Onco Chat

Upcoming cancer conferences - will you be there?

The last quarter of the year is always a busy one on the conference circuit in oncology, particularly in December with the annual ASH and the SABCS meetings back to back. We almost always need the Holidays after that just to recover! 

Here's my schedule for the next few weeks:

Oct 20th: Xconomy, 'War on Cancer', Boston hosted by Millennium

Oct 27-30th: AACR colorectal cancer biology and therapy symposium, Philadelphia

Nov 8-13th: Greenspan Chemotherapy Foundation Symposium, Marriott Marquis Times Square, NY

All three meetings look particularly interesting this year, with a big focus on biology and new product development.

While Pharma is facing some big patent cliffs over the next two years, there are a lot of interesting new compounds coming along in the pipeline in phase I/II right now. Hopefully, some of these will make it through to regulatory filing in a few years time.

If you are around at these meetings, do stop and say hello - it's always good to meet readers in person, however briefly. If you haven't put any of these in your diary, do check them out!

FDA rejects the Roche Immunogen T-DM1 accelerated approval filing

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.}

New potential targets in ovarian cancer?

Treatment for ovarian cancer hasn't changed much in the last ten years, reflecting the lack of biomarkers and biochemical targets for the disease. Chemotherapy with a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel) has therefore formed the bedrock of therapy, along with other options such as gemcitabine or pemetrexed, as illustrated in the latest NCCN Guidelines.

The good news is that the use of paclitaxel-based combination chemotherapy has been shown to increase progression free survival (PFS) and overall survival (OS) in women with primary peritoneal or ovarian cancers.

While a proportion of ovarian cancers have been shown to be highly chemosensitive, a large number unfortunately fail to respond to primary taxane therapy, leading to the emergence of resistant disease.

The big unanswered questions are therefore why does this happen and what can be done about it to improve outcomes and overall prognosis?

It was with great interest that I read about the findings of a new study just published in Cancer Cell from researchers at MD Anderson (see e-link in the references below).  According to the MD Anderson news alert:

"For the first time, Salt Inducible Kinase 2 (SIK2) has been found to play a critical role in cell division and to regulate the response of some ovarian cancers to chemotherapy."

It's not often when you see the mention of both a potential target and prognostic/predictive biomarker mentioned in the same sentence as ovarian cancer, so this is huge news!  The press release went on to claim:

"Researchers found that depleting SIK2 from ovarian cancers sensitized the cancer cells to paclitaxel, a commonly prescribed chemotherapeutic agent that inhibits cell division, making the drug more effective in stopping the cancer's growth. Levels of the SIK2 protein are increased in approximately 30 percent of ovarian cancers and are associated with poorer survival in women with the disease."

The researchers analysed nearly 780 pools of siRNAs to identify proteins that alter sensitivity to paclitaxel. They found that SIK2 regulates sensitivity to paclitaxel and prevents cell division. This means that SIK2 may offer a useful therapeutic target for pipeline drugs to be developed in ovarian cancer.

What was even more fascinating was that another related article on ovarian cancer from Bast's group appeared in the same journal. In essence, they used siRNA-loaded nanoparticles to stifle a protein, Zeste homolog 2 (EZH2), which is associated with poor survival. This resulted in inhibition of angiogenesis (formation of new blood vessels) to the tumour and caused a steep reduction in the tumour burden in a mouse model of ovarian cancer.

In this study, the authors looked at human 180 ovarian cancer tumours and found that the protein was overexpressed in the tumour samples (66%) and in the endothelial cells (67%). It is relevant to note that endothelial cells line the inside of blood vessels and play a crucial role in angiogenesis.

In practice, they found that women with increased EZH2 levels in their tumours had a median survival of 2.5 years compared to 7.33 years for those without. Looking at overexpression in the endothelial cells, the difference was 2.33 years versus 8.33 years for those with normal levels.

Like me, you're probably wondering how these nanoparticles work.  According to MD Anderson:

"The nanoparticles accumulate in the cancer cell and vasculature passively as they circulate in the blood stream. Chitosan nanoparticles are so small that they can flow through tiny holes in the tumor vasculature. They also accumulate in other organs, so the researchers are working to add a targeting molecule that will limit nanoparticle uptake to tumors and their vasculature."

Targeting EZH2 may have application beyond ovarian cancer, since it been associated with the progression and spread of bladder, breast, prostate and gastric cancers and cancer of the pharynx.

All in all, a really interesting pair of papers from Bast's group, which may have clinical promise and real application to the future treatment of ovarian cancer.

 

Ahmed, A., Lu, Z., Jennings, N., Etemadmoghadam, D., Capalbo, L., Jacamo, R., Barbosa-Morais, N., Le, X., Vivas-Mejia, P., & Lopez-Berestein, G. (2010). SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer Cancer Cell, 18 (2), 109-121 DOI: 10.1016/j.ccr.2010.06.018

Lu, C., Han, H., Mangala, L., Ali-Fehmi, R., Newton, C., Ozbun, L., Armaiz-Pena, G., Hu, W., Stone, R., & Munkarah, A. (2010). Regulation of Tumor Angiogenesis by EZH2 Cancer Cell, 18 (2), 185-197 DOI: 10.1016/j.ccr.2010.06.016

Michael Douglas has throat cancer?

