Pieter Droppert | Biotech Strategy Blog

Which posters were hot at ASH 2011?

In my final post about the 2011 American Society of Hematology (ASH) annual meeting, I want to highlight a few of the 4000+ posters that appeared to attract a lot of interest.

The three ASH poster sessions in the equivalent of an aircraft hangar, had a lot of interesting science and clinical data.

All the posters had merit in order to be selected for publication, so my selection is entirely subjective:

Bruton’s Tyrosine Kinase (BTK)

Two posters on products targeting BTK attracted a lot of traffic:

#3485 Clinical Development of AVL-292; A Potent, Selective Covalent Btk Inhibitor for the treatment of B Cell malignancies

#3688 Activity of Bruton’s Tyrosine Kinase (Btk) inhibitor PCI-32765 in Mantle Cell Lymphoma (MCL) identifies Btk as a Novel Therapeutic Target

Sally Church on Pharma Strategy Blog has written an in-depth piece on Bruton’s Tyrosine Kinase Inhibitors in B-Cell Lymphomas and talks about the above two abstracts.

She also discusses the oral presentation at ASH by Dr Susan O’Brien on the phase I/II data for PCI-32765 in CLL.

Dr Anas Younes from MD Anderson Cancer Center also picked BTK as a hot lymphoma topic on his blog about the ASH meeting. On Facebook he notes,

“There is a lot of buzz about the promising clinical results with the oral small molecule inhibitor PCI-32765, which inhibits an enzyme called Bruton kinase (BTK).”

PI3-Kinase Pathway

PI3-Kinase was another topic I noticed there was interest in, and several posters were presented at the meeting. In particular, those on CAL-101 attracted a lot of attention, I have highlighted a couple below:

#1787 A phase I study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K∂) Inhibitor, CAL-101 (GS-1110), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

#2699 A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kδ) Inhibitor, Cal‑101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Previously Treated, Indolent Non-Hodgkin Lymphoma (iNHL)

CAL-101 is an inhibitor of the PI3K delta isoform, which is thought to play a key role in lymphomas.

I overheard several people comment that the PI3K space was now becoming very crowded.

With multiple companies including Gilead, Novartis, Roche/Genentech, Sanofi-Aventis, Pfizer and Intellikine to name a few, interested in this target, it will be interesting to see how this market segment develops.

Update December 21, 2011

Little did I know how hot PI3K inhibitors were when I wrote the above with the announcement in the past 24 hours of two PI3K related deals:

Takeda/Millennium have acquired Intellikine. This deal shows you can still build a biotech company and make money. Congratulations to Intellikine CEO Troy Wilson.
Exelixis entered into a licensing deal with Merck for their PI3K-delta inhibitor (XL499) that is still in preclinical development.

Interesting contrasts in the two deals: one a total acquisition of the company, the other a licensing deal, but both highlight the potential strategic importance that companies see in having a PI3-kinase inhibitor in their pipeline.

Sally Church on Pharma Strategy Blog has written more about the Intellikine & Exelixis deals in her lymphoma update from the 2011 American Society of Hematology annual meeting.

AML update from 2011 ASH annual meeting

At the recent American Society of Hematology (ASH) annual meeting in San Diego, I had the opportunity to hear a few presentations on Acute Myeloid Leukemia (AML).

Those of you familiar with the ASH annual meeting will know that most of the oral presentations for the biology and therapies take place in simultaneous sessions on Monday. This sadly results in many session conflicts if you want to follow several products, pathways or multiple disease areas.

It’s unfortunate that there’s no virtual meeting such as at ASCO or that presentations are not more spread out during the meeting. My AML update is therefore focused specifically on FLT3 inhibition.

A good definition of AML comes from a recent paper in the journal, “Blood” where Yang Shen and colleagues from the Shanghai Institute of Hematology and other Chinese institutions describe it as:

“A group of heterogeneous diseases with considerable diversity in terms of clinical behavior and prognosis.”

A lot of work has been done in identifying the cytogenetic abnormalities associated with AML. Considerable effort has been spent in attempting to correlate the molecular changes with clinical outcome.

