Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘cancer’

Today is my 801st post…

By on January 20, 2011

Writing this many articles certainly wasn’t one of my goals when I first started blogging about the science behind cancer, 100 seemed like the north face of the Eiger at the time! I’m not sure how many of you have been with me since the first few posts, but this seems a great opportunity to thank everyone for dropping by and reading, whether it’s your first time or you’ve been a regular for a while. All the comments and emails received have been very much appreciated.

Earlier this month, I put up a one question poll asking what sort of content you wanted to read more about and here are the results (accessed on Jan 18th):

The most popular requests were for more reviews of companies (27%), interviews with thought leaders (20%), with a fifth of those voting saying the mix was about right.  The poll is still running for those of you who missed and want your vote to count.  I’ll be re-running it later in the year to keep tabs on what readers want to see here on the blog.

The conference meeting insights will be rolling out in the newsletter, which will go out to subscribers by email occasionally.  If you haven’t signed up yet, you can add your name and email in the signup box in the right hand margin.

Over the next few days I plan on posting an interview with Dr Michael Kastan of St Judes who did a lot of stellar work on p53 and a review of Mirna Therapeutics, who have an interesting microRNA platform.

If anyone would like to suggest thought leaders or companies they would like to hear more about, please do add them in the comments below.

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Why RSS is not dead in science

By on January 14, 2011

There’s been a lot of noise on the internet from some early adopters who think Really Simple Syndication (RSS) is dead with so much information now available, often shared by people through Twitter and Facebook.  For me, though, that’s not true and here’s why:

  1. It depends on the tool you’re using to consume the RSS feeds
  2. Not many people in my circle share cancer journal items I’m interested in
  3. I use RSS feeds as a searchable database for key information

What tool is useful?

One tool I particularly love is Reeder, which can be used on a Mac computer, an iPad, iPhone or Android device essentially to read your RSS feeds hosted in Google Reader. You can read them online or offline.  This app allows you to skim through the news or science items in a more user friendly way.

Instead of clicking j/k and taking ages to move through items, the layout is much more pleasing and easier to read, like this:

Using RSS to search for interesting or relevant articles:

One of the challenges though, is that some journals such as Nature (in the example above) only provide the title and authors without even an abstract, which is frustrating and more than a little ungenerous of the publisher.

Others such as the Blood journal, however, do provide a useful summary of an article.  I found this one by quickly searching for ROS signaling, for example:

Once, found, it’s easy to star or bookmark for later use.  You can also cut/paste the information or quotes easily to notes or a presentation, adding to the overall utility of the tool.  It’s also a convenient way to search for information, assuming you have input journal RSS feeds into Google Reader, as I have done.  Although time consuming to do, it is well worth the effort in the long run.

Pictures also show up really well in Reeder:

I particularly enjoy skimming, searching and bookmarking my journal RSS feeds while offline on a plane on a laptop as it is a great productivity tool, but this approach would work equally well on an iPad too, which would make flipping through the curated material even more user friendly.

If you have a Mac, iPhone, iPad or Android gadget, then head over here to check it out.

What do you like about RSS?

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Impact of the Supreme Court case on adverse events including cancer

By on January 11, 2011

My colleague who writes the Biotech Strategy Blog, posted an interesting analysis this morning on the Matrixx Zicam case currently being reviewed by the United States Supreme Court (SCOTUS).  At the heart of the issue is whether or not adverse events should be disclosed to investors, even if not statistically significant. The way the questioning appears to be going from the Justices so far, it looks like they believe they should be.

The reason I bring this topic up is because it has important implications for Pharma and Biotech companies.

Recently, several obesity drugs were reviewed by the FDA Advisory Committees.  It’s not an area I usually follow, except that one of them, Arena Pharmaceuticals ($ARNA), caused a stir when many analysts and investors were surprised by the FDA briefing documents.  In it, was a hidden gem – the drug in question appeared to have an increased risk of developing cancer in rats – but the company hadn’t publicly revealed this fact. Why?  Because the CEO, Jack Lief, and the Board didn’t think it was material.