This afternoon I was chatting with a Pharma friend via IM when she sent me a surprise link:

Michael Douglas to Undergo Chemo for Tumor in Throat Cancer

Oof, he was one of my favourite actors growing up as a child - I just loved the Streets of San Francisco!  He also made Gordon Gekko famous in Wall Street.

There's a lot of throat cancer in the news lately.  The most recent was Alex Higgins, the incredible Irish snooker player who was a truly sensational player from my childhood.

I wrote about him recently here.  Be warned - the before and after pictures are a little shocking.

A recent photo of Michael Douglas on ABC News was also a shock, as he looks much more haggard than I remember :(

Lately, I've been watching re-runs in the evenings of the classic gritty but violent English detective drama from the 1970's, The Sweeney, starring John Thaw and Dennis Waterman.  Idly clicking through to IMDB, I wondered what had become of Thaw, who also starred in Inspector Morse, only to discover that he, too, had passed away in 2002 - from throat cancer.

What is common with these three men? Well, alcohol and cigarette smoking contributed no doubt, as the American Cancer Society lists both of these as two of the potential risk factors for laryngeal and hypopharyngeal cancer, the medical term for throat cancer, which is often referred to as oesophageal cancer in the UK.  The median age of diagnosis is round 65, so Douglas, Thaw and Higgins were all around the peak of the age range bell curve (60-65).

Hopefully, Michael Douglas's cancer has been picked up early and he will make a full recovery from chemotherapy.  I really hope so, it's very sad to see one's favourite childhood heroes dropping :(

 

Photo Credits:

Manny the Movie Guy

The Sweeney Info

Time for FDA and ODAC to decide on Avastin in breast cancer

Today I will be out of the office at client meetings, but many of you will be wondering what will happen at the FDA ODAC briefing meeting, which will be discussing the bevacizumab (Avastin) data in breast cancer this morning. You can take a look at the briefing documents here.

Background

As far as I can remember, Avastin was granted accelerated approval back in 2008 based on the E2100 study in combination with paclitaxel by the FDA after a split ODAC panel voted 5-4 against it, which makes today's proceedings even more interesting.  In the accelerated review process, a drug's efficacy is determined using a surrogate marker such as response rate, with full approval considered later once the survival data is collected and analysed.  

According to the FDA:

"The addition of bevacizumab to paclitaxel resulted in a 52% increase in progression-free survival (HR 0.48, 95% CI 0.39, 0.61; p< 0.0001) with an observed 5.5-month difference in median PFS, based on an independent radiographic review. There was no significant difference in overall survival, a secondary endpoint, between the two treatment arms. The tumor response rate was higher with bevacizumab plus paclitaxel as compared to paclitaxel alone (48.9% versus 22.2%)."

In Roche/Genentech's case, Avastin was approved to much fanfare because it was basically shown to shrink tumours quite dramatically and the magnitude of the PFS data suggested benefit in favour of adding Avastin to chemotherapy.  Full approval would be thus debated once the data was available:  

"As a condition of the accelerated approval, Genentech was required to submit data from two ongoing, placebo-controlled trials (AVADO and RIBBON1) to provide verification of the treatment effect on PFS and to provide additional information on the effects on overall survival."

Breast cancer was one of the early tumour types that Genentech tested the drug in but despite promising phase II data, the phase III study was negative and thus they decided to go back to the drawing board with the statisticians and investigate the drugs safety and efficacy in another large scale phase III trial. Meanwhile, colon cancer overtook breast cancer and became the first approved indication for Avastin instead.

Fast forward to 2010.

The data from AVADO and RIBBON1 is now available in the FDA briefing documents.  Here is a quick synopsis from each.  I confess that I found the FDA summary of the data a little confusing but the tables tell the picture more easily and have included the efficacy data tables from the briefing documents, where appropriate.

AVADO

This study comprised a double-blind, placebo-controlled, three-arm trial of:

• docetaxel plus placebo
• docetaxel plus bevacizumab 7.5mg/kg
• docetaxel plus bevacizumab 15 mg/kg

with all therapies given on a standard three-weekly schedule.

A total of 736 patients with HER-2 neu negative tumors who had not received prior chemotherapy for metastatic breast cancer were enrolled.

Overall the data was summarised as follows: 

Source: FDA (pdf link)

The OS Kaplan-Meier curve for the AVADO study looks like this - you can see that they cross over just coming up to two years:

Source: FDA (pdf link)

The FDA went on to describe the tolerability data as thus:

"Safety data showed an increase of grade 3-5 adverse events, serious adverse events and study drug discontinuation with the addition of bevacizumab to docetaxel. More patients in the bevacizumab-containing arms required interruption/dose reduction or discontinuation of docetaxel due to an adverse event."

RIBBON1

This was a double-blind, randomized, parallel group study conducted in people with metastatic or locally recurrent HER2-neu negative adenocarcinoma of the breast, who had not received prior chemotherapy for their advanced or metastatic cancer.  A total of 1237 patients were randomized (2:1) to receive anthracycline or taxane-based chemotherapy (n=622) or capecitabine (n=615) in combination with either bevacizumab or placebo.