In their Blood paper, Shen noted that in more than 50% of AML patients, no cytogenetic markers can be found. In an analysis of 1185 patients, they found:

“A correlation pattern among NPM1, DNMT3A, FLT3, IDH1, CEBPA, and TET2 mutations. Multivariate analysis identified DNMT3A and MLL mutations as independent factors predicting inferior overall survival (OS)”

What this research highlights is the challenges in attempting to target specific mutations in AML, such as FLT3, when multiple mutations are associated with the disease.

FLT3 has been shown to be prognostic of poor survival, but is it an attractive molecular target in AML?

That was the question asked by Catherine Smith (UCSF) in an oral presentation at ASH 2011. She first noted that FLT3 is over over-expressed in the majority of AML, and is one of the most commonly mutated genes (~20%). Patients with internal tandem duplications (ITD) of FLT3 have been shown to have a worse prognosis.

But is FLT3 a driver lesion in AML?

(For an excellent review of the difference between driver and passenger mutations see Sally Church’s video interview with Gordon Mills at ECCO/ESMO 2011 on Pharma Strategy Blog.)

Smith noted that a “lack of clinical efficacy called into question validity of FLT3 as a therapeutic target.” Only sorafenib has anecdotal reports of a complete remission, she noted.

Using Next Generation Smart Single Molecular Real Time Sequencing, Smith evaluated the drug resistant mutations in 8 patients with acquired resistance to AC220 (quizartinib), a selective FLT3/KIT inhibitor currently in development by Ambit Biosciences & Astellas.

Smith concluded that:

FLT3-ITD is a valid therapeutic target in human AML
Mechanism of action of AC220 in AML involves FLT3 inhibition
FLT3 “gatekeeper” and activation loop mutations represent high value targets for next generation FLT3 inhibitors.

AC220 shows efficacy in relapsed/refractory AML

In a poster presentation at ASH 2011 (abstract #2576), Jorge Cortes (MD Anderson Cancer Center), presented updated interim results for AC220 in FLT3-ITD positive refractory/relapsed acute myeloid leukemia.

Cortes concluded from the phase 2 open-label trial:

Preliminary data suggest that AC220 (quizartinib) achieves clinically meaningful responses in patients with both refractory and relapsed FLT3-ITD+ AML
Many patients were successfully bridged to HCST [hematopoietic stem cell transplantation]
These encouraging efficacy results and an acceptable high-risk profile support continued evaluation of AC220 (quizartinib) in mono- and combination therapy.

I was pleased that Ambit Biosciences made it easy to obtain a copy of their poster by using a QR code. Both Novartis and BMS also used QR codes on their posters at the ASH meeting.

As more people attending meetings have smartphones and iPads, being able to email or download a PDF of a poster by scanning a QR code is becoming more accepted. I currently scan all paper copies of posters, so obtaining an electronic PDF version in the first place is more time efficient, as well as being ecologically friendly.

Two other FLT3 presentations by Catherine Smith from the University of California at San Francisco (UCSF) also caught my attention at ASH.

PLX3397 is a FLT3 inhibitor in early-stage clinical development

In a presentation with colleagues from the University of Pennsylvania and Plexxikon, Smith evaluated the in-vitro activity of PLX3397, a selective FLT3 inhibitor.

Readers may recall that PLX3397 was mentioned in my post from the 2011 San Antonio Breast Cancer Symposium on targeting macrophages in breast cancer.

Smith noted that a phase 1/II study of PLX3397 in FLT3-ITD+ relapsed/refractory AML is ongoing. This certainly looks like an interesting compound to watch.

Ponatinib shows clinical activity against AC220-resistant FLT3-ITD mutants

In another excellent presentation by Catherine Smith, she looked at the potential for ponatinib in AML.

“Ponatinib is an ABL/FLT3 inhibitor that potently decreases signaling and viability in FLT3-ITD driven MV4;11 cells,” said Smith.

At the ASCO 2011 annual meeting this year, Moshe Talpaz (Michigan) presented results from a phase 1 study of ponatinib in AML that showed 2 out of 7 FLT3-inhibitor naïve FLT3-ITD+ patients achieved a complete remission (incomplete).