Inevitably, a lot of investors were rather dismayed not to have known that information before deciding whether or not to invest in the company.  Most of the industry watchers on Twitter, including myself, were certainly a little flabbergasted to hear it for the first time from the FDA.

Of course, the drug did not get recommended for approval, partly because of the marginal efficacy data, but also there was genuine concern over heart valve problems, and it is hard to imagine that the undeclared rat cancer didn’t factor in either.  In the end, a complete response letter (CRL) was issued.

I love Adam Feuerstein of The Street’s tweet around that time:

Adam Feuerstein ARNA tweet on rat cancer

Now, if we fast forward to the SCOTUS discussion on this very issue, it is not hard to see that this kind of information ought to be revealed to allow investors to make a rational decision on whether to invest or not.

The final SCOTUS decision is expected by the summer, so it will be interesting to see what happens if they decide that adverse events, whether significant or not, should be declared.  personally, I think they should and people can then do their own due diligence and research on whether they think it increased their risk tolerance or not.

This decision may well have a far reaching impact on the Pharma and Biotech industry and force company Boards to be far more rigorous and diligent in providing relevant information to potential investors.

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Update on circulating tumor cells in colorectal cancer

By on December 28, 2010

Earlier this year we discussed some interesting papers on circulating tumour cells (CTC’s) in prostate cancer and how they are becoming a potentially useful surrogate marker in clinical trials for other cancers including lung cancer.

I was therefore intriqued to see another paper looking at the role of CTC’s in colorectal cancer (CRC) – see link below in the reference section at end of the article:

“Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents”

One of the challenges with some targeted therapies such as bevacizumab (Avastin) now routinely used for treatment of metastatic colorectal cancer is that while they improve overall survival, not all patients will actually respond to treatment.

While several studies have shown that the KRAS mutation status predicts response to EGFR therapy such as cetuximab (Erbitux) and panitumumab (Vectibix) in colorectal cancer, there is no known equivalent biomarker for determining who is most likely to respond to VEGF therapy with bevacizumab.

This situation creates a dilemma for the medical oncologist, because other than excluding those patients most at risk from the side effects (patients with cardiovascular disease, hypertension etc), perhaps 1 in five of the advanced CRC patients, there is no way to determine which of the remaining 4/5 people will respond, thus potentially exposing all to the not insignificant systemic effects of the drug with no idea who might be an ideal candidate.

Previously, research from Cohen et al., has shown in advanced CRC that the CTC at baseline and during treatment were prognostic for OS and PFS (see references below). These studies included a broad heterogeneous population of untreated and pre-treated patients who received different schedules of treatment, making it difficult to draw specific conclusions.  That said, the research demonstrated that the technique is useful and can be measured from blood samples while not requiring invasive biopsies.

In this article, the researchers decided to see whether CRC’s would be a useful tool for predicting the responders from non-responders better in a more homogenous population.

What did the results show?

Perhaps the most interesting quote in this journal article was the finding that:

“The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone.”

Clearly, RECIST measurements are not going to go away, but combining the data with newer biomarker analysis that reflects the underlying biology may well be a good compromise.

What does this all mean?

Historically, physicians have used pathologic measures of measuring tumour response using RECIST criteria, but the problem with this approach is that tumour shrinkage alone does not always translate into an improvement in meaningful outcome for the patient. Sometimes patients can have no shrinkage and stable disease but still a reasonable and functional quality of life, as happens with some soft tissue sarcomas, for example.

New surrogate markers of survival are therefore needed that also tell us something about about the risk of recurrence.   This new paper provides additional evidence that:

“The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.”

They based this conclusion on the results that demonstrated:

“The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1–2 weeks after the start of treatment 20.0% and 95.1%, respectively.”

They also went on to note that:

“We demonstrate that CTC counts identify a small group of patients with unfavourable outcome early during treatment. However, whether a change in treatment on the basis of CTC count will result in a better survival for this group is yet unknown, and this issue should be addressed in a prospective trial.  In such a design, it will also be worthwhile to investigate the cost-effectiveness of CTC testing.”