The efficacy data looks like this:

Source: FDA (pdf link)
 

The FDA also summarised the side effect profile:

"Overall, the incidence of grade 3-5 AEs and serious AEs were almost twice as high in the bevacizumab arms compared to placebo arms in both cohorts. In the taxane/anthracycline cohort, taxane subgroup, there was slightly more deaths in the bevacizumab containing arm than placebo arm (49.8 % versus 43.1 %). 

The vast majority of the deaths were attributed to breast cancer. Adverse events known to be caused by bevacizumab were, as expected, increased in the bevacizumab containing arms in both cohorts. The most common AEs associated with bevacizumab were hypertension, bleeding/hemorrhage and febrile neutropenia."

Essentially though, the incidence of AEs is not significantly different than currently described in the prescribing information.

Overall:

In the summing up to the ODAC committee, the FDA document declares:

"AVADO and RIBBON 1 are well conducted, double-blinded trials. The magnitude of the improvement in PFS observed in these two studies failed to confirm the magnitude of PFS improvement observed in the E2100 trial, the basis for the accelerated approval. 

The magnitude of treatment effect is clinically important because it is really a measure of delaying symptoms from tumor progression, which has to be weighed against drug toxicity that is present for the duration of treatment."

The short answer is that the overall survival data suggested hazard ratios favoring the placebo arms in the AVADO study and the taxane/anthracycline cohort of the RIBBON1 study. This is important, because it raises the issue of risk:benefit because the women are being exposed to significant toxic side effects with no impact on overall survival.

What next?

Looking at the data from the two trials objectively, it is hard to justify treating women with newly diagnosed breast cancer with Avastin, when they would appear to live longer and have less side effects with chemotherapy alone. The PFS effect seen in E2100 has not been confirmed.

I wonder what ODAC will decide?

My educated guess is that one of two scenarios might happen:

1. Approval remains, but modify the PI language similarly to Iressa to indicate that there is no overall survival advantage associated with adding Avastin to chemotherapy.
2. Withdrawal of breast cancer indication for Avastin.

Technically, logic would suggest the latter option is more likely given the rules governing accelerated approval, but these panels are a notorious minefield sometimes, very hard to predict and the FDA doesn't always follow their advice, as the original approval for Avastin in breast cancer demonstrated!

What do you think?

{UPDATE: ODAC voted 12-1 to withdraw Avastin from the market.  The big question now is what will the FDA decide?}

The Long Tail of Cancer Research

"What's really amazing about the Long Tail is the sheer size of it. Combine enough nonhits on the Long Tail and you've got a market bigger than the hits." 

Source: Chris Anderson, Wired

The other other day, while barely lucid in the early hours of the morning, I was thinking about the herd instinct, the tendency to follow the masses and the counterpoint to that, i.e. the long tail.

If you're wondering what the long tail is, think of those statistical distribution plots where everything is bunched around the median, creating 50% on one side and 50% on the other.  At either end the plots tail off into infinity.  That's the long tail.  

The long tail looks small at first, but creative marketers realise that added up (as Chris Anderson's quote above shows), you can in effect still have quite a large niche market while every one else focuses on minute shares in the middle.

I first realised the long tail effect as a sales rep in the tough anti-cholesterol market.  You can spend fruitless hours chasing the majority of the primary care doctors who see reps but don't remember you when the relevant patient appears, or you can carefully invest time in the ones who don't see reps but are busy with appropriate patients and eventually crack if you try enough times. Once convinced, they often switch wholesale and your job is done with a smaller group of physicians who others can't see :-).

If we apply the principle of the long tail to cancer research, we can see things more clearly.  In the old days, the majority of patients got treated pretty much the same with various chemo doublets, irrespective of whether they might work or not.  In fact, in many cases, there wasn't even biomarkers such as ERCC1 to determine which patient should get platinum or not, but things are changing and now it's much easier to make these decisions and start segmenting patients according to their biochemical profile and make decisions based on the profile.

Today, we can take this niche idea to treatment a lot further.  

In colon cancer, for example, we now know that patients with wild type KRAS are more likely to respond to an EGFR therapy than those with mutant KRAS. However, in lung cancer, the old adage was that erlotinib (Tarceva) was best suited for patients who were female, asian, non-smokers with adenocarcinoma is giving way to a more precise definition, i.e. do they have the EGFR mutation or not? If they do, they're more likely to respond, irrespective of smoking status. Offering these patients maintenance treatment may also be an effective treatment strategy that impacts outcomes.  

We can see this effect in other cancer types too.  Trastuzumab (Herceptin) is approved for women with Her-2 breast cancer, imatinib (Gleevec) and other TKIs such as dasatinib (Sprycel) and nilotinib (Tasigna) for Philadelphia-chromosome positive chromic myeloid leukemia (CML).

Histology is a very crude way to select patients, but looking at the aberrant mutations essentially creates niche long tail opportunities to treatment for pharma and biotech companies.  Patients who are more likely to respond to a given therapeutic get appropriate treatment, without having to expose others who would not to unnecessary systemic effects. This is a win-win solution all around.  

Why?  

