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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘herceptin’

“Ipilimumab is not recommended for the treatment of advanced (unresectable or metastatic) malignant melanoma in people who have received prior therapy.

The Committee was satisfied that ipilimumab meets the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.

The Committee acknowledged that few advances had been made in the treatment of advanced melanoma in recent years and ipilimumab could be considered a significant innovation for a disease with a high unmet clinical need.

Despite the combined value of these factors the Committee considered that the magnitude of additional weight that would need to be assigned to the QALY gains for people with advanced (unresectable or metastatic) melanoma would be too great for ipilimumab to be considered a cost-effective use of NHS resources.”

NHS NICE Guidance

In other words, it’s too expensive and the NHS doesn’t want to pay the £80K ($120K) sticker price. This news is no great surprise given the cost-benefit ratio when considering that there is no way to tell who might benefit most from treatment upfront.

The is, however, a huge difference between hope and false hope, as NPR Shots astutely noted when discussing Avastin in breast cancer earlier this week and in some ways that sentiment applies here too. By this I mean it would be much more compelling to both patients and NICE if an oncologist could talk about a new therapy in specific and useful terms.

Examples of doctor-patient conversations about treatment in the near future might look more like this….

Either:

“You have an 70-80% chance of responding to this therapy because you have X (mutation, translocation, biomarker etc), where this drug has been shown to be highly effective and extends life by over 2 years in many of our advanced patients with this disease to date.”

Or:

“This drug may do more harm than good in your case, as it has been shown to effectively target X (mutation, translocation, biomarker etc), which you do not have, and therefore, are unlikely to respond. I believe it would be better to consider these alternatives in your situation… “

We all know about heterogeneity – it’s the very underpining of what makes a cancer survive despite our best efforts to tame it until we can subset into more homogenous and predictable groups.  This means that offering a broad therapy to all patients with a given advanced cancer without any idea of its predictive value is fast becoming a misnomer in today’s world of emerging targeted therapies.  Now, manufacturers (marketers even) might think it’s better not to ‘limit’ their market opportunity, but the reality is many healthcare systems are looking at ways to limit treatments to where it’s needed most, not only for cost reasons, but also to direct resources where they are more likely to work. The current model is not sustainable in the long run.

Of course, if a predictive biomarker was available to determine which patients are more likely to respond to ipilimumab, then the QALY calculation would be considerably different, and possibility even within the realms of the current guidelines.

That’s a whole different ballgame, but hopefully one that will begin to emerge as we have seen with new targeted therapies such as vemurafenib (Zelboraf) in BRAF V600E malignant melanoma, crizotinib (Xalkori) in ALK-positive advanced lung cancers and everolimus (Afinitor) in combination with exemestane in ER/PR+ HER2- breast cancers that have relapsed after initial aromatase inhibitor therapy.

It will be interesting to see how NICE handles all of those situations in the future, since they are all targeted agents showing a significant impact on a patients ability to live longer,with a more precise, and therefore, limited patient definition.  As a Brit and a scientist, I may have reasonable expectations that NICE will make a rational and logical decision in the face of limited resources, but this is also tinted with a large dose of healthy scepticism after the trastuzumab (Herceptin) debacle in HER2-positive breast cancers that lead to the utterly ridiculous and unfair post code lottery in the UK.

We are not talking absolute costs here, but the relative costs of seeing real efficacy benefits of six months or more in those patients most likely to respond, while at the same time giving an offering that truly extends life in a meaningful fashion without exposing too many to the toxic side effects of a given treatment. Dealing with cancer is tough enough without being treated with a regimen that had absolutely no hope of helping people live longer and feel better.

Way back in November 2009 at the American Association of Cancer Research (AACR) Molecular Targets meeting in Boston, there was a fascinating poster on the early promise for nanotechnology as a new form of efficient drug delivery for cancer therapeutics (see the blog post here).

Fast forward 18 months and my attention was drawn to a new article published in Cancer Research about how nanotechnology has been used preclinically to deliver therapy for breast cancer into the cancer cells rather than to the cells.  This is a subtle, but important, difference.