Unfortunately, although a reasonably large number patients were evaluated (n=467) in this study, half were treated with capecitabine, oxaliplatin, and bevacizumab and half received the same regimen plus weekly cetuximab, but the results were oddly described in the aggregate.  We therefore have no idea whether CTC’s were more useful in the bevacizumab only arm, or when cetuximab was added.  We do know that in the patients who did poorly, although their specific treatment is not described, they did have high CTC levels and poor disease control.

CTC’s are something we will likely hear a lot more about in research going forward from a biomarker perspective though, as researchers begin to incorporate their measurement into the design of more clinical trials.

References:

ResearchBlogging.orgTol, J., Koopman, M., Miller, M., Tibbe, A., Cats, A., Creemers, G., Vos, A., Nagtegaal, I., Terstappen, L., & Punt, C. (2009). Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents Annals of Oncology, 21 (5), 1006-1012 DOI: 10.1093/annonc/mdp463

Cohen, S., Punt, C., Iannotti, N., Saidman, B., Sabbath, K., Gabrail, N., Picus, J., Morse, M., Mitchell, E., Miller, M., Doyle, G., Tissing, H., Terstappen, L., & Meropol, N. (2009). Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer Annals of Oncology, 20 (7), 1223-1229 DOI: 10.1093/annonc/mdn786

Cohen, S., Punt, C., Iannotti, N., Saidman, B., Sabbath, K., Gabrail, N., Picus, J., Morse, M., Mitchell, E., Miller, M., Doyle, G., Tissing, H., Terstappen, L., & Meropol, N. (2008). Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer Journal of Clinical Oncology, 26 (19), 3213-3221 DOI: 10.1200/JCO.2007.15.8923

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Amgen receives approval for denosumab (Xgeva) in SRE for cancer

By on November 19, 2010

After hearing Amgen’s denosumab (Dmab) was approved late yesterday for skeletal related events (SRE) in the oncology solid tumour indications (but not multiple myeloma) and is now named Xgeva, I was tempted to write a Fun Friday post on how Pharma brand names make the mind boggle lately as you can see a few weird looking names have emerged this year alone.  Seriously, some of them look as though they’ve been hastily put together from Scrabble tiles sometimes, or represent words more usually associated with the old Soviet Eastern bloc countries, never mind figuring out how they ought to be pronounced!  {Update: this one is pronounced x-GEE-va not x-JAY-va as a European might think ;)}

According to the NY Times, the Wholesale price for Dmab in the oncology setting will be $1650 per month, making it around double the price of Zometa (Novartis).  Still, the good news for patients is that Amgen do have a patient assistance program for it and I understand from several sources that Amgen has a co-pay program that offers Xgeva to the patient with no co-pay the first month and only $25 afterwards.  There are apparently no income limits to participate, which if true, would be most unusual.  {Update: here is the link to actual details of the coupon program.}

At the NY Chemotherapy Foundation Symposium last week, several oncologists I spoke to said that a high price would be a significant barrier to use, so it would be reserved for those who do not respond or tolerate Zometa, or have poor renal function.  Urologists would probably be more interested in Xgeva, since Zometa is an infusion product and they tend to refer patients to the oncologist for this.  Xgeva, as a subcutaneous therapy, would therefore potentially be a more convenient option for urologists who have patients that progress to symptomatic metastatic prostate cancer.

The other interesting thing I noticed from the data presented on Dmab at the NY Chemotherapy Meeting, was that while time to SRE was significantly improved with Xgeva compared to Zometa, there was no difference in survival between either therapy, as measured by both progression-free survival (PFS) and overall survival (OS).  There is a risk that oncologists will look at that data and see no meaningful benefit in survival at twice the price for their cancer patients.  We’ll see what unfolds over the next few months, although the slow uptake of Prolia in the non-oncology setting does not portend well for Amgen.

