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ASCO GU 2013 Prostate Cancer Preview #GU13

What’s hot in prostate cancer at the forthcoming American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) (twitter hashtag #GU13) that takes place in Orlando from February 14 -16?

That’s the question I was asked recently, and while the abstracts have not yet been published, (embargo lifts at 6pm ET on February 12, 2013) the titles of the posters and choice of oral presentations offer some insight into what may be newsworthy data.

In the oral abstract session on February 14, 2012 two of the presentations of particular interest to me are:

Bristol Myers Squibb dasatinib (Sprycel) Phase 3 Trial Data

Abstract #LBA8. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial.

Presenter: John C. Araujo, MD, PhD

I correctly predicted in my October 2012 blog post that the dasatinib phase III prostate cancer trial data would be at ASCO GU.

Bristol Myers ($BMY) stock has experienced an upwards run in the last few weeks, so we will soon see whether the company has a new treatment option for prostate cancer and one with a very different target (Src).

I have no thoughts on whether the data will be positive or negative. I hate to sit on the fence, but the impression I have is the results could go either way.

Aragon Pharmaceuticals ARN-509 

Abstract #7. ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC).

Presenter: Matthew R. Smith, MD, PhD

I recently wrote about the ongoing Medivation v UCLA/Aragon litigation on this blog. ARN-509 is a second-generation androgen (AR) inhibitor that along with enzalutamide came out of the work by Charles Sawyers and Michael Jung’s lab at the University of California Los Angeles (UCLA).

Irrespective of whether Medivation appeals the recent summary judgement decision in favor of Aragon, ARN-509 is of considerable interest. Sawyers observed in the preclinical testing that it may be a more complete AR antagonist than enzalutamide; see Sally Church’s Interview with Dr Charles Sawyers on Pharma Strategy Blog for further commentary.

At ASCO GU there is also an oral presentation on the pre-chemo data for abiraterone (Zytiga) from the COU-AA-302 trial that I wrote about from ASCO last year.

Without much fanfare, and without any significant overall survival data, abiraterone’s pre-chemo indication was approved by the FDA last December.  It will be interesting to see what new data is presented at the meeting.

There are also several interesting posters that did not make into the short oral session.  One to look out for is the first data for enzalutamide (Xtandi) in hormone-naive prostate cancer:

Abstract #18. Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer.

Presenter: Bertrand Tombal, MD, PhD (@BertrandTOMBAL)

It will be interesting to see how enzalutamide compares to bicalutamide, in what is a market segment with a very large potential.

Another poster of note is the pain analysis for radium-223 (Alpharadin) (Abstract#19).

I’m also looking forward to the poster on the use of chimeric antigen receptor (CAR) modified T cells to target prostate-specific membrane antigen (PSMA) (Abstract #72).  This is an emerging technology that was highlighted at ASH 2012.

For those interested in learning more about the potential of CAR based therapies, Sally Church, PhD (@MaverickNY) will be publishing a report in the not too distant future.

ASCO GU 2013 (#GU13) looks to have some interesting data in prostate cancer and I look forward to contributing to Xconomy from the meeting.

If you would like to receive information about my post-conference prostate cancer report and other insights, please sign up for an email alert.

Update Feb 12, 2013 – Dasatinib phase 3 prostate trial is a failure

Well, it’s gone 6pm and the #GU13 abstracts are now accessible on the ASCO GU Symposium website. The big news is that the dasatinib phase 3 trial data is negative!

According to the abstract, “The addition of DAS to standard-of-care chemotherapy in mCRPC pts did not improve OS.”

As commentators have already noted on Twitter, this is disappointing given the promise of the phase 1/2 trial results that were published in the journal “Cancer” on January 1, 2012 by Dr Araujo and colleagues.

Update Feb 15, 2013 – Winners & Losers at ASCO GU

Thanks to @ldtimmerman for editing my guest post on Xconomy. Here’s a link to my post about the prostate cancer drug winners and losers at ASCO GU 2013.

ASH 2012: CTL019 chimeric antigen receptor technology emerging as a new leukemia treatment

For many attendees, the most exciting news at the 2012 annual meeting of the American Society of Hematology (ASH) held last December in Atlanta was the prospect of personalized T cell therapy for the treatment of patients with B cell cancers such as chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).

The potential of this new treatment option was recognized at ASH 2012 by the award to Dr Bruce R. Blazar, MD and Carl H. June, MD of the Ernest Beutler Lecture and Prize for research that generated major translational advances in T-Cell Infusions.