“The overall response rate in the AML cohort was 25% (3/12): 2 pts (29%) had CRi and 1 (14%) had PR. All responses observed were in the subset of pts with the FLT3/ITD mutation who were naïve to FLT3 inhibitors: 3/7 (43%).”

Talpaz et al, J Clin Oncol 29: 2011 (suppl; abstr 6518)

Smith’s conclusion from her in-vitro analysis of ponatinib against AC220-resistant mutants, was that “a phase II study of ponatinib in FLT3-ITD+ AML is warranted.”

Given the promising early data, it seems highly likely that Ariad will move forward with a phase II trial of ponatinib in AML.

My conclusion from ASH 2011 is that targeting FLT3 shows some promise for a subset of AML patients, but more clinical data is needed to validate the preliminary responses seen. In addition, midostaurin (PKC412) is currently enrolling patients in a large phase III CALGB trial in the maintenance setting, so results will not be available for a little while.

There are some interesting questions to address in this field:

Will FLT3 inhibitors be more effective in the maintenance setting after induction therapy to prolong CRs and outcomes?
Or will they be best used in the relapsed, refractory setting where FLT3 could be driving aberrant activity?

I look forward to seeing more data on quizartinib, ponatinib and midostaurin in AML at future meetings. PLX3397 looks like an interesting compound to watch.

Shen, Y., Zhu, Y., Fan, X., Shi, J., Wang, Q., Yan, X., Gu, Z., Wang, Y., Chen, B., Jiang, C., Yan, H., Chen, F., Chen, H., Chen, Z., Jin, J., & Chen, S. (2011). Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia Blood, 118 (20), 5593-5603 DOI: 10.1182/blood-2011-03-343988

CML update from 2011 ASH annual meeting

The annual meeting of the American Society of Hematology (ASH) took place in San Diego this past weekend. There was a lot of interesting science, and over the next three posts I will be writing a brief summary of what caught my attention in CML, AML and the poster sessions.

Brian J. Druker & Janet D. Rowley received the Ernest Beutler prize and presented a lecture on “Chronic Myeloid Leukemia (CML): A Success Story from Chromosomes to Effective Therapy.”

As a result of the development of imatinib (originally STI571), “CML has been converted to a manageable condition”, said Druker.

He also noted that, “the next quantum improvement would be disease eradication.”

Can we aim at a cure? This question was asked by Junia Melo (Adelaide) in the excellent CML education session that also included presentations by Neil Shah (UCSF), Andreas Hochhaus (Jena).

The ASH annual meeting spends a lot of time and effort on educational programs and each year different topics are selected. In previous years I have listened to excellent presentations on AML & CLL. The session is a good way to come up to speed with an area, and usually the presenters highlight topical abstracts at the meeting that are noteworthy.

In her CML education session, Melo suggested that the concept of an “absolute cure: the eradication of the last leukemia cell from the patient’s body” was something that was almost impossible to measure. More realistic was the concept of an “operational cure: the disappearance of all signs of disease and the possibility of blastic transformation.”

Melo presented interesting research on targeting CML stem cells, and conceptual models for drug-free remission (“cure”) that involved stem cell depletion and exhaustion. This may be an area for future drug development.

FTY720 (fingolimod) inhibits self-renewal and promotes apotosis of the quiescent stem cell, said Melo. BMS-214662 was also mentioned as an interesting compound in this area.

The most newsworthy CML data presented at the meeting was on Ponatinib. Jorge Cortes (MD Anderson Cancer Center) presented the phase II results from the PACE (Ponatinib Ph+ ALL and CML Evaluation) clinical trial.

Ponatinib is being developed by Ariad and is an oral, pan-BCR ABL tyrosine kinase inhibitor (TKI) that has activity against the T315i mutation, which is not targeted by other TKIs currently on the market.

Cortes made the following conclusions about the PACE trial results:

Ponatinib has substantial anti-leukemic activity in a heavily pretreated population
Responses observed in all cohorts, regardless of mutation or disease stage
Responses improving over time
Favorable safety profile in heavily treated patients
Early efficacy signals similar to initial response results reported in the phase 1 setting
Ponatinib has the potential to become a promising new treatment option for patients with multi-refractory relapsed CML.