Well, it's good news for patients as you increase the chances of successful outcomes rather than relying on hope alone.  It's also good news for manufacturers because smaller patient populations ultimately involve fewer patients in clinical trials, thereby making clinical development more cost effective and as cancer therapy moves from an acute to chronic disease, so longer term revenues are generated despite a small patient base.

As more oncology companies start looking at their pipelines, we can see many asking the critical questions - which patients are more likely to respond to a given treatment and why?  As we learn more about the underlying biology of the disease, so companion diagnostics are also evolving in sophistication and sensitivity.

The other marketing advantage of developing niche targeted therapies and diagnostics is that often, you see less competition for smaller subsets of disease because it creates a high barrier to entry. Diagnostics also create barriers to entry because of the extra costs involved in their development.  For smaller biotechs this can be prohibitive, and many are more actively seeking Pharma and Biotech partners to fund late stage research and clinical trials.  Overall, the long tail opportunities offer big and small hurdles, depending on the circumstances.  

Roche's VEGF monoclonal antibody bevacizumab (Avastin) has a very high barrier to entry in colon cancer, for example, as other VEGF inhibitors have fallen by the wayside, unable to beat the results already obtained by the first to market drug.  

At the other end of the scale, the barrier to entry is much lower in renal cell cancer with numerous targeted therapies now approved for a relatively small niche indication, including sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor), pazopanib (Votrient) and bevacizumab (Avastin), probably reflecting the improvement over IL2, without completely reducing unwanted side effects or dramatically improving efficacy.

Some of the marketed therapies mentioned in this post are now billion dollar blockbusters despite cancer being a relatively niche market opportunity compared to the much bigger primary care markets such as metabolic or cardiovascular disease, proving that there are valuable nuggets to be found, even in the long tail.  

The future in cancer research is not in broad acting systemic chemotherapies that target normal cells as well as cancer cells, but in the niche development of better and less toxic targeted therapies based on the underlying biological abnormalities with easy to use diagnostic technology based on fluid-based biomarkers.  To achieve this though, will take a lot of bright smart people with expertise in oncology who dare to think differently and boldly, whether they be scientists, marketers or clinical research professionals.

Watch this space!

Pharma R&D is a rollercoaster - Mylotarg withdrawn and Ziopharm stumbles

Interesting news in Pharmaland today as we hear that Pfizer has decided to voluntarily withdraw gemtuzumab ozogamicin (Mylotarg) from the market and the FDA declined to grant Ziopharm an SPA for their phase III trial with palifosphamide (palifosfamide for those reading in American English) in soft tissue sarcoma.

The first is unexpected, the second interesting.

Mylotarg

In 2000, Wyeth (now part of Pfizer) were granted accelerated (fast track) approval in AML for Mylotarg, an anti-CD33 monoclonal antibody, on the basis of response rates, with the intent that survival data would provide evidence for full approval. Unfortunately, like Iressa's situation in lung cancer, that did not happen so polite withdrawal is the only option in this situation. Perhaps the only surprise is that it took a decade for it to happen.

It's not a big loss for elderly AML patients, given the drug never showed any major efficacy benefit and the side effect profile of fevers, chills, nausea and vomiting severely impacted quality of life for many frail people. Many AML patients are over 60 and in much less robust health compared to younger, fitter patients who might be candidates for high dose chemotherapy and a transplant. This is where Mylotarg was supposed to offer hope, given the limited options. In this setting, the ideal drug would be a targeted therapy without too many debilitating adverse events. Early toxicities with Mylotarg, however, were not pleasant:

"... among all patients evaluable for early toxicity the fatal induction toxicity rate was significantly higher in subjects given the combination of standard induction chemotherapy and Mylotarg than in those treated with chemotherapy alone."

Source: Pfizer

I always look at sales as a good indicator of whether physicians like a drug or not.  At around $35M annually, Mylotarg clearly wasn't a popular option. Sometimes we need to focus on what matters - response rates per se (around 10-13% complete responses) don't mean much in isolation, but extending lives does, hopefully without too much collateral damage. In this situation, Pfizer made a good call.

Palifosfamide

Ziopharm's management team have been very bullish and brimming with confidence lately, however, such sentiments can sometimes turn out to be irrational exuberance.  The phase II PICASSO trial with palifosfamide and doxorubicin versus doxorubicin alone has completed enrollment with initial promising interim results in metastatic or unresectable soft tissue sarcoma and the company were clearly hoping to negotiate an SPA with the FDA for the phase III trials, but it seems negotiations have broken down on that front, with concomitant fall in the share price.

The trial design is interesting for several reasons.  

Firstly, the current standard of care for treatment of soft tissue sarcoma is ifosfamide plus doxorubicin but there's no comparator arm with ifosfamide, an old chemotherapy now available generically.

According to the company:

"Palifosfamide (ZIO-201) is a proprietary stabilized metabolite of ifosfamide."

Meaning it's a second generation version of the generic, but is it any better than ifosfamide?  We won't know with the proposed design. Of course, the current reimbursement structure means that oncologists will make more revenue from a branded drug (6% of $1000 is more than 6% of $100), whereas in the old scheme, there was more usage of generics because the spread was greater than for newer, more expensive therapies.