For those of your wondering what nanotechnology is, my colleague Pieter Droppert reviewed some basics earlier this month in a blog post:

“Nanotechnology is the application of science and engineering to materials that are between 1 and 100 nanometers (nm) in size.”

He went on to put this in layman terms:

“1nm is one-billionth of a meter.   To put this in context, 1nm is one seven-thousandth of the width of a red blood cell or one eighty-thousandth of the width of a human hair.  These are unimaginably small materials that are engineered to operate at the molecular and atomic level.”

The approach in the latest preclinical research (see references below) is to take trastuzumab (Herceptin) and combine it with biodegradable polymers to form nanoconjugates that are small enough to enter cancer cells because they are more water soluble rather than attack the outside of the cells, thereby potentially reducing toxicities associated with the therapy.

The same group also tried this technique with brain cancer (see references below), allowing the nanocells to cross the usually impenetratable blood-brain barrier, which:

“resulted in a marked inhibition of tumor angiogenesis and growth.”

In the breast cancer research, the group compared the results of their polymer-trastuzumab conjugate with trastuzumab alone in mice:

“Our experiments confirmed that a proper design of the lead nanobiopolymer was possible for efficient blocking of HER2/neu-positive breast tumor growth through dual inhibition of HER2/neu and Akt phosphorylation, and as a result, promoting enhanced tumor cell apoptosis.

The nanobiopolymer’s unique combination of features resulted in highly specific drug accumulation in the tumor tissue and inside tumor cells.”

It will be most interesting to see if this idea is developed clinically in human trials and whether the results will be reproducible or not.

Significance of the findings:

The nanoconjugate concept has promise, not just in allowing a novel drug delivery system to cross impenetrable barriers, but also in reducing the toxicities associated with systemic targeted therapy.  Randomised clinical trials in patients with cancer are required to determine if there is viability in humans.

References:

ResearchBlogging.orgInoue, S., Ding, H., Portilla-Arias, J., Hu, J., Konda, B., Fujita, M., Espinoza, A., Suhane, S., Riley, M., Gates, M., Patil, R., Penichet, M., Ljubimov, A., Black, K., Holler, E., & Ljubimova, J. (2011). Polymalic Acid-Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity Cancer Research, 71 (4), 1454-1464 DOI: 10.1158/0008-5472.CAN-10-3093

Ljubimova, J., Fujita, M., Ljubimov, A., Torchilin, V., Black, K., & Holler, E. (2008). Poly(malic acid) nanoconjugates containing various antibodies and oligonucleotides for multitargeting drug delivery Nanomedicine, 3 (2), 247-265 DOI: 10.2217/17435889.3.2.247

Ding, H., Inoue, S., Ljubimov, A., Patil, R., Portilla-Arias, J., Hu, J., Konda, B., Wawrowsky, K., Fujita, M., Karabalin, N., Sasaki, T., Black, K., Holler, E., & Ljubimova, J. (2010). Inhibition of brain tumor growth by intravenous poly( -L-malic acid) nanobioconjugate with pH-dependent drug release Proceedings of the National Academy of Sciences, 107 (42), 18143-18148 DOI: 10.1073/pnas.1003919107

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Interesting news arrived in my email box this morning:

"Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the company’s trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). As planned Roche will continue with its ongoing Phase III EMILIA registration study. Roche will continue to work with the FDA and expects a global regulatory submission of T-DM1 mid 2012.

The BLA submitted in July 2010 requested accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2 positive breast cancer, who had received on average seven prior medicines, including two HER2 targeted agents."

There was a lot of excitement around the initial phase II results (one third of the women experienced tumour shrinkage, for example).  Yet, to much surprise, the application was rejected:

"In their review of the BLA, FDA stated the T-DM1 trials did not meet the standard for accelerated approval because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population."

At first reading of the press release, my thoughts centred around:

  1. How could the FDA possibly reject such an application?
  2. Was an SPA agreed up front?

The first question is easy to be indignant about, but what criteria were used for the trial and what does the data actually show?