Dr Cortes presented several papers at the meeting, including the 24-month follow-up results from the BELA trial (Bosutinib versus imatinib in newly diagnosed Chronic Myeloid Leukemia).

In the BELA study, the data according to Cortes showed “superior rates of MMR and similar rates of CCyR for bosutinib compared with imatinib with 24 months of follow-up.”

“Bosutinib may offer a new therapeutic option for patients with newly diagnosed CP CML” he noted. Whether bosutinib can obtain regulatory approval remains to be seen given that it did not show superiority to imatinib in its primary endpoint, ie complete cytogenetic response (CCyR).

Another presentation by Dr Cortes was the phase 1 results of DCC-2036, a novel oral inhibitor of BCR-ABL1 Kinase, in patients with Ph+ leukemia including those with the T315i mutation.

DCC-2036 is a switch control inhibitor that inhibits SFK and FLT3, but spares c-KIT. It appears to be a potent inhibitor of BCR-ABL1, and BCR-ABL1 mutants, including the highly resistant T315i mutation. The Phase 1 results showed the drug was well tolerated at MTD with efficacy in refractory CML patients with multiple prior TKI treatments.

One of the benefits of attending ASH is the opportunity to meet experts from around the world. I had a very enjoyable conversation with Professor Dong-Wook Kim from Korea, who told me how he goes mountain climbing every month with his CML patients.

He runs a clinic that sees 50-60% of Korean CML patients and is the lead investigator for Radotinib, (IY5511), a new second generation TKI that is currently in phase 3 trials in Asia.

I was also delighted to note in the CML education session that Dr Hochhaus drew attention to role of CML patients’ advocates.

“The CML community is an outstanding example of global patient advocacy – not to be seen in many other cancers,” Hochhaus said.

With the prospect of generic imatinib in 2015, companies with CML products in development may be in a race against time to seize the market opportunity. It will be interesting to watch the market dynamics over the next few years.

What role do macrophages play in breast cancer?

I have had the privilege to attend many scientific and medical congresses this past year, and my belief from listening to many presentations is that drug development innovation comes from understanding basic biology, then applying this knowledge.

Lisa Coussens (UCSF) at the 2011 San Antonio Breast Cancer Symposium (SABCS) provided a good example of how scientific knowledge is being translated into medicine and applied to drug development.

In her plenary presentation, she outlined how our understanding of the biology of macrophages and the importance they play in breast cancer may lead to new drug targets. As an example of this, she showed pre-clinical animal work on the Plexxikon drug PLX3397. A human phase 1b/II clinical trial will start in the near future.

I have aggregated some of the live tweets from the session using Storify. Social media can be a powerful tool to share highlights and top-line messages with those not at meetings, as well as have a real-time conversation with those in the same session. It was disappointing that the lack of wifi in meeting rooms prevented many international scientists and researchers from sharing their insights.

I look forward to watching the development of PLX3397, and am sure that we will see more drug development targeting macrophages. Coussens presentation was outstanding and the highlight of SABCS for me.

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What makes a great scientific meeting?

By Pieter Droppert on December 8, 2011

San Antonio – there is a lot of exciting new data at the San Antonio Breast Cancer Symposium (SABCS) this week.

As Sally Church pointed out in her SABCS video on Pharma Strategy Blog, the update to the BOLERO2 data (previously presented by Jose Baselga at ECCO/ESMO 2011 in September) will be presented later this morning at SABCS.

As a side note it is worth noting that the NEJM paper published yesterday contains the Stockholm data, not the updated data that will be presented later today that will show further improvement in progression free survival (as compared to placebo) in post menopausal ER+ HER2- women who took everolimus combined with exemestane.

Despite the presentation of exciting data at SABCS this week, my opinion is that this is a good meeting, but not a great one (yet). The reason is not the quality of the science being presented this week, but the lack of quality discussants.

The unheralded discussant is the expert that puts the science in context for the audience. Whether it’s a discussion of a simple poster or of a plenary session, the discussants play an important role.

Yesterday at SABCS I sat through two general sessions (the equivalent of plenary sessions at other meetings) in the cavern like auditorium that I estimate sits two thousand attendees.