Dr June, in his accompanying lecture discussed preliminary data for the trial of CTL019 (formerly CART-19), a novel chimeric antigen receptor-transduced T cell therapy against CD19. Subscribers to premium content can login to read more below:

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In the 12 patients (10 adults CLL and 2 children with ALL) who have received CTL019, the responses have been extremely promising with a clinical response (CR+PR) seen in 9 out of the 12.

There have already been several reports in the media about this trial with many news outlets reporting that one of the children with ALL had been “cured.” That this treatment has tremendous potential is undisputed, but in my view it is a case of “hype over hope” at this stage to say that anyone has been cured in the absence of long-term follow up over at least five years.

In August 2012, Novartis announced they had formed an alliance with the University of Pennsylvania and had obtained a worldwide license to commercialize CART-19 (now CTL019). In December 2012, Novartis purchased a NJ manufacturing facility from Dendreon for $43M that will used for the production of personalized immunotherapy.

Novartis, through their recent acquisition of the Dendreon facility in NJ, are fortunate to gain access to the technology, state-of-the-art tracking system that matches the product to each patient, as well as the Good Manufacturing Practices (GMP) that were pioneered in the production of sipuleucel-T (Provenge).

In the immediate future, Novartis and U Penn have the challenge of showing that the dramatic results seen in some of the initial patients are reproducible in a larger trial and also at institutions other than Penn.

In his ASH lecture, Dr June noted that there are side effects and toxicities associated with CTL019 including tumor lysis syndrome (TLS), and Cytokine Release Syndrome (CRS) was seen in all patients.

This suggests it is unlikely this therapy will be used outside of the hospital setting.  In the United States, I would not be surprised to see it only used at hematology transplant centers, where there is the necessary expertise to deal with both the process and any complications that arise. Novartis may end up with a high priced therapy targeted at a small niche market.  It will be interesting to see the commercial strategy that Novartis decide to adopt.

I expect we will hear a lot more about chimeric antigen receptor technology in 2013. Personalized immunotherapy is a complex topic and one that will require significant investment in medical education by Novartis if a broader audience is the intended target. Dendreon failed miserably at launch in explaining how sipuleucel-T (Provenge) worked and did not convince large numbers of medical oncologists that their immunotherapy worked.  Even to this day, there remains considerable sceptism amongst that physician segment.

If you would like to know more about the science behind CAR therapy and it’s potential in hematology, Sally Church, PhD (who co-launched Gleevec in the US while at Novartis Oncology) will be offering insights in a monthly newsletter to be launched soon. Check out Pharma Strategy Blog for more information.

 

ASH 2012: ABT-199 shows promise in CLL and MCL

The “Hallmarks of Cancer” paper by Douglas Hanahan and Robert Weinberg is a classic, and a must read (allow plenty of time) for anyone interested in cancer drug development.

The original 2000 paper, updated in 2011, identified six hallmarks of cancer, “distinctive and complementary capabilities that enable tumour growth and metastatic dissemination:”

  • Sustaining Proliferative Signaling
  • Evading Growth Suppressors
  • Activating Invasion and Metastasis
  • Enabling Replicative Immortality
  • Inducing Angiogenesis
  • Resisting Cell Death

Apoptosis or programmed cell death according to Hanahan and Weinberg is “a natural barrier to cancer development.” One of the ways cancer cells survive is by resisting cell death and disrupting the apoptosis signaling pathway; in other words the normal signals that trigger cell death don’t get through.

Researchers have shown that apoptosis is controlled at the cellular level, in the mitochondrion, by the Bcl-2 family of regulatory proteins (BCL-2, BCL-XL). Targeting BCL-2 (a protein that prevents apoptosis) could induce cell death and be a potentially successful anti-cancer strategy.

The result of our increased understanding of cancer biology has been the development of novel targeted drugs such as ABT-199, a potent and selective BCL-2 inhibitor. This is in early clinical development by AbbVie ($ABBV), a new biopharmaceutical company spun off from Abbott Laboratores ($ABT) last week.

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I previously wrote about the potential for ABT-199 in Chronic Lymphocytic Leukemia (CLL) following Steven Elmore’s presentation at the April, 2012 annual meeting of American Association for Cancer Research (AACR).

The data presented at AACR has now been published in Nature Medicine, online ahead of print (AOP) on 6 January 2013: “ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.”