Looking at the available clinical trials for T-DM1, this one looks most likely as 100 patients were required and the inclusion criteria stated:

  • HER2-positive disease
  • Metastatic breast cancer
  • Disease progression on the last chemotherapy regimen received in the metastatic setting
  • Prior treatment with an anthracycline, trastuzumab, a taxane, lapatinib, and capecitabine in the neoadjuvant, adjuvant, locally advanced, or metastatic setting and prior treatment with at least two lines of therapy (a line of therapy can be a combination of two agents or single-agent chemotherapy) in the metastatic setting
  • At least two lines of anti-HER2 therapy must have been given in the metastatic setting as monotherapy or combined with chemotherapy or hormonal therapy. The HER2-targeted agent can include trastuzumab, lapatinib, or an investigational agent with HER2-inhibitory activity.

There are only two approved treatments for HER2-positive breast cancer, trastuzumab and lapatinib, plus others in clinical trials, eg pertuzumab, which was also allowed as one of the prior therapies.  All patients appear to have been refractory to at least two of these drugs, most likely trastuzumab and lapatinib.

The prior chemotherapies included anthracyclines, taxanes and capecitabine, which is quite heavy pre-treatment and includes all of the considered standards of care for several lines of therapy.  Indeed, the results of the trial presented at the San Antonio Breast Cancer Symposium last December showed that the average number of prior treatments in the metastatic setting was 7.

The others that could be used in the treatment of breast cancer include nab-paclitaxel (Abraxane), which I'm assuming would be covered in the taxane group and ixabepilone (Ixempra), an epothilone approved in by the FDA for metastatic breast cancer following progression on a taxane and anthracyclines, with or without capecitabine.

Ixabepilone is not a taxane or an anthracycline and therefore technically not covered in the inclusion criteria as a prior therapy, although some of the women would likely have received it, but not all.  It is, however, a taxane-like compound in that it targets the microtubules, as described in the PI:

"Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to B-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of aB-II and aB-III microtubules."

If that was the criteria for rejecting the trial as not truly refractory in a very heavily pre-treated setting, I would be surprised.  It's a bit of a technicality and nit-picking. Ixabepilone is not a commonly preferred treatment at all and BMS reported very low sales in 2009.  Most US physicians appear to prefer the well established taxanes such as paclitaxel, docetaxel and nab-paclitaxel rather than a synthetic taxane-like agent and probably consider it as a last resort. It is used as a standalone therapy in the refractory/salvage setting.

However, we're talking about a potential indication for a targeted agent that inhibits HER2 dimerization not a chemotherapy, so I would have thought that most of the important bases were covered by including the most common chemotherapies, trastuzumab and lapatinib in the inclusion criteria.

With regards to the latter question, Twitter chat this morning suggested that no, an SPA wasn't formally agreed upon, but Roche held discussions with the FDA that led them to file for accelerated approval. Thanks to Adam Feuerstein of The Street for being the first to answer that question.

My general opinion is that if you have an agreed Special Protocol Assessment (SPA) and meet the defined targets, it's much easier to move forward and gain approval. If you don't, things may turn into a crapshoot and it can go either way.  And that seems to be what has happened here.

The other factor that comes into play in this discussion is the ongoing discussion of the accelerated approval for Avastin in metastatic breast cancer and the overwhelming negative ODAC opinion last month.  That will not have helped, although one would like to think it shouldn't influence any decision making at the FDA.  We would probably be naive to think otherwise given the full protocol included PFS rather than OS as the endpoint.

To be fair, Roche appear to be addressing this issue, in their announcement this morning:

"Roche will amend the Phase III randomized EMILIA study in order to rigorously evaluate overall survival in addition to progression-free survival and will submit data from EMILIA to support a global regulatory submission in mid 2012."

Overall, I think it's a disappointing decision by the FDA given the heavily pre-treated population and lack of options for women who are refractory to both trastuzumab and lapatinib. Chemotherapy has not been shown to be particularly effective in HER2 disease, and by then the women generally have a poor prognosis. When you look again at the SABCS data, you find an objective response rate (ORR) of approximately 30% and a clinical benefit rate of around 40%, which is quite startling in a heavily pre-treated group.

Meanwhile, for now we'll have to wait another two years to see what the survival data looks like.  That's a rather long time for women who have failed Herceptin and Tykerb to wait for a drug that appears to have significant activity.