Of the 15 presentations, only the 3 on bisphosphonates were given a discussant. That is why this meeting to me is good, but not great. Both ASCO and ESMO/ECCO do a much better job at having a expert put the data in context in an independent and unbiased review.

Why is a discussant important when it’s all about the scientific data?

The challenge with medicine, law and any other professions is that there is so much new data that we can only be experts in a very small area or subset of knowledge.

At SABCS there are basic scientists, medical students, researchers, oncologists, community physicians, patient advocates and survivors. What does the data presented mean to them?

The discussant looks at many aspects of a presentation and can be critical, positive and negative in their observations about:

Clinical Trial Design: what were the limitations?
Results: did it meet the endpoints, was the data significant?
Adverse events: is the AE profile a concern?
Comparison to literature: how does this data compare to the literature?
Future research: does this data suggest rational future trials or research?
Practice implications: does the data impact the standard of care?

There are many more questions that come to mind. Listening to a good discussant brings science to life.

It is, however, challenging being a discussant because like writing a blog, you are generating original content and expressing an opinion.

My view is that if a presentation is good enough to receive an oral presentation at a major meeting, then it’s good enough to be discussed. I hope that SABCS will offer more discussants in future years and make this a great scientific meeting in return.

Can you reduce your environmental risk of breast cancer?

San Antonio – at the San Antonio Breast Cancer Symposium (SABCS), the Institute of Medicine (IOM) report on “Breast Cancer and the Environment” was eagerly anticipated.

Published today, the report appears to me to offer little in the way of new insight into how women should live in order to lower their environmental risk of breast cancer.

The review of the scientific literature undertaken by the IOM notes that epidemiologic studies have shown an association between some environmental risk factors and breast cancer. These include ionizing radiation & combination hormone therapy.

The report goes on to say that for many other environmental factors, the evidence is “limited, contradictory or absent”.

The conclusion from the report is that “women may have some opportunities to reduce their risk of breast cancer through personal actions:”

Avoiding unnecessary medical radiation throughout life
Avoiding some forms of postmenopausal hormone therapy
Avoiding Smoking
Limiting Alcohol Consumption
Increasing physical activity
Minimizing weight gain (for those at risk of postmenopausal breast cancer)

Much of the above advice would apply to anyone looking to maintain a healthy lifestyle, but it’s hard to quantify the potential benefit. The report notes the “potential risk reductions for any individual woman will vary and be modest.”

Given that non-smokers can end up with lung cancer, it’s hard to predict who will get cancer and to what extent exposure to environmental factors may have an impact.

Are some people more disposed to environmental risk factors than others?

As we move towards personalized medicine and a greater understanding of the individual genome, it will be interesting to see if we will gain more insight into who is most at risk from the environment.

Perhaps in the future we will be better able to identify those individuals whose genetic make-up result in them being more at risk from others of certain environmental stresses.

In the meantime, if you have an interest in the IOM Breast Cancer and the Environment report it is freely available to download.

Photoimmunotherapy may be a new way to deliver molecular-targeted cancer drugs

Photoimmunotherapy (PIT) that uses a near-infrared (NIR) dye conjugated to monoclonal antibodies (mABs) that target epidermal growth factor receptors (EGFR) is a new type of molecular-targeted cancer therapy that appears to offer considerable promise.

Research by Makoto Mitusnaga and colleagues from the Molecular Imaging Program at the National Cancer Institute (NCI) was published recently in Nature Medicine. This paper is well worth reading if you have an interest in this area.

The NCI researchers developed a:

“mAb-based photosensitizer that is activated by NIR light for targeted PIT only when bound to the target molecule on the cancer cellular membrane.”

I think this is exciting research because unlike conventional photodynamic therapy that also damages normal tissue, photoimmunotherapy kills only antibody-bound cancer cells with no normal tissue damage:

“Further, because this agent also emits a diagnostic fluorescence, it can be used to direct the application of light to minimize exposure to nonrelevant tissues and to noninvasively monitor any therapeutic effects of excitation light.”

You can read more in the Nature Medicine paper about this exciting research that may offer an innovative new drug delivery mechanism for targeted cancer therapies.