Meanwhile, this week  I’m in the office working on client reports instead of having fun at cancer conferences such as the EORTC-AACR-NCI Molecular Targets meeting that is currently ongoing in Berlin 🙂

A couple of interesting stories in preclinical or early phase development have caught my eye from the meeting so far.

The BBC wrote about nanocarriers and brain cancers, based on some research in mice, for example.  We’ve previously covered nanotechnology at other AACR meetings (in pancreatic cancer), and this is probably one of my favourite disruptive technology concepts to emerge over the last twelve months.  It may be a while before something is actually approved for use in human cancer though.

Another interesting item was data on a new PARP inhibitor, MK-4827, from Merck.  I first posted on the science behind PARP inhibition way back in 2006, with quite a few subsequent posts on the clinical data since (you can find them all by using the Search widget on the right and typing PARP.   Three main compounds have already emerged with a growing body of clinical data, mainly in breast and ovarian cancers:

  1. Olaparib (KuDos/AstraZeneca)
  2. Iniparib (BiPar/Sanofi Aventis)
  3. Veliparib (Abbott)

We can now add the Merck compound to the growing list of PARP inhibitors with data in human trials from phase I and beyond.  According to the ECCO press release, the new data extends beyond breast and ovarian cancers:

“In a Phase I trial conducted at the H Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumours such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers.  Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.”

These patients had metastatic, advanced disease, typically already received treatment with several other therapies and had experienced recurrence.  In this setting, response rates are expected to be low given the high tumour burden:

“The researchers saw anti-tumour responses in both sporadic and BRCA1/2 mutation-associated cancers.  Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment.  Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.”

Of course, it’s still early days yet in a phase I trial, but it will be interesting to see how this new class of cancer agents evolves over the next couple of years.

Photo Credit: Amgen

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NY Chemotherapy Foundation Symposium

By on November 8, 2010

This week heralds a busy one with the upcoming annual NY Chemotherapy Foundation (Greenspan) meeting that begins tomorrow at the Marriott Marquis in Times Square with the Pediatric session in the afternoon and finishes on Saturday with the Nursing session.

I’ll be at the Greenspan event from Weds to Fri, please do say hello if you see me around.

In the meantime, I’ve been pleasantly surprised at the number of signups to the conference newsletter (see the sign up widget in the right hand margin —>).   The first one, from AACR on colon cancer, goes out this on Wednesday week, please sign up before then if you would like to receive it.

More newsletters will follow soon on the Greenspan Meeting, ASH and SABCS.

I’ve just added a new meeting to my January conference schedule and will be attending the 6th International Society of Gastroenterological Carcinogenesis in Houston, Texas. It’s hosted by MD Anderson and you see the program here.  Many thanks to Drs Ray DuBois and Anas Younes for alerting me to the event.  There are some interesting speakers and topics so it looks like being a good meeting.

You can see my active schedule in the Conference Schedule tab at the top of the site. More events will be added for 2011 as dates firm up.

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Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas

By on November 4, 2010

This morning I was delighted to see that one of my favourite medical doctors on Twitter, Dr Anas Younes from MD Anderson, has published a paper in the New England Journal of Medicine on a clinical trial of a promising new agent in development for a particular type of lymphoma.

Dr Younes is very active in social media on Twitter and Facebook and has garnered quite a following of lymphoma patients interested in learning about new treatments for the disease.   This also means that patients and caregivers following him are able to find out about new clinical trials as they open up.  MD Anderson Cancer Center probably has access to more clinical trials across all tumour types than any other cancer center, offering lots of options for cancer patients to receive novel therapies that may help their condition.   Another benefit of a physician being involved with social media is that awareness of the trials will reach more people this way and hence probably accrue faster.

What’s new in Hodgkins Lymphoma?

Before we discuss the NEJM paper, the other side of social media is that MD Anderson also use it to communicate the results of their trials on the Institution website and Dr Younes also has a nice video for patients, explaining how the drug works, about the trial and the results that they found.