{UPDATE: I posted this analysis in a hurry, uncaffeinated, and in a rush to head out to a meeting.  Of course, one remembers later that SPA's apply to phase III not phase II trials, so a formal agreement wouldn't apply here. Thanks also to the two people who gently reminded me of this. Usually though, there are some discussions with FDA around the trial design for accelerated review. Essentially, in layman terms, it means patients are refractory to existing treatments for the disease concerned. Note that Roche, in their press release defined it as, "Consideration by the FDA for accelerated approval requires recognition of a defined patient population of unmet need (a life-threatening disease with limited treatment choices)." It looks like the FDA are applying it more strictly to ALL therapies, although the number of women who might have taken ixabepilone AND be HER2-positive will likely be miniscule.  I would still maintain that refractory to all available HER2 therapies and most chemotherapies apply for the majority in this case.}

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At last weeks investor meeting held by Roche in downtown Wall Street, the Board reviewed the pipeline opportunities in a number of areas.  Earlier this week I wrote about the non-oncology pipeline and today will form an overview of the cancer drugs in development.

One of the things that Roche is renowned for is life cycle management.  They do this better than many in the industry in my opinion and it makes an enormous difference not only to continuity, but also long term revenues and performance. Too many companies take a short term view and do not think ahead to the future. This is a big mistake. Perhaps they get bogged down in classic silos or management do not see it as a priority, but it does make a difference. 

Why?

Well, for starters, think about the basics of marketing. It is much easier to sell new products to existing customers than it is to sell existing products to new customers and even harder to sell new products to completely new customers.  

Thus life cycle management is a smart strategy and done well, enhances the experience for everyone involved whether employees or investors.  I only wish more companies paid closer attention to this important aspect of Pharma marketing.

The other thing I like about Roche's approach to R&D is rigorous and strong proof of concept studies (usually in phase II). Between Roche and Genentech, they both do this particularly well in oncology, it seems to be their signature. This partly explains why they mostly end up with a continuous wall of data across several products including trastuzumab (Herceptin), rituximab (Rituxan) and bevacizumab (Avastin). Of course, negative trials do occur but overall, they seem to have more positive trials than not. This partly explains why they have fewer phase III flops than say, Pfizer, because they spend the time in phase II working things out rather than rushing aggressively ahead on the basis of early evidence.

So what did we learn from the pipeline presentations last week?

There are late stage oncology products in development that look promising.

One example is trastuzumab-DM1, which is basically modified Herceptin with a potent cell killing agent, DM1, bolted on. The goal is to improve the action of Herceptin in metastatic breast cancer, and at the same time invetigate whether the xenograft data in a variety of cancers (breast, ovarian, lymphoma and prostate) with an armed antibody is an effective strategy in people. Recent phase II data from the San Antonio Breast Cancer Symposium in heavily treated women with metastatic breast cancer look encouraging. Phase III trials have already begun and if all goes well, filing is currently anticipated by 2012.

Also potentially strengthening the breast cancer franchise is pertuzumab, a monoclonal antibody that targets HER2. Early phase I trials in several cancer types produced so-so results, but more recent phase II data in breast (combined with Herceptin) and ovarian cancer (in combination with gemcitabine) published this month in JCO look interesting.

Perhaps the most exciting compound though, is PLX4032/RG7204, a BRAF inhibitor being evaluated in malignant melanoma. Currently available data suggests survival is improved by 6 months so the big question is what causes resistance to develop and how this can be overcome. Data on this compound is expected at ASCO, where many are keen to see how it stacks up with ipilimumab (BMS).

In hematologic malignancies, GA101 or galiximab is being evaluated in non-Hodgkin's Lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It appears to target a different part of the CD20 isotope than rituximab and this may increase it's efficacy. Phase III trials began in 4Q09 thus it will be a little while before we see some results. There is clearly an unmet medical need in the 3rd line refractory disease for more tolerable agents and rituximab is very much the bedrock of treatment for both across multiple lines of therapy either alone or in combination with chemotherapy. A similar agent will likely have good take up with the right approach.