Mitsunaga, M., Ogawa, M., Kosaka, N., Rosenblum, L., Choyke, P., & Kobayashi, H. (2011). Cancer cell–selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules Nature Medicine DOI: 10.1038/nm.2554

Overcoming barriers to new cancer drug development

San Francisco – “Translational research is the key to successful drug development” according to William N. Hait MD, PhD, global therapeutic area head of oncology, Johnson & Johnson.

Hait presented a plenary session on “overcoming barriers to new drug development” at the recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference in San Francisco.

How do we define translational research?

The definition Hait most likes is from Duke Ellington: “if it sounds good, it is good”

The challenge of drug development is that with rare exceptions the process is slow, inefficient and expensive.

Hait outlined several challenges to translational research, including:

Complexity – imagine blocking the traffic in mid-town manhattan. If you blocked one cross-town route, traffic would slow and then find another route.

This in my opinion is a good visual metaphor for the cross-talk that occurs in cancer. Block one target, and the cancer finds another route. This highlights the need for combination therapy.

“rational combinations of targeted agents may require studying two or more unapproved agents” said Hait.

Novel-novel combinations are something that many companies are nervous about, but if there is a solid scientific rationale then this is something I think we will see more companies doing.

For further insight into how academia is facilitating this type of combination trials, I recommend Sally Church’s interview on Pharma Strategy Blog with Gordon Mills at ECCO/ESMO in Stockholm.

Inaccuracy of preclinical models – our models don’t always predict preclinically what activity a drug will have in the clinic.
Efficacy of Clinical Trial Recruitment – need to have alignment of incentives. 20% of US patients are eligible for clinical trials, but only 3% participate.
Developing Biomarkers. Difficult to obtain serial biopsies for oncology biomarker analysis. Circulating tumor cells may be future, but current instruments can only capture and enumerate and offer limited characterization. According to Hait, the next–generation platform will be exciting. It will allow third parties to offer additional functionality that can be integrated with the platform.
Drug resistance – a nemesis that just doesn’t want to go away.
Overcoming the Regulatory Environment – challenges include: scientific complexity, endpoint consistency, global harmonization, companion diagnostic tests, proper comparators, equipoise.

In spite of this complexity, Hait noted the FDA approved 34 new drugs in 2011. Several cancer drugs had a short time from submission to approval and met their PDUFA target date. “These are incredible accomplishments,” he said.

Market Access – Hait asked the audience: “Would you buy a Porsche 911 that only works for 20% of the people, but we don’t know if you are one of the 20%?” Healthcare authorities need to decide cost/benefit of drugs, and regulatory approval does not automatically mean a new product will be reimbursed. There may be need for future trials with health comparators, or innovative agreements where the healthcare authority only pays for those patients who respond.
Workforce – academic physicians may end up being segmented into three groups: master clinicians, clinical investigators, physician-scientists. This may provide better career development than the current system.

Hait offered a few suggestions for improvement:

Move to phenotypic screening rather than target-based screening. In vivo shRNA screening was discussed.
Disease based drug discovery teams – the hope is that in-depth focused teams will predict better results.
More intense academic-industry collaboration with a focus on complementary expertise.

The limitation of this plenary presentation was that it only offered the perspective of one senior industry professional. I would have welcomed a balance of views on the barriers to new cancer drug development, and more focused take-home solutions.

If you want to hear more on this topic, AACR have a free podcast that you can download of an interview they did with Dr Hait at the Molecular Targets meeting.

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Improving Cancer Clinical Trial Design #AACR Molecular Targets

San Francisco – the AACR-NCI-EORTC international conference on Molecular Targets and Cancer Therapeutics kicked off last Saturday with two educational sessions, including one that I attended on “Clinical Trial Paradigms in the Era of Novel Therapies.”

The session had an impressive line-up of speakers:

New paradigms for early-phase trials (James Doroshaw)
Phasing out phase III trials: How much evidence do we need if the target is clearly hit? (Jaap Verweij)
Development of clinical trials incorporating genomic signatures: Lessons learned? (Lisa McShane)
Clinical trial designs for targeted therapies (John Crowley)

James H. Doroshow, deputy director for clinical and translational research at the National Cancer Institute, started his presentation by reviewing the causes of phase II trial failure:

19% Safety
51% Efficacy
29% Strategic

He stated that the overall success rate of recent phase II trials was 18%.