Andrew Souers and colleagues from AbbVie and other institutions discuss how they re-engineered the since-discontinued navitoclax (ABT-263) to create a different and less toxic BCL-2 inhibitor. This new compound, unlike navitoclax, does not cause the thrombocytopenia associated with BCL-2-like1 (BCL-XL) inhibition.  It’s a compelling story of science-based cancer drug development.

At the December 2012 annual meeting of the American Society of Hematology (ASH) in Atlanta interim data was available from the phase 1 clinical trial of ABT-199 in Non-Hodgkin Lymphoma (abstract #304).

Matthew S. Davids, MD, Instructor in Medicine at Harvard Medical School & attending physician at the Dana Farber Cancer Institute, presented the results from the first-in-human phase 1, open-label, dose escalation, multicenter international trial in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL).

Of the 30 NHL patients enrolled, Dr Davids told the audience that 20 remained active, with a median time on study of 80 days (range 7 to 413).

ABT-199 particularly active in CLL & MCL

In 7 patients who had mantle cell lymphoma (MCL) in the 30 subject NHL trial, all seven (100%) obtained a partial remission.  A 72 year old man with stage IV MCL obtained complete clinical resolution of auxiliary node clinically and 2 x 1 cm neck nodes by day 8.

ABT-199 is also active in CLL. Dr Davids briefly shared data previously presented at the 2012 Congress of the European Hematology Association (EHA) last year.  The waterfall plot was quite impressive, unfortunately I could not obtain permission to share an iPhone photograph here.  However, by my eye, the plot appeared to show that 30 of the 37 evaluable patients had a greater than 50% reduction in nodal size!

Dr Davids shared by email some additional commentary on the potential of ABT-199 in CLL:

“ABT-199 appears to be very active in patients with relapsed refractory CLL irrespective of high risk features such as del(17p).

Given its distinct mechanism of action from the BCR pathway antagonists, it has the potential to become an important additional treatment option in the armamentarium of CLL therapies.

Whether ABT-199 will be most useful as a signal agent, in combination with chemotherapy, or in combination with other novel agents will be an important question moving forward.”

ABT-199 has an acceptable safety profile

ABT-199 related grade 3 / 4 neutropenia was experienced in 3 of the 30 NHL phase 1 trial participants (10%).  Dr Davids noted there were:

  • No discontinuations due to adverse events
  • No dose limiting toxicities observed in NHL patients
  • No evidence of dose-dependent thrombocytopenia

He concluded that ABT-199 had an acceptable safety profile and further research is ongoing in NHL, both as a single agent and in combination with bendamustine/rituximab.  The lack of severe thrombocytopenia is a definite improvement on its predecessor navitoclax.

Overall, ABT-199 is an exciting new agent in development with potential as a new treatment option for CLL & MCL.  I look forward to hearing more about it at future scientific meetings.

Court rules Medivation has no IP rights to Aragon Pharmaceuticals ARN-509 $MDVN

Medivation investors hoping for a windfall will be disappointed to hear that on December 20, 2012 a California judge ruled the company had no rights to what is now known as Aragon Pharmaceuticals’ ARN-509, a next-generation androgen receptor (AR) antagonist for advanced prostate cancer, similar in chemical structure to enzalutamide (Xtandi).

Enzalutamide (formerly MDV3100) was developed in the UCLA laboratory of Drs. Charles Sawyers and Michael Jung and licensed by Medivation from the University of California. Medivation believed their licensing and sponsored research agreements gave them rights to any follow-on compounds. However, instead of giving Medivation first right of refusal, the University licensed what is now ARN-509 to Aragon Pharmaceuticals, a privately-held company whose owners include Sawyers and Jung.

You can read more about ARN-509 on Pharma Strategy Blog: “Is ARN-509 potentially better than MDV-3100?” Sally Church (@MaverickNY) also interviewed Dr Charles Sawyers in May 2011 just before Medivation commenced a lawsuit against the University of California, Sawyers and Jung claiming breach of contractual agreements.

Concern about the ownership of intellectual property rights to ARN-509 has overshadowed Aragon with many thinking Medivation had a strong case. This has likely hindered the ability to raise capital or obtain a potential partner, although Aragon did announce on October 4, 2012 they had raised $50M in series D financing. However, ARN-509 has been slow to move through development and has yet to enter phase 3 clinical trials.

Based on the limited public information available about the lawsuit between Medivation, University of California and Aragon, my thoughts last year were that the case would settle as none of the parties would want a trial that exposed sensitive intellectual property and financial information.