Genentech are investigating various new and improved approaches to angiogenesis, but these are in much earlier development and the bar is very high with bevacizumab (Avastin), even for the company who manufacture it. The list of anti-angiogenesis compounds that didn't make it to market is very long indeed.

I've left the best to last, as hedgehog (Hh) signalling is one of my favourite pathways – it always reminds me of the cheerful cartoon character, Sonic the Hedgehog. RG3616, licensed from Curis, is currently in phase II trials for advanced basal cell carcinoma and trials are also underway for medulloblastoma. If interested, you can find out more about the pathway and the science here.

Overall, the oncology pipeline has a nice mix of follow on compounds to strengthen life cycle management with a raft of monoclonal antibodies with different targets in new cancer types.  Such a strategy should reduce risk and drive the future bottom line if the promise delivers in phase III trials.

ResearchBlogging.org

Baselga, J., Gelmon, K., Verma, S., Wardley, A., Conte, P., Miles, D., Bianchi, G., Cortes, J., McNally, V., Ross, G., Fumoleau, P., & Gianni, L. (2010). Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy Journal of Clinical Oncology, 28 (7), 1138-1144 DOI: 10.1200/JCO.2009.24.2024

Makhija, S., Amler, L., Glenn, D., Ueland, F., Gold, M., Dizon, D., Paton, V., Lin, C., Januario, T., Ng, K., Strauss, A., Kelsey, S., Sliwkowski, M., & Matulonis, U. (2009). Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Journal of Clinical Oncology, 28 (7), 1215-1223 DOI: 10.1200/JCO.2009.22.3354

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Last night many people in the NY-NJ-CT region missed the Oscars beamed from the Academy Awards after an argument over money between CableVision and ABC.  If a Biotech company and their big Pharma partner has a spat, it is rarely as public or has as much impact as TV deals do, but the shock waves can certainly be felt through the investor community every time a high profile predatory shareholder such as Carl Icahn gets their teeth into a biotech such as Genzyme or Biogen IDEC.

image from graphics8.nytimes.comIt was interesting that the year’s biggest grossing, most expensive and stunning film, ‘Avatar’, lost out to a smaller, niche film about the Iraqi war, ‘The Hurt Locker’, with a stronger plot, storyline and superb acting. 

It’s a bit like a baby Biotech producing a string of new products with solid efficacy doing well, much as Genentech did with Herceptin, Tarceva and Avastin or Amgen did in their early days with Neupogen and Epogen.  Eventually, of course, the new kid on the block becomes household name and new companies rise behind them with new science and a solid underpinning.

After the austerity of last year’s Awards ceremony, this year’s Oscars were a little more lavish by comparison. I wonder if that is a metaphor for the economy in general, with less doom and gloom and some signs that things are picking up?

Art ultimately reflects life.

The big question is, who are the next generation of big Biotech's in the making?

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Things were so busy in the Icarus office yesterday I didn’t get a moment to post on the Roche/Genentech news that the latest topline phase III trial analysis for bevacizumab (Avastin) were disappointing.  The company announced the findings in a press release:

“Avastin (bevacizumab) in combination with Xeloda (capecitabine) or fluorouracil and cisplatin chemotherapy in patients with inoperable, advanced or metastatic gastric cancer (stomach cancer). The study, known as AVAGAST, did not meet its primary endpoint of extending overall survival in patients treated with Avastin in combination with chemotherapy compared to the same chemotherapy plus placebo.”

The full data will be presented at ASCO in June.

Now, while initially disappointing, anyone who was at ASCO last year will remember the stunning data from the ToGA trial, presented by Eric van Cutsem.  This study looked at the benefit of adding a different Roche drug, trastuzumab (Herceptin), to standard chemotherapy in patients with HER2 positive gastric cancer, and found a significant benefit of approximately 2.5 months compared to chemotherapy alone.

What is the significance of these two trials for gastric cancer?

Well, Avastin targets VEGF, Herceptin targets HER2, the first was negative, the second positive, which may tell us something useful about the biology of the disease and what mechanisms are driving the tumour growth.

Sometimes a negative result tells us more than we may realise at first.  It helps define what really matters.

Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy. 

Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J

Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting. Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy. Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature. Updated OS analyses are reported. 