Secondly, the big sticking point for the FDA was the proposed primary endpoint, ie PFS rather than overall survival (OS).  One does not always follow the other, but seriously, accepting OS as the goal may well have been an easy win-win for Ziopharm. It seems a little odd that they chose not to go there in the initial discussions with the FDA:

"In a recent communication, FDA has indicated that the Company could conduct the pivotal trial as designed without SPA and that approvability would be determined by the data, balanced with risks and benefits. FDA presently considers the endpoints as designated for the proposed pivotal trial as not supportive of SPA in this disease setting, although they would grant SPA with modified endpoints."

If changing the endpoint from PFS to OS is all that is needed for garnering an SPA, I think I would grab it and go. It's much easier to gain approval if you meet the criteria for a pre-negotiated SPA, as Roche/Genentech have shown with Tarceva several times, even with marginal, yet significant improvements, based on well powered studies. Going it alone without agreement with FDA is a recipe for disaster down the road, as many small biotechs have discovered to their dismay over the last 18 months.

Two new cancer drugs approved - cabazitaxel and nilotinib

Yesterday brought two new approvals in a day from the FDA in completely different cancer types.

In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule.  This approval comes hot on the heels of Dendreon's sipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.

What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break.  It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.

The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none.  Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists. 

Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.

The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over. 

Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.

Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).  

If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?  

What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly. 

Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.  

It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates - in this case - complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).

Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year survival data will evolve.

Disclosure:  I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :).  Many thanks to @erohealth for proofreading suggestions.

The interesting dichotomy of oncology research vs clinical medicine

Over the past few years it has been interesting to watch AACR organise and group it's sessions by pathways, so you end up with a higgledy piggledy collection of different inhibitors, therapeutics, chemotherapies etc as well as a mix of different tumour types.  This works well for the scientist, less so for the clinician who may specialise in only a few cancer types.  

Meanwhile, at ASCO, everything is organised by cancer track, so if you want to search for data on say, MEK, AKT or c-MET inhibitors for example, then the data is now all over the place and trying to get round and find it all is much more difficult.  The chances of missing something, or worse, having clashes in interesting sessions is much higher.  I'm already looking a potential schedule with too many clashes and periods of nothing.  That's not a very efficient way to organise the data, yet this was not something I experienced at AACR to the same extent.

Personally, I find myself much preferring the AACR approach because it's ultimately logical and allows you to see patterns and trends more strategically, providing you approach it sensibly. You do need to think in 3D though, much like that 3 level chess board beloved by Spock in the original Star Trek. This way allows you to see potential connections and future approaches more easily rather than being hemmed in by tumour siloes.

In the long run, I confidently predict that the future trend of personalised medicine is going to be more based on a pathways approach allied with mutational analysis based on constitutive activation, rather than simply thinking in terms of cancer type by line of therapy.  Once you start understanding which subsets exist and which inhibitors can be combined together, it is not hard to see a new world evolving out there that may lead to better outcomes and improved quality of life.

Who knows, we might even be able to get rid of toxic chemotherapies altogether and prescribe a cocktail of more targeted agents based on the patients characteristics.

Now that would be a fine thing indeed.  Thoughts?

Photo Credit: GiftsforyouBiz

New developments in castration resistant prostate cancer - MDV3100

Last night I received an alert from Medivation announcing that an article would be published in today's online The Lancet regarding their prostate cancer agent, MDV3100.  Sure enough, here's the article:

Although the trial is an early phase I/II study, encouraging antitumour effects were reported in 140 men, of whom 65 were chemotherapy naïve.  Time to disease progression (TTP) was 47 weeks, which is decent considering the men in the study were all castration resistant and likely had advanced disease.  

Obviously, it is too early to tell yet quite what Medivation and Astellas have here, but to put things in context, docetaxel (Taxotere), was approved for hormone refractory prostate cancer (HRPC) with prednisone in androgen independent (hormone refractory) metastatic prostate cancer with a median overall survival of 18.9 months (approx. 85 weeks) in a large phase III trial. 

We must also remember that in another more recent trial, it was demonstrated that men who received cabazitaxel (sanofi-aventis' follow on taxane to docetaxel) lived a median of 15.1 months (68 weeks), compared with 12.7 months (57 weeks) for those who receive mitoxantrone, a difference that was statistically significant.

That said, the side effect profile of chemotherapy is certainly not benign, with significant risk of myelosuppression and infectious complications.

However, what was encouraging about the Medivation trial was early Kaplan Meier response curves, which demonstrated those men who had no previous chemotherapy generally did better than those who received it in terms of both PSA and radiological progression.

At the AACR Molecular Targets meeting last November, Charles Sawyers gave a keynote talk on prostate cancer and looked at the various opportunities for investigating new therapeutics in clinical trials for prostate cancer.  He suggested that circulating tumour cells (CTCs) might be a more useful marker for disease status than PSA.  In The Lancet study, the authors noted that:

"We recorded early post-treatment conversions from unfavourable to favourable in 75% of patients not exposed to chemotherapy and in 37% of those who were exposed. Decreases in PSA were generally associated with parallel falls (or no progression) in CTCs, but this finding was not consistent, suggesting that these measures assess different aspects of the malignant process. PSA decreases might in some cases be an indicator of the mechanism of action of MDV3100 as an androgen-receptor antagonist rather than an actual antitumour effect. However, the benefit of MDV3100 on several assessments, including CTCs and radiological time to progression, suggest that MDV3100 does have a true antitumour effect."