However, in a December 20, 2012 Order, Judge John E. Munter of the Superior Court of California granted summary judgment to The Regents of the University of California on a number of issues, finding that Medivation’s contracts with the University gave them no ownership or licensing rights to ARN-509.

 

Many thanks to biotech investor (@lomu_j) for sharing the news on Twitter – definitely worth following if you do not do so already.

Based on the evidence submitted by the parties, Judge Munter decided that the University of California did not breach the Sponsored Research Agreement (SRA) with Medivation.

According to the court Order, the SRA provided that Medivation would have “a time-limited first right to negotiate an option or license, which may be exclusive” with respect to “Subject Inventions” that occurred during a specified performance period i.e. the University of California was required to disclose follow-on compounds such as ARN-509 to Medivation during this time.

However, anyone who has been involved in contractual disputes will know the devil is in the detail, and the court Order explains why Medivation did not prevail, as many had expected.

The SRA defined “Subject Invention” to be an invention that was “first conceived” and “actually reduced to practice” during the performance period which it was agreed would start on November 1, 2005. However, during discovery The Regents of the University of California presented evidence from a research scientist, Dr Samedy Ouk that A52, the compound that became ARN-509, was conceived and reduced to practice prior to this date. You can read more in the following excerpt from Judge Munter’s Order:

Superior Court of California Order excerpt MDVN Aragon ARN-509 dispute

Since the University was only obligated to disclose inventions after November 1, 2005, the court found they did not breach the SRA by failing to give Medivation the right to option or license a compound that was invented prior to this. A close call when you look at the dates, but that is what the parties agreed to in writing.

The court Order discusses several of the claims and disputes between the parties, some of which remain ongoing. It is of course possible that Medivation might appeal, but I was persuaded by Judge Munter’s cogent opinion. In essence the court ruling, unless it is overturned on appeal, means Aragon can move forward unhindered with the development of ARN-509.

Here’s my take from this case:

  1. When negotiating a contract, the devil is in the details. Good contract drafting should avoid the need for future litigation. Negotiating contracts can take months, but it’s never wise to sign anything just for the sake of expediency.
  2. A contractual dispute can occur years after an agreement was signed highlighting the importance of document retention, e.g. laboratory notebooks, especially where intellectual property is involved.
  3. Contracts typically have an integration clause that says what is written reflects the “entire understanding of the parties.” This means a court will only look to what is in written down and not what may have been said or verbally agreed prior to signing the agreement. It’s important to make sure the written contract is clear and unambiguous.
  4. IP litigation can delay a potential competitor and deter others from investing or partnering. By the time ARN-509 makes it to market, the prostate cancer landscape will be more competitive than it is today.  Through the delay Medivation ends up winning irrespective.
  5. Aragon may now be an attractive partner for companies with an established urology/prostate franchise who would like to compete against Medivation.

While many are excited about ARN-509 in advanced prostate cancer, it must be noted that Aragon have yet to show that ARN-509 is more effective than enzalutamide in patients. A phase 3 clinical trial of ARN-509 in the post-docetaxel prostate cancer setting will not be easy given it will most likely require comparison to the current standard of care (Xtandi or Zytiga) and not placebo.

The prostate cancer market remains a dynamic one with multiple new products in development and the potential for combination approaches. The forthcoming ASCO GU meeting in Orlando, from February 14-18, 2013 is worth watching for new updates.

Update May 29, 2013: Medivation announces they will appeal decision in favor of Aragon

According to the SEC filing that @ColfaxCapital kindly shared the link to last month on twitter, Medivation have not unsurprisingly announced they will appeal the California court decision in favor of Aragon.

The Medivation SEC 8-K filing notes that the appeal was filed on April 15, 2013 and will most likely take 12-18 months, so a California Court of Appeals decision is not expected until sometime in 2014.

There is also ongoing litigation between the University of California and Medivation over whether the company has to make royalty payments to the University when it receives commercial milestone payments from Astellas and a trial on this issue is scheduled for July 2013. Another trial over Medivation’s allegations of fraud against Dr Jung is set to start in October 2013.

There’s still plenty of legs left in this story and a time to go before we have a definitive outcome given that any trial decisions will most likely also be appealed in due course.

Update June 17, 2013: Johnson & Johnson announces acquisition of Aragon Pharmaceuticals with $650M upfront payment

J&J have this morning announced the acquisition of Aragon, and the rights to ARN-509 in a deal with a $650M upfront payment and contingent milestone payments of upto $350M.

Here’s a link to the press release published on the WSJ.