Now, this was a phase I trial so normally we wouldn’t expect to see too much from an efficacy standpoint, as the main goal of these studies is to assess the range of toxicities and determine the maximum tolerated dose (MTD) for phase II trials, which look at the efficacy signal in more detail.

That said, what Dr Younes and his colleagues found was quite impressive responses in a disease that has not seen much in the way of new treatments for more than a decade.

It should be noted that the agent targets CD30 antigen that is expressed on Hodgkin Lymphoma and anaplastic large-cell lymphoma (ALCL) cells.  Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity.  What’s different about this new agent is that it is an antibody-drug conjugate (ADC), with an anti-CD30 monoclonal antibody linked to monomethyl auristatin E (MMAE), an anti-cancer agent.

The drug they were evaluating, brentuximab vedotin (SGN-35), from a partnership between Seattle Genetics and Millennium, elicited complete responses (CR) or partial responses (PR) in 38% of the patients with Hodgkin Lymphoma (HL).  In the NEJM article it boldly stated that:

“The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86%).”

Looking at the data in the article, what was amazing was that there were 17 objective responses (38%), 11 of which (25%) were complete remissions, which essentially means disappearance of all evidence of the disease.  In addition, CT scans showed that 36 of 42 (86%) of evaluable patients saw their tumours shrink.

What’s next?

Overall, I think these very promising results raise hopes that the phase II trial will also produce positive results at the American Society of Hematology (ASH) in December, which will be really great news for patients with Hodgkin Lymphoma.

If the phase II results also look positive, then we can probably expect Seattle Genetics and Millennium to file in the first half of 2011.

ResearchBlogging.org Younes, A., Bartlett, N., Leonard, J., Kennedy, D., Lynch, C., Sievers, E., & Forero-Torres, A. (2010). Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas New England Journal of Medicine, 363 (19), 1812-1821 DOI: 10.1056/NEJMoa1002965

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#ESMO 2010 round-up #3

By on October 14, 2010

Back from Milan and ESMO 2010, I thought it would be a good idea to quick a final quick overview of some of the early data from phase II trials that look interesting and might be worth watching as the research evolves (in no particular order).

1. Addition of cetuximab to cisplatin increased survival in triple negative breast cancer

Jose Baselga presented the results of a multi-centre randomised trial (from Spain, Belgium, Austria, Portugal, the UK and Israel) that compared the combination of cetuximab (Erbitux) with cisplatin versus cisplatin alone in 173 women with triple negative breast cancer (TNBC).

Although the overall response rate (ORR) trended in favour of the combination (20.0 vs 10.3%), the result did not meet the pre-specified assumptions. Interestingly though, the progression-free survival (PFS) showed a significant improvement with the addition of cetuximab (3.7 vs 1.5 months, P<0.03). Two months doesn't seem much, but in an advanced, highly aggressive disease, it may represent a disproportionally large improvement.

I'm not sure why cisplatin was chosen as a comparator, especially as TNBC is a particularly hard subset to treat, but the trial is ongoing to determine overall survival and a phase III study will likely evolve to determine if the results are repeatable in a larger population.

2. GSK2118436 in advanced melanoma with brain mets looks promising in a phase I/II study

By promising, I mean this was a very small cohort of patients who saw some early and unexpected evidence of tumour shrinkage in brain mets that had evolved from primary melanoma. The scans shown by the presenter, Georgina Long, from the Melanoma Institute Australia and Westmead Hospital in Sydney actually gave me goosebumps and it wasn't the chill in the room. You just don't expect to see such noticeable shrinkage with a single agent in this setting because this is a horrid, aggressive disease that has a nasty tendency to metastasize easily.

What was interesting about this study is that GSK2118436 is a BRAF inhibitor that also specifically targets V600E, similarly to Plexxikon/Roche's PLX4032. In both cases, they bind to the protein and shut down signaling activity. Although the trial is very early, since it looked at 3 different cohorts, the small subset with brain mets (n=10) were what caught everyone in the audience's attention, although good responses were also seen in the advanced melanoma group without brain mets.