The other interesting observation that Sawyers made was that traditionally, early prostate disease is treated with oral hormonal therapies and once castration resistance sets in, the patient is referred to an oncologist for consideration of chemotherapeutic options.  With the advent of new therapies with different MOAs in development such as MDV3100, abiraterone (Cougar/J&J) and Provenge (Dendreon), the lives of men with prostate cancer can potentially be extended further before stage IV metastases sets in. 

At AACR last November, Sawyers also discussed the importance of androgen receptor signalling in the disease (previously discussed here with simple models) and the data from this trial seem to bear out his elegant theory.  I'd like to see more analysis though and learn whether those men who had AR amplified prostate cancer did better on MDV3100 than those who did not?

All in all, this is an exciting time for men with prostate cancer.  Dendreon's Provenge may well be the first new drug that fits between the hormonal therapies and chemotherapy, since the FDA PDUFA date is May 1st, although since that is a Saturday, we may well here the Go/No Go news on Friday 30th April.  

In the meantime, the annual AACR meeting in DC this weekend can't come soon enough!

Scher, H., Beer, T., Higano, C., Anand, A., Taplin, M., Efstathiou, E., Rathkopf, D., Shelkey, J., Yu, E., & Alumkal, J. (2010). Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study The Lancet DOI: 10.1016/S0140-6736(10)60172-9

Improved survival in a rare cancer with chemotherapy

An interesting article has been published in the latest New England journal describing how the addition of a cisplatin to gemcitabine improved survival by two months in biliary tract cancer.  Currently, there is no standard treatment for this rare disease, so a solid phase III trial (ABC-02) represents an important step forward for treatment.

Biliary tract cancers are tumours that develop in the gallbladder and bile ducts. Those that develop in the bile duct within the liver are known as cholangiocarcinomas.  Approx. 6500 new cases of gallbladder carcinoma are diagnosed each year in the US.  Interestingly, chronic inflammation appears to be a common aetiologic factor in the disease development.  There has been a rise in incidence of the cancer in recent years, which may possibly be attributable to the association between liver disease and increasing hepatitis C virus infections.

Although there are no standards, gemcitabine has been the bedrock of palliation therapy for the disease based on the experience in pancreatic cancer.  The earlier ABC-01 phase II trial suggested a benefit in adding a platinum to gemcitabine.  

In the current ABC-02 phase III trial, the median overall survival with the combination was 11.7 months and 8.1 months in the gemcitabine alone group, a significant improvement of 3.6 months.  

As a result, the combination of cisplatin and gemcitabine is likely to become the new standard of care for the treatment of biliary tract cancer.  As we learn more about the science and biology underlying the disease, further improvements may be possible with the addition of targeted agents.

Reference
Valle, J., Wasan, H., Palmer, D., Cunningham, D., Anthoney, A., Maraveyas, A., Madhusudan, S., Iveson, T., Hughes, S., Pereira, S., Roughton, M., Bridgewater, J., & , . (2010). Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer New England Journal of Medicine, 362 (14), 1273-1281 DOI: 10.1056/NEJMoa0908721

West, J., Wood, H., Logan, R., Quinn, M., & Aithal, G. (2006). Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001 British Journal of Cancer, 94 (11), 1751-1758 DOI: 10.1038/sj.bjc.6603127

El-Serag HB, Engels EA, Landgren O, Chiao E, Henderson L, Amaratunge HC, & Giordano TP (2009). Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans. Hepatology (Baltimore, Md.), 49 (1), 116-23 PMID: 19085911

Genvec's TNFerade fails in phase III trials for pancreatic cancer

It's been a busy week on the road here at Icarus and today and tomorrow are no exception, so finding time to blog is a little more challenging.

Yesterday, I got back from a biomarker symposium in Princeton to find that my Twitter and almost everything else Pharma related were full of Genvec's announcement that their phase III trial for TNFerade was being discontinued in pancreatic cancer. 

It's not really a drug, more an experimental gene therapy, that according to Genvec:

"Acts as an adenovector, or DNA carrier, which contains the gene for tumour necrosis factor-alpha (TNFα), an immune system protein. It is directly injected into the tumour. After administration, TNFerade stimulates the production of TNFα in the tumour."

The abandonment of the trial isn't really big news though, as the drug previously failed in melanoma and other cancers, despite the magic words, "promising phase II data."  Let's face it, pancreatic cancer is also probably one of the toughest nuts to crack out there in the oncology world. Sadly, it was doomed to failure from the beginning; I would have been more surprised had it actually worked.

Genvec have a raft of other trials that are either currently enrolling people with various cancers or have recently finished enrollment; I wonder what the fate of the overall program will be given the repeated negative results?

At the beginning of this month many pharma and biotech pundits smiled at the 'beware the Ides of March' quips on Twitter, but by the end of March they seem much more accurate than one may realise!  

Looking back through the months posts, there were several spectacular phase III flops from Pfizer and Roche, Roche's ocrelizumab and AstraZeneca's cediranib bit the dust, the ODAC meeting on 22nd was brutal for Cell Therapeutics and ChemGenex with neither getting approved, Antisoma's ASA404 crashed on Monday, Merck KGaA are reviewing the EU cardiac data for Erbitux, which may also have implications for BMS and ImClone in the US.  Yikes, I could go on...