 

2012 was a Grand Cru year for the FDA with 39 NMEs approved

As we herald in a New Year, it is time to reflect a little on the past year. 2012 was, to paraphrase Professor Bertrand Tombal’s quote about prostate cancer drug development, “a Grand Cru year” for the United States Food & Drug Administration (FDA) with 39 new molecular entitites (NMEs) approved. This is the highest approval number in the last 10 years, beating the previous high of 36 obtained in 2004. Reuters report it is a 16 year high.

Unfortunately, I don’t think can we can draw many conclusions about the state of drug development innovation from this 2012 high.

The FDA in their 2011 report on novel new drugs note that “the number of NMEs approved over time has not been substantially increasing.”

To me, the overall picture looks pretty flat. There’s bound to be variation between years as a result of timing differences with some regulatory submissions obtaining priority review, while others do not.  Some companies can take longer than others to close a clinical trial database and prepare a dossier.  We also have to factor in that some clinical trials may end earlier than expected, if the data is positive.

Regulatory approval is the result of innovation that started several years ago. It only represents the point at which you have a safe and efficaceous product that can be sold to the public. The number of approvals in any given year is not a surrogate benchmark for the state of current innovation.

Given it typically takes several years to bring a new product to market, what we are looking at today is the result of research done 5-10 years ago. It is, however, interesting to note that of the 39 NME approvals in 2012, one-third (13) were cancer related.

A key driver of innovation in this area is the increased knowledge we have of cancer biology.

In my view, investors will continue to support companies that develop new products with:

  • a clear scientific rationale as to why their mechanism of action may impact the disease
  • a focused clinical development plan that through use of biomarkers and diagnostics targets those most likely to respond
  • a market opportunity worth going after in what is increasingly a competitive landscape

2012 was a “grand cru year” for the FDA. I look forward to what 2013 may bring and to learning more about the new products in development that may make a difference to the lives of patients.

Happy New Year!

 

The Evolving Multiple Myeloma Landscape

New treatments for multiple myeloma (MM) are changing the treatment landscape and that is set to continue over the next few years as several new products come to market.

This year we have seen the FDA approval of subcutaneous bortezomib (Velcade®) and carfilzomib (Kyprolis®). Approval for pomalidomide is anticipated soon.

Earlier this week at the 2012 Chemotherapy Foundation Symposium in New York, Sundar Jagannath, M.D., Professor of Medicine at Mt. Sinai School of Medicine presented on “New IMiD and Proteasome Inhibitors.”

Dr Jagannath told a large audience at the Symposium (also known as the Greenspan Meeting) that he hoped “pomalidomide will get accelerated approval and be in your hands by New Year”. 

In his presentation, Jagannath discussed some of the new products in development. One that he mentioned in detail was MLN9708/ixazomib (Millennium), a new reversible, oral proteasome inhibitor currently in early clinical trials.

He noted that is not just being developed as a single agent in advanced disease, but is already being tested in combination with lenalidomide and dexamethasone therapy in earlier settings.

Companies with MM drugs in the pipeline will need to look closely as to how the treatment landscape may change in the next few years if new products such as ixazomib are approved and replace existing products such as bortezomib.

Although Dr Jagannath’s talk was very informative from a new product development perspective, I did wonder whether some of the community medical oncologists in the audience, who only see a few myeloma patients, might have benefitted from a more practice orientated perspective.

I sat next to a community oncologist from Florida, for example, who told me he found the MM treatment regimens difficult to understand for the few patients that he saw.

Dr Jagannath concluded his presentation with the thought that “rapid strides in genomics promises new drugs and personalized medicine in the near future.”

I look forward to hearing more about the latest research in Multiple Myeloma at the annual meeting of the American Society of Hematology (ASH 2012) in Atlanta next month.

The Evolving CML Market – which drug to give when?

One of the enduring legacies from the development of imatinib (Gleevec®/Glivec®) for the treatment of chronic myeloid leukemia (CML) is the long-term survival data from the IRIS (International Randomized Interferon versus STI571) trial that enrolled 1106 patients between June 2000 and January 2001.

Hagop Kantarjian, M.D. Professor and Chair, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston told the 2012 Chemotherapy Foundation Symposium (also known as the Greenspan Meeting in honor of the late Ezra Greenspan, M.D.) that:

the 10 year survival rate is 85% in patients treated with imatinib, and that this rises to 90% if you exclude deaths not related to CML.