Methods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted. OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests. Analyses adjusting for baseline prognostic factors and crossover were also performed. 

Results: 296 women were randomized (148 per arm). The median number of prior trastuzumab-containing regimens for MBC treatment was 3. Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm. At data cut-off for updated OS, 218 deaths (74%) had occurred. Median OS following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks for lapatinib alone. A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 0.74; 95% CI: 0.57, 0.97; P=.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 0.71; 95% CI: 0.54, 0.93; P=.012). A trend toward a clinically relevant 25% reduction in risk of death (P=.080) was also observed after adjusting for crossover.

Conclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone. The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover.

Source: SABCS.org

This data from the Sam Antonio Breast Cancer Symposium last month showed that heavily pre-treated patients including prior trastuzumab (Herceptin) who received a combination of two HER-2 inhibitors, trastuzumab and lapatinib (Tykerb) improved their survival by 4.5 months over lapatinib alone:

Picture 160

The EGF104900 study included 296 women and resulted in an overall survival rate of 56% in patients randomized to lapatinib (1,000mg/day) plus trastuzumab compared to 41% in those assigned to lapatinib (1,500mg/day) alone.

Presently, trastuzumab is approved for first treatment of HER-2 positive breast cancer and lapatinib is given in second line once Herceptin fails.  It is interesting that there wasn't a Herceptin only arm, only a lapatinib only arm, but then the patients had previously progressed on trastuzumab therapy.

Previous studies with Herceptin and anthracyclines have shown an increase in cardiotoxicity associated with mainly with doxorubicin.  There was no suggestion of a cardiac safety issue with the HER-2 combination therapy in this study.

Lapatinib and trastuzumab target HER-2 through different mechanisms, which may account for the apparent additive effect in combination.  Previous preclinical and animal studies have suggested synergistic benefits for the combination, including enhanced apoptosis, anti-proliferative effects and downregulation of survivin.

This is the first study to show a survival improvement for any anti-HER2 agent taken beyond first line therapy.  It validates the concept that trastuzumab is an important drug to maintain through disease progression beyond initial therapy in patients who have previously done well on combined chemotherapy and HER-2 regimens before developing disease progression.

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The American Cancer Society estimates 183,000 new cases of breast
cancer will be diagnosed in the United States this year with more than
40,000 dying from the disease.  A portion of these are women who have triple negative breast cancer, which confers a poorer prognosis.

Triple negative breast cancer occurs where the tumour does not express
estrogen (ER) or progesterone (PR)  receptors or HER2 protein.  This means that standard
treatment with hormone blocking agents and agents that target HER2
such as tamoxifen and
Herceptin respectively, are ineffective weapons against this subtype of breast
cancer.  Women with triple negative breast cancer generally have shorter survival than those who are ER/PR positive.   Identifying better combinations of chemotherapy
and novel biologic agents that are effective in this disease is
therefore critical.

Here in New Jersey, at the Robert Wood Johnson Cancer Center, they are starting a new trial aimed at previously untreated women with triple negative breast cancer using triple combination therapy of doxil, carboplatin, and the anti-angiogenic therapy, Avastin.

Extensive research has suggested that the formation of new blood
vessels plays an important role in the establishment of distant sites
of breast cancer by providing nutrients needed for cell growth to reach
a tumour. 
Avastin has been found to interfere with the production of
new blood vessels, thereby interfering with cell growth and survival at
distant sites. 

Doxil and carboplatin are potent chemotherapies that have been found to prevent the
growth of cancer cells by inhibiting cancer cell reproduction.  Overall, this important
study seeks to determine the response of the patient's tumour to this
novel combination and to assess the side effects.

The new trial is part of the CINJ Oncology Group (CINJOG), which involves physicians throughout New Jersey from the CINJ Network of
hospitals.  For additional information on how to participate,
individuals should call (732) 235-7251.

According to a recent report from the American Cancer Society,
the death rate from breast cancer went down 2.2 percent per year from
1990 to 2004.  Much of that improvement has come as a result of clinical trials and new therapies being developed to treat the disease.

This article is part of the Cancer Research Blog Carnival being hosted by the
Sciencebase Science Blog
last week.

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