Let's hope that April and May bring more positive news to talk about.

Antisoma and Novartis lung cancer drug ASA404 flops in phase III

This morning I did a double take at an email alert that flashed through my email:

"ATTRACT-1 phase III trial of ASA404 halted following interim analysis"

Ugh, that's not good news considering the phase II data previously discussed in January looked very promising with a solid improvement (source data), ie median time to tumor progression was 5.5 months by investigator assessment and median survival was 14.9 months when used in combination with carboplatin-paclitaxel compared to the standard alone.

The Antisoma press release was very downbeat and clearly they were not expecting to receive any more funding from their partner, Novartis:

"The planned interim analysis of data from the ATTRACT-1 phase III trial of ASA404 in previously untreated non-small cell lung cancer (NSCLC) has shown that continuation of the trial would be futile, as there is little or no prospect of demonstrating a survival benefit with ASA404 in this setting. The ATTRACT-1 trial will therefore be halted."

Novartis (a client, but not on this particular agent) bought the global rights to ASA404 (vadimezan) from Antisoma, a British company, approximately three years ago. ASA404 was leading a new class of chemotherapy agents known as vascular targeting or disrupting agents, designed to inhibit angiogenesis and disrupt the flow of blood to tumours. The concept works in a different way to Roche and Genentech's bevacizumab (Avastin), which starves tumours from growing new blood vessels and proliferating the cancer mass.  ASA404 exerts direct and indirect effects on endothelial cells rather than the VEGF receptor, as this diagram shows:

Source: Novartis Oncology

Novartis and Antisoma were also developing ASA404 in breast cancer as well as non-small cell lung cancer, so we'll have to wait and see what happens to that program going forward.  For now, the negative news in lung cancer meant that investors cleared out their shares, sending the stock into a major freefall this morning.

It's been a tough year for cancer drugs in lung cancer in 2010 already, following several spectacular rounds of futile data from Pfizer's figitimumab, Novelos's NOV-002 and now ASA404, all of which had promising but early data in phase II, only to stumble in phase III.

Thoughts on the pixantrone FDA ODAC meeting

Yesterday was quite day, with one thing and another.  For starters, the FDA ODAC committee finally held a session for Cell Therapeutics pixantrone in 3rd line NHL and ChemGenenex's omacetaxine, for people with the T315i mutation in CML.  The previously scheduled meeting was cancelled due to the Snowpocalyse that hit DC last month. 

I had to dash off to a doctor's appointment myself so missed most of the action on Twitter and rushed back to catch up at lunchtime by checking Twitter buddies such as Kerri Wachter who was live tweeting from the meeting and Adam Feuerstein of The Street's excellent live blog.

Image via Wikipedia

You can see my original review of the February FDA documents here.  Sadly, the analysis turned out to be accurate and Adam had noted:

"That was brutal."

Approximately 20 minutes into Richard Pazdur's opening introduction. 

In particular, the FDA felt that:

"Pixantrone has demonstrated evidence of biologic activity, but the mere demonstration of biologic activity is not sufficient for approval."

Ouch!  At that point it becomes incumbent upon the company presenters to argue persuasively to the nine panel members to convince them otherwise.  However, that was going to be a tall order given the FDA concerns regarding:

1. Neutropenia and infections were higher in pixantrone than the control
2. Cardiac toxicity was higher in pixantrone than control, including heart failure and ejection fraction

As highlighted in the original analysis of the pixantrone filing, the FDA were also unhappy about the shortened study given only 140 people were enrolled out of the planned 320, leading them to conclude:

1. Study was not well executed or complete.
2. Study was inconsistent (only 8 people enrolled in the US and none had a complete response).
3. Trial did not demonstrate statistical significance or robust findings.

What was weird about the proceedings though, was a clear disconnect between the two parties, as Adam Feuerstein reported live via the webcast:

"Pazdur: FDA not consulted about halting enrollment in trial, not pre-specified in study's statistical plan."

"Bianco: In March 2008 after 140th patient was enrolled, study was closed to enrollment. We consulted with FDA about this."

Checking my Twitter stream, Kerri reported:

Personally, I was surprised that CTI thought that the statistical parameters would not change if they only recruited 140 of the 320 people expected and could proceed on that basis.  This is basic college level statistics - if you majorly change one input, the outliers must also be adjusted.  For this reason, the FDA's decision to treat the data as if an interim analysis had been done is fair and reasonable.

Going forward, it is likely that either all 320 patients would need to be enrolled in a study to meet the minimum FDA requirements or new studies in combination with other agents would be needed.  This latter approach is probably more likely, because the US sites (28 of them) only enrolled 8 people because the preferred treatment in the 3rd line refractory setting is combination chemotherapy, not single agent therapy. 

Perhaps the snowpocalypse last month was a portend of what was to happen.  Either way, yesterday was a bad day in DC for CTIC.

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The future of Oncology

A short while ago on this blog we began a series on Making a Difference about people in the cancer field who have a real passion and excitement for lasting and impactful change.  The first one was an interview with Alain Moussy of AB Science in Paris.