To put the results in context, all 10 patients experienced some control of their brain mets, with 9 of the 10 patients having reductions in the overall size of their tumours. The overall reductions ranged from 20-100% of brain metastases that were 3mm or larger in diameter before treatment.

That just doesn't happen with advanced melanoma with brain mets… at least, I've never seen such dramatic responses before.

The big questions for me are how long will the responses be durable before resistance sets in and how soon is a larger scale trial going to get up and running? This is a very promising and most unexpected development that is worth following.

Dr Long summed it up very nicely:

“The ability to inhibit oncogenic BRAF is the most important development in the history of drug treatment of melanoma.”

3. ARQ-197 continues to show positive results in NSCLC

In this presentation, the final results of the phase II trial in non-small cell lung cancer (NSCLC) were discussed. We've covered this promising agent, ARQ-197 (ArQule/Daiichi Sankyo), a small molecule c-MET inhibitor, before on this blog.

A final analysis looked at the complete results in more depth. Patients treated with ARQ 197 plus erlotinib (Tarceva) developed new metastases in a median time of 7.3 months compared with 3.6 months for patients treated with erlotinib plus placebo.

What I found interesting in this study was that this effect was more pronounced among patients with non-squamous (NS) histology, since the median time to develop new metastases was 11.0 months in the ARQ 197 plus erlotinib arm compared to 3.6 months for those treated with the control arm (erlotinib plus placebo). I'm not sure why the NS over squamous histology should matter, but they clearly benefitted more.

The sponsors, ArQule and Daiichi Sankyo, have announced that they plan to pursue a phase III trial in this setting. It would, however, be nice to see an analysis of any lung biopsies collected to see if there are any relevant biomarkers that would explain the differences in histology and responders, otherwise many physicians may see this as an incremental improvement, if confirmed in a larger trial. Were thre any differences in people who were EGFR mutation or MET positive, for example?

There was certainly some energetic discussion in the Q&A, with tough questions asked of the speaker regarding why go ahead with a phase III study given a small benefit and why use OS when PFS is small and complicated by crossover, all very fair questions. Like many, I'd really like to see more granular analysis of who is responding to this agent and why before rushing into a phase III trial that may see a disappearing of any positive signal when investigator bias is eliminated in a larger randomised trial.

4. METMAB showed promising results in a subset of lung cancer patients

In the same session, David Spiegel presented the data from a phase II study with a different c-MET inhibitor. Here, patients with advanced NSCLC (n=128) were randomly assigned to receive either erlotinib plus METMAb (Roche/Genentech), a monoclonal antibody that binds specifically to the MET receptor on cancer cells or a control arm (erlotinib plus placebo).

The reason for the interest in c-MET inhibitors is that MET activation has been implicated in the resistance of lung cancers to EGFR inhibitors such as erlotinib. The big question is therefore whether a combination of the two would overcome resistance or not, thereby prolonging life.

In this study, participants were tested for mutations in the EGFR gene and also for expression of MET in tumour samples. 

The results were interesting – 51% of patients whose tumours expressed MET and those who received METMAb plus erlotinib had better OS and longer PFS than those who received erlotinib plus placebo.

Furthermore, in the subset of MET+ patients, adding METMAb to erlotinib nearly halved the risk of disease progression or death during the study compared to those treated with erlotinib plus placebo. In addition, patients whose tumours did not express MET protein appeared to do worse when treated with the METMAb/erlotinib combination, suggesting that the biomarker may be able to determine who is more likely to respond to therapy.

This is good news if it is repeatable in a phase III trial and show durable efficacy with good tolerability, because then potentially, oncologists would be able to screen and preselect patients for treatment with METMab rather than expose all patients to the systemic side effects without hope of it working.

Last but not least, there was some updated information on the novel trastuzumab-DM1 (T-DM1) combination therapy (Roche/Genentech).

