.

It is, however, decay heat that creates challenges, ie heat that has been stored in the rods and is expelled rapidly if they are not cooled sufficiently or exposed to air, thereby creating hot steam and pressure.  The NY Times has an excellent simplified graphic that explains how nuclear reactors work for those interested.

The problem is that high levels of radioactivity in the sea or air is never a good thing for life around it.  Years ago, there was a hugh debate (that’s an understatement) about the increased incidence of leukaemia and lymphomas in children around the Sellafield nuclear plant in Cumbria, UK, with different groups arguing for and against it (see references below as a snapshot).

The argument about cause and effect doesn’t seem to have been settled either way judging from various epidemiology studies and intense papers/letters to journals such as the BMJ over the past few decades.  Still, I’m sure most of us would probably agree that exposure to direct prolonged radiation from the sea or air is, intuitively, probably not a good thing in the long run.  Strontium, for example, one of the chemicals produced as a by product in nuclear reactors, tends to build up in teeth and bones, and may well be an irritant that can cause mutations over time.

What is clear, is that once sea water is pumped into a reactor, it is essentially dead and can never be used again, necessitating a massive clean up operation that may well take years to effect.  If anyone can do it efficiently and effectively, it is probably the Japanese with their superb engineering and sadly, experience from the Hiroshima clean up after the Second World War.

This morning, the availability of clean air, food and water took on an entirely different meaning.  In the meantime, my thoughts are sincerely with the Japanese people in their hour of need.

References:

ResearchBlogging.orgGardner, M., Snee, M., Hall, A., Powell, C., Downes, S., & Terrell, J. (1990). Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. BMJ, 300 (6722), 423-429 DOI: 10.1136/bmj.300.6722.423

Gardner MJ, Hall AJ, Snee MP, Downes S, Powell CA, & Terrell JD (1990). Methods and basic data of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. BMJ (Clinical research ed.), 300 (6722), 429-34 PMID: 2107893

Roman E, Watson A, Beral V, Buckle S, Bull D, Baker K, Ryder H, & Barton C (1993). Case-control study of leukaemia and non-Hodgkin’s lymphoma among children aged 0-4 years living in west Berkshire and north Hampshire health districts. BMJ (Clinical research ed.), 306 (6878), 615-21 PMID: 8461811

Watson GM (1991). Leukaemia and paternal radiation exposure. The Medical journal of Australia, 154 (7), 483-7 PMID: 2005848

Draper GJ, Little MP, Sorahan T, Kinlen LJ, Bunch KJ, Conquest AJ, Kendall GM, Kneale GW, Lancashire RJ, Muirhead CR, O’Connor CM, & Vincent TJ (1997). Cancer in the offspring of radiation workers: a record linkage study. BMJ (Clinical research ed.), 315 (7117), 1181-8 PMID: 9393219

Now that the dust has settled on the news from sanofi-aventis yesterday that iniparib did not achieve it’s primary survival endpoints in the phase III trial in newly diagnosed triple negative breast cancer (TNBC), it’s time to take stock of this class.

Yesterday was another major snow shovelling day in New Jersey so I missed the AstraZeneca year end conference call.  A Pharma Strategy Blog reader kindly filled me in with some relevant information – the company discontinued the development of their PARP inhibitor, olaparib, in BRCA breast cancer – scroll down to the discontinued section to see the note.

Our source also listened to the Q+A and in response to questions on olaparib from the analysts, Martin Mackay, the Head of R&D observed that:

“We decided to focus on serious ovarian cancer, and really focus our attention to that in the first instance and wait to see how those results play out in Phase III. Then we’ll revisit… breast cancer.”

This raises some interesting questions about PARP inhibitors in general.

Yesterday, we noted the fine line that needs to be trod between potency/efficacy and tolerability.  Last ASCO we saw how challenging it was to manage the toxicities with olaparib in combination with chemotherapy.  Iniparib doesn’t appear to add to the adverse event profile in combination, but missed its efficacy endpoints.

Meanwhile, Abbott’s PARP inhibitor, veliparib, is being tested in the I-SPY breast cancer trial, so while it will be a while before we see any data, it will be interesting to see how it pans out given that it is also more potent than iniparib.  Pfizer, BMS and Merck are also potential players in the PARP class, but their inhibitors are in earlier stage development. Based on the latest news with iniparib and olaparib it will be fascinating to see what they decide to do.

The latest developments in triple negative breast cancer also raise other critical issues:

  1. Was the olaparib decision based on toxicities, lack of efficacy or being behind iniparib, since they recently announced their phase II results?
  2. How will neliparib fare in the neoadjuvant setting and what toxicities might be expected?
  3. TNBC are mainly basal cell histology so many will also be BRCA1 or 2 positive – did these women do better in the olaparib trial?
  4. Will the Pfizer and Merck compounds have a better risk:benefit profile?
  5. What biomarkers will emerge to indicate subsets or predict response to therapy?
  6. If (5) does evolve, how will this develop from a diagnostics perspective?
  7. What will happen in ovarian, lung and prostate cancers, all of which have a very small proportion of people who have the BRCA1 or 2 mutation.

The current situation with iniparib and olaparib raises more questions than answers, so it will be interesting to see what learnings emerge from the data and whether the once promising class is salvageable or dead.

All in all, 2011 is turning out to be an interesting year and we have yet to get past January.