Today, I had the pleasure of chatting with the admirable Dr. Susan Desmond-Hellmann, formerly Head of R&D at Genentech and now Chancellor at UCSF.  It's a strange business sometimes as we were both working in industry at the same time on different targeted cancer drugs in liquid and solid tumours but our paths never crossed, although it seems we share similar views on cancer drug development, ie purer targeted agents and finding faster ways to market for effective therapies that impact the lives of people with cancer.

Which brings me to the main topic of today's discussion.

There are many challenges in cancer drug development, not least of which are regulatory hurdles, time consuming, risky and expensive clinical trials (we've seen a lot of phase III failures lately), basic research, biomarker development and many others. Traditionally, cancer trials take two main strategies to market:

• Head to head comparison with standard care or a with and without approach if adding a new agent to the combination
• As a single agent in the relapsed, refractory setting

Both of these approaches are typically tested in the advanced or metastatic setting when the disease burden is relatively high and the risk of a drug failing in phase III trials is also high.  In solid tumour cancers, once a drug has been shown to be effective, studies tend to move into the earlier, adjuvant setting after surgery has taken place but these trials can take a very long time to reach fruition, typically 5-10 years in some cases.

For many of us, the challenges of how to think outside the box and speed up development while treating earlier stage of disease more effectively has occupied many thoughts.  Sometimes the bureaucracy across so many functions is just mind boggling.

No more.

Dr Desmond-Hellmann was telling me about the Investigation of Serial Studies to Predict your Therapeutic Response with Imaging and Molecular Analysis (I-SPY) project, which was launched in DC this morning and aims to change the way we think about cancer drug development. 

"What's really neat about the I-SPY trial is that Laura Esserman, the PI of the trial, is a breast cancer surgeon here at UCSF and has added so much value to the project because she sees patients early and has a unique opportunity to offer neoadjuvant therapy.

Patients are getting their primary therapy before they get surgery, so for imaging and biomarkers - either established or exploratory - it is a fantastic opportunity. The endpoint is pathological complete response, so you can see if the tumour has disappeared or not."

Treatment with therapeutics prior to surgery is known as neoadjuvant therapy and has a much shorter time span (around a year) for collecting results than adjuvant trials.  Furthermore, Dr. Hellmann elaborated what is exciting about this new approach:

"It's a fantastic rapid readout model so you can get answers much more quickly in a year, including pathological specimens, along with the answers from biomarkers and imaging, which are important.

The FDA has allowed a master IND agreement for this study, so it will be possible to move agents in and out of the trial quickly.

So if agent A looks promising it can be advanced quickly and more patients put on it, but if agent B looks toxic, it can be discarded quickly.  It's not just a clinical trial but a experimental trial process that gives you a rapid readout of whether the agent works or not.

The hope is that you won't wasting time and money in phase III trials, but most importantly, patients experience on that molecule.  If the answer is yes on I-SPY, you then have a biomarker hypothesis for that agent and can then do a more traditional phase III trial having increased your chances of success."

In this way, we will also learn more about the biology of the cancer and effectiveness of the treatments earlier in the course of the disease, which may lead to better long term survival than if treatment is delayed to the later stage of disease, when the cancer has spread and metastasised.

You can find out more about the clinical trial process here and here.

The trial will look at the following protocol:

Source: I-SPY2.org

For breast cancer, the standard of care is paclitaxel followed by four cycles of anthracycline therapy.  In this model, women with breast cancer can also receive other therapies, either marketed or investigational, to see if their outcome can be improved.  For this I-SPY2 project, the five initial investigational agents are provided by Pfizer, Abbott and Amgen:

1. ABT-888 (veliparib) from Abbott, is a PARP inhibitor
2. AMG 655 (conatumumab) from Amgen is an APO/TRAIL protein that causes apoptosis
3. AMG 386 from Amgen is a VEGF angiogenesis inhibitor similar to Genentech's Avastin
4. CP-751,871 (figitumumab) from Pfizer is an IGF-1R inhibitor that targets the insulin receptor
5. HKI-272 (neratinib) from Pfizer is a Pan ErbB inhibitor similar to Herceptin

None of the I-SPY-2 breast cancer project would have been possible without the passion, energy and enthusiasm of women such as Drs Sue Desmond-Hellmann, Laura Esserman or Janet Woodcock of the FDA, who has been pressing for more creative solutions to fast track better cancer drugs for some time.  This consortium is particularly fascinating to watch because it brings together the major players - academia, industry and the FDA, in a way that has never been done before.  We should salute their originality and endeavour to think, and more importantly, do things differently.

If the basic concept proves successful, such a revolutionary clinical trial process may well become the new model for early and more effective drug testing, not only in cancer, but also for other diseases such as alzheimers, diabetes and other chronic diseases.  In the long run, this approach may also lead to lower healthcare costs by improving efficiencies. 

While Dr Hellmann was excitedly describing the process, I was thinking how much intuitive sense it makes and wished that the bureaucratic hurdles to more collaborative academia-industry-FDA clinical trials had fallen long ago.  

The important thing though, is that's it's actually happening right here, right now and for people with cancer, that is good news indeed.

The future of Oncology... is in neoadjuvant and biomarker led trials.