4. T-DM1 continues to show solid results in metastatic breast cancer

Edith Perez presented the results of a phase II study looking at first line treatment with a new combination agent, trastuzumab-DM1 or T-DM1, in metastatic breast cancer.

As far as I know, T-DM1 is the first of a new type of cancer therapy known as an antibody-drug conjugate. Basically, it binds together two existing cancer drugs with the aim of delivering both drugs specifically to cancer cells, ie trastuzumab (Herceptin), an approved monoclonal antibody that targets the protein HER2 and DM1, a chemotherapy agent that targets microtubules. The goal of the new combination is too see if cardiotoxicity, a common problem associated with standard anthracycline therapy, is reduced and if efficacy is subsequently improved.

Women with breast cancer were randomised to treatment with either trastuzumab plus the chemotherapy drug docetaxel, or T-DM1. All 137 participants had HER2-positive metastatic cancer, with no prior chemotherapy for their metastatic disease.

The good news is that the early results demonstrated that T-DM1 has good anti-tumour activity as well as much lower toxicity when evaluated side by side to standard therapy.

After a median of approx 6 months of follow up, the overall response rate of in women who received T-DM1 was 48% compared with 41% in the control arm (trastuzumab plus docetaxel). The rates of clinically relevant adverse events were also significantly lower in the T-DM1 arm (37%) compared to the rate in women given traztuzumab plus docetaxel (75%).

Overall, I think the slight improvement in ORR was more than compensated by the dramatic improvement in side effects, which ultimately affect a patient's quality of life when undergoing cancer treatment. According to my chicken scratch notes from the session, cardiotoxicity and myelosuppression were both much improved in the T-DM1 arm over standard therapy.

Perez noted that the final analysis of the PFS data is expected in 2Q 2011, which I'm sure will be eagerly awaited based on the encouraging early data, although feeling better is one thing, but ultimately the sine qua non is will the women live longer?

All in all, I'm glad I trekked all the way to Milan for ESMO. There was more positive and promising early data than expected and aside from the repetitive blister walks, it was an enjoyable event. It was also nice to catch up with some friends in person and meet several readers of this blog who kindly came up and introduced themselves – I hope you all enjoyed the conference as much as I did!

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Greetings from ESMO in Milan

By on October 8, 2010

Oh my, I can't believe I slept for 9 hours solid last night and woke up with no jetlag and access to the New Twitter interface, finally! It must have been the long walk I took around the Duomo and Brera districts or perhaps the Negroni apperitivo, but hard to believe that is a logical anti-jetlag solution!

Duomo Today is Super Friday at ESMO, in other words, the corporate symposia. There are a lot of interesting presentations that I'm looking forward to, but they are rightly embargoed and I can't talk about them yet. Thus we have a whole day of corporately sponsored 'educational sessions'. I may not tweet these events, except perhaps two; one from Roche at 3pm on angiogenesis and another from J&J at 4.30pm discussing advanced ovarian and prostate cancer.  

Sadly, I'm not as big a fan of Super Fridays as I used to be. Why? Because they used to be educational events, now many seem more biased and shilling a company's drug without fair balance or context. Am hoping that's not the case here, but in the last couple of years, the focus has definitely drifted too far at some meetings. 

For me, I'm much more of a purist and a fan of sessions that address pros and cons, controversial issues and with fair balance, then let the audience vote and decide before and after the presentations as that often keeps the presenters on their toes.

Ah well, times change, like Mrs Thatcher famously said, this lady's not for changing on the issue for now ;)

 

Biomarkers in cancer research – thoughts from AACR in Denver

By on September 29, 2010

This week I'm adjusting to the high altitude of Denver while at the American Association of Cancer Research (AACR) meeting on molecular diagnostics and cancer therapeutics. It's a great little meeting, networking opportunities are excellent and I'm learning a lot about what new cutting edge ideas are being explored.

I will be doing some highlights from each day series later in the week once I've had time to process all the information, as there is a lot to digest here.