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“Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFβ-dependent biological outputs such as epithelial–mesenchymal transition (EMT).

In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFβ pathway.

Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFβ-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3.

Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFβ-dependent transcription and EMT.

Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFβ-induced EMT.

Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFβ stimulation.

Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads.”

Source: Oncogene

That was an abstract I was browsing over coffee in my oncology RSS feeds and while it was a bit heavy for early in the day, I was intrigued because Smads have been cropping up in GI sessions at meetings over the last six months or so.  Smads are signal transducers for members of the transforming growth factor-beta (TGF-beta) superfamily, so they occupy a key role in transcription of proteins:

The biology of TGF-beta and Smads

In addition, I’ve included a link to an open access article on the biology of Smads in the references below.

Essentially, the translational research from Soond and Chantry (2011) is suggesting that blocking the WWP2 gene could prevent metastasis, ie cancers from spreading to other organs of the body.  Many of you will remember the post on Norton and Massague’s cancer cell seeding theory and this new finding could well have implications for that research too.

Overall, the latest findings mean that if we have a valid target, we can design a drug to target the rogue gene sending signals.

Of course, these are still very early days yet, but it will be interesting to see if the basic science can be translated into R&D and eventually, a real clinical impact in the long run.

For those of you wanting a simpler version of the abstract, BBC Health did a nice job of putting the research into plain English.  Do check out their short report with pretty pictures here.

References:

ResearchBlogging.orgSoond, S., & Chantry, A. (2011). Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT Oncogene DOI: 10.1038/onc.2010.617

Attisano, L., & Tuen Lee-Hoeflich, S. (2001). The Smads Genome Biology, 2 (8) DOI: 10.1186/gb-2001-2-8-reviews3010

Izzi, L., & Attisano, L. (2004). Regulation of the TGFβ signalling pathway by ubiquitin-mediated degradation Oncogene, 23 (11), 2071-2078 DOI: 10.1038/sj.onc.1207412

This morning my emails greeted me with an announcement that the long awaited phase III SUCCEED trial data in soft tissue sarcomas from Ariad and Merck has been announced:

“… showing that ridaforolimus, an investigational oral mTOR inhibitor, met the primary endpoint of improved progression-free survival (PFS) compared to placebo in the Phase 3 SUCCEED trial conducted in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy.

Merck is currently developing ridaforolimus in multiple cancer indications under an exclusive license and collaboration agreement with ARIAD.   Complete findings from the SUCCEED trial will be submitted for presentation at an upcoming medical meeting this year.”

In the analyst teleconference I just listened to, the CEO Harvey Berger also stated that aside from presenting the data at a meeting this year, Merck was planning on filing the data with the regulatory authorities.

The good news is that no new safety signals have emerged and the common side effects reported previously, ie stomatitis (mouth sores), fatigue, diarrhea and thrombocytopenia appear unchanged.

Correspondence and interviews with a number of the SUCCEED trialists in the US and EU over the last year has taught me that ridaforolimus is generally well tolerated and quite a few patients have experienced prolonged stable disease (SD) while on ridaforolimus maintenance therapy between chemotherapy.

According to Ariad, the initial aggregated data from SUCCEED was as follows:

“Based on the full analysis of 552 PFS events in 711 patients, determined by an independent review committee, the blinded prospective study achieved its primary endpoint, with a statistically significant (p=0.0001) 28 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.72). Determination of median PFS for each arm of the trial demonstrated that ridaforolimus treatment resulted in a statistically significant 21 percent (3.1 week) improvement in median PFS (ridaforolimus, 17.7 weeks vs. placebo, 14.6 weeks).

Based on the full analysis of PFS determined by the investigative sites, there also was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.69).  Ridaforolimus treatment resulted in a statistically significant 52 percent (7.7 week) improvement in median PFS (ridaforolimus, 22.4 weeks vs. placebo, 14.7 weeks).”

There are several important things to note here:

  1. The PFS is less than a month, but highly significant
  2. The conditions for the SPA (primary endpoint was PFS) appear to have been met
  3. The last patient enrolled early last year, so hopefully the OS data (secondary endpoint) will be ready by the filing and will be positive
  4. The excellent hazard ratios suggest that the curves are well separated, leading me to think/hope that the OS might actually be more encouraging than PFS
  5. PFS is a difficult surrogate end point to measure; many trials end up with a difference between investigator estimate and central review as a result

We also need to look at these results in the context of soft tissue sarcomas (STS) as a disease.  By this, I’m thinking about the following issues:

  • STS is a heterogeneous disease made up of many different subtypes
  • It is a difficult to treat, aggressive disease and many patients are treated with multiple lines of chemotherapy to progression but sadly still relapse as resistance develops
  • Some subtypes are highly chemosensitive, some are not
  • Stable disease and quality of life are valuable to people with sarcoma
  • The danger of a ‘catch-all’ trial is that the non-responders cancel out the responders, lowering the overall response rate
  • Did any particular subsets do better on ridaforolimus than others?
  • Did any biomarkers emerge around mTOR, PI3-kinase, AKT, MEK or some other factor?
  • What factors were associated with the development of resistance?
  • If so, would this help us learn what might be a useful combination approach going forward?

Overall, based on what I’ve seen, this data looks promising so far and I’m keen to see more granular data when it is presented at a scientific meeting soon… Perhaps the data made the ASCO late breaking abstract cut-off this month?

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