As the debate continues about whether more cancer clinical trials should be done in Phase 2, the key issue according to Doroshow remains lack of a demonstrable proof of mechanism (POM) in many drug trials. That goes hand-in-hand with a lack of molecular markers which can be used to select trial subjects.

“Lack of molecular markers with proven clinical utility follows lack of clinically-demonstrable proof of mechanism”

He provocatively asked:

Should we perform early phase trials without generating evidence supporting POM patient by patient?

His view was that to obtain POM, you need to demonstrate drug action on intended tumor target early in development, prior to expectation of efficacy.

Jaap Verweij in his presentation used the examples of crizotinib, vismodegib, vemurafenib and imatinib in GIST as examples of drugs that had:

functionality for a target
aimed at a specific population
availability of a selection marker.

They are the poster children of targeted therapy, and he convincingly showed that the phase 1 trials of those compounds were largely predictive of the phase 3 results.

His conclusion was that phase I trial can be considered predictive of a phase III study so long as there is a large enough sample size.

“We may need to look for bigger increments which should allow us to perform smaller trials,” he said. This would allow trials that are quicker and cheaper. However, he acknowledged that it was not likely we can completely eliminate phase 3 trials particularly for combination therapies or chemotherapies.

John Crowley reviewed the different phase III trial designs, including my least favorite, the “all comer” design. The ridaforolimus sarcoma phase 3 trial presented at ASCO this year is a good example of how an “all comer” design yielded less than stellar results, and failed to identify the subset of sarcoma patients that optimally respond. This is the type of phase 3 trial that runs the risk of failure if there are too many non-responders in the heterogeneous patient population. This problem can often be avoided by more rigour in phase 2 trials to identify the optimal treatment period, relevant biomarkers and subsets of patients most likely to respond.

There is a lot of interest in how to design cancer clinical trials better, bring drugs to market more quickly and more efficiently. While I enjoyed the content of this session, I did wonder whether it would have been better presented as a roundtable with more audience interaction and engagement rather than the perspective of a few.

A webcast of this session will be available on December 8 from the American Association for Cancer Research (AACR).

Prostate Cancer Session at AACR-NCI-EORTC Molecular Targets San Francisco

By Pieter Droppert on November 17, 2011

The recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics international conference in San Francisco was an informative meeting.

What I particularly liked was the strategic overview that took place in many of the plenary sessions.

As an example, Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research/The Royal Marsden in London highlighted the potential drug development targets based on prostate cancer biology:

Androgen Receptor (AR)
Heat Shock Proteins (Hsp)
Signaling: HER3, MET, IGF-1R, CCL2, IL-6, Src
PI3K/AKT/TOR signaling
PARP and BRCAness
Estrogen receptor (ER)
c-MYC & CHK1

His presentation discussed the possible therapeutic approaches, and complexity involved in developing novel targeted therapies for prostate cancer.

This is something that I expect we will hear more of at the AACR special conference on Advances in Prostate Cancer Research early next year.

In particular, de Bono discussed drug development strategies to target androgen receptor signaling, and some of the future challenges including:

Proving to the regulatory authorities that circulating tumor cell (CTC) count falls are a robust immediate endpoint of overall survival
Developing improved imaging for bone metastases

As a side note, there were several posters for cabozantinib (XL184) at the meeting (available on the Exelixis website), including preliminary research on computer-aided quantitative bone scan assessment.

However, as de Bono mentioned in his presentation, “diffusion weighted MRI shows hot spots not detected by bone scans.”

2010 and 2011 were good years for prostate cancer drugs, and with new approvals for MDV3100 and radium-223 (Alpharadin) expected, 2012 is set to be another “grand cru” year, to paraphase Bertrand Tombal.

If you were not able to make it to San Francisco for the Molecular Targets and Cancer Therapeutics conference, webcasts of many sessions will be available on the AACR site.

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