What is interesting though, is to look at big picture trends, both in academia and basic research and also what industry are doing in their research teams, since these ideas may well get incorporated into early phase I clinical trials for validation and pilot purposes. More about this later in the week.

Although a lot of the attendees are from the diagnostics end of the business (either academic or industry), there are quite a few serious researchers and thinkers here too. Gordon Mills from MD Anderson gave one of the best talks I've seen at an opening session in a long while. David Parkinson from Nodality also laid out a strategic and thoughtful overview of how things are currently, and how they will continue to change in cancer research with new approaches. 

One thing really struck me here in Denver. While outsiders and FDA become more paranoid about conflicts of interest, it is clear to me that what we actually need is closer and more collaborative relationships between basic and clinical research in order to translate the knowledge and ideas into practice or the clinic more quickly.  To do this requires fresh ideas, a fresh approach and better communication and collaboration. 

By collaboration, I don't just mean between academia and industry, but between labs and between companies, rather than competition. Increasingly, I'm seeing smart researchers presenting data that was generated on behalf of several groups, often in different cities or even countries, each providing different skills and expertise to the research. This used to happen sporadically between friends and former colleagues, but now it's starting to become more commonplace. It's a good sign and a great way to synergies resources and bring more expertise to projects.

Industry are typically very slow to change and tend to see other companies as rivals rather than for collaborative purposes, which is a great shame given that we're all working towards the same goal: fight cancer. 

That said, there are some exciting new, albeit subtle changes afoot. When I think of cancer research, the first two industry research powerhouses I think of are Genentech, who have traditional sought strong relationships with academia and Novartis, who have the Novartis Institute for Biomedical Research (NIBR) and the Genomics Institute of the Novartis Research Foundation (GNF).  

More recent examples include Novartis and GSK, who appear to have been collaborating on research projects and the other major one that surprised many was the Merck-Astra-Zeneca hookup on specific, but related compounds with relevant cancer pathways.

Which brings me to Gordon Mills stirring talk on Monday evening. He made the case that this is the time for systems biology to make it's mark. Rather than looking at adding in a targeted therapy eg an EGFR, a MEK or whatever inhibitor (TKI or monoclonal antibody) to shut off one particular piece of a complex pathway, we need to start looking at a broader concept, which he called 'pathwayness'. That is, we have learned that cancer biology is highly complex and shutting off one aberrant or overexpressed protein, won't shut down the whole engine because either the cancer adapts or other parts continue to function and drive the tumour's survival.

For me, what was spooky about this well thought and well argued talk was that it was eerily similar as a concept to what Frank McCormack was describing earlier this year using PI3K as an example. Both McCormack and Mills are probably ahead of their time.

What we need to see is industry listening to what they have to say and start to think more strategically about what to do with all the inhibitors we already have out there for the 12 critical cancer drivers that Bert Vogelstein discussed at AACR earlier this year.  

Mills argued cogently that we actually have many of the potential tools we need to take a deeper systems biology approach to personalized medicine and by looking at each patients cancer biology we could potential develop a treatment approach relevant to them. He called this 'listening to what the patient tells us'.

This reminded me that recently, there was an article in Forbes about why personalized medicine is bunk, written by a MD at a VC firm. The article annoyed me, mainly for it's lack of critical thinking, fair balance or even a basic understanding of what is happening in medicine and clinical research. Rather than vent in the comments, I turned up at this AACR meeting and was greatly reassured that cancer research is in good hands and we have many excellent people and resources focused on the whole concept of matching treatment to a patients tumour. It will happen. In many ways the revolution has already begun; we just need to get better at it. Every failure tells us something new and important about what to do next.

We have the tools, but there are also a lot of hurdles and challenges to be addressed along the way, not least the regulatory side of things and a different way of thinking about testing and validating the ideas in clinical trials. The good news is that there is much needed activity going on behind the scenes at the policy level, as witnessed by the Cancer Caucus in DC today, where Harold Varmus is kicking off a new era at the NCI. I'm hopeful that the think tank will have open minds and the passion to change the way we think about cancer research.

 

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