No second-generation tyrosine kinase inhibitor (e.g. nilotinib, dasatinib, bosutinib) has yet to show a superior long-term survival benefit to imatinib. Dr Kantarjian noted that “whatever comes as a new treatment in the frontline therapy has to be able to beat that time, of a 10 year survival, if there is a big cost difference.”

The IRIS trial survival data for imatinib remains the gold standard by which other tyrosine kinase inhibitors will be judged.

In other words, notwithstanding the myriad of published CML data that shows second generation TKIs offer a deeper or more rapid molecular response, there’s still no data that shows you will actually live longer if you take any of them instead of imatinib.

That’s not to say there are no benefits to the newer second generation TKIs.

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However, it is interesting that we have not seen Novartis publish an update to the IRIS trial for a while.  Instead, faced with imatinib going off patent in 2014, Dr Kantarjian noted that the company has raised the price of imatinib and destroyed the price differential to nilotinib to encourage more nilotinib usage.  It’s hard to compete against your own successful product!

In the short-term, this marketing strategy may promote the use of nilotinib instead of imatinib. The reality, however, is that we can expect generic imatinib to be widely used frontline once available, where cost is an issue, whether it be for out of pocket patient co-pays, or in countries where healthcare reimbursement is government funded.  It will be interesting to see whether this will put some pressure on companies to lower the price of second-generation TKI’s.

In terms of current treatments for CML, Dr Kantarjian told a large audience at the Greenspan Meeting that the choice of FDA approved TKI therapy for CML in frontline is imatinib 400 mg daily, nilotinb 300 mg BID or dasatinib 100 mg daily. In second or third line therapy, the choice of TKI options is nilotinib, dasatinib, bosutinib or ponatinib (pending FDA approval in 2013).

Choice of TKI in CML

Dr Kantajarian discussed in detail the factors that clinicians need to consider when choosing a TKI for patients with CML. These include:

  • Efficacy – CGCR, MMR, CMR, EFS, survival
  • Toxicities
  • Disease status – frontline, salvage, tranformation
  • Salvage – Mutation status
  • Comorbidities: COPD, CHF, diabetes, pancreatitis
  • Cost

It’s beyond the scope of a blog post to go into detail on these. However, when it comes to efficacy, it is important to look at outcomes.

Dr Kantarjian told the audience that with second generation TKIs “so far there is no survival benefit” over imatinib and that “many patients who fail imatinib can be salvaged effectively with second TKIs.”

Important Response Categories in CML

If you are looking for an improvement in survival, you need to achieve a complete cytogenetic response, you do not have to have a major molecular response, said Kantarjian.

Table modified from Hagop Kantarjian, M.D. presentation at 2012 Chemotherapy Foundation Symposium

Dr Kantarjian noted that in a survey of 507 U.S. community oncologists: 72% had Major Molecular Response (MMR) as the desired treatment outcome with only 17% seeking a Complete Cytogenetic Response (CGCR).

The Golden Rule in CML Monitoring

Dr Kantarjian shared with the Chemotherapy Foundation Symposium audience some of his golden rules in CML monitoring, one of which was:

“Do not discard a TKI unless there is a loss of CGCR (not MMR) at the maximum tolerated adjusted dose that does not cause grade 3-4 or chronic grade 2 (affecting QOL) toxicities.”

He went on to advise that when analyzing mutations in CML:

  • If CG or hematologic relapse occur, mutations studies help
  • No role for mutation studies pre-Rx or in imatinib responding patients

As for the choice of TKI at the MD Anderson Cancer Center, Dr Kantarjian told the audience that they currently use investigational ponatinib in both frontline and salvage settings.  He noted that as an investigational drug it was free to the institution and patients.

The CML market remains one that will undergo further evolution over the next few years as new drugs such as ponatinib come to market and existing drugs such as imatinib go off patent.

It will be interesting to watch the market dynamics and whether the clinical benefits of the second-generation TKI’s justify their significantly higher cost over generic imatinib.

 

Will dasatinib be effective in prostate cancer?

The results of the phase 3 clinical trial of dasatinib (Sprycel) plus docetaxel/prednisone versus placebo and docetaxel/prednisone in men with castration-resistant metastatic prostate cancer (CRPC) are expected soon.

BMS recently updated the clinicaltrials.gov website to show that the dasatinib phase 3 randomized prostate cancer “READY” trial (NCT00744497) of 1500 men completed data collection in August.

Data is expected before year end and, If positive, could be a late breaker at the ASCO Genitourinary Cancers Symposiusm (ASCO GU) in Orlando from Feb 14-16, 2013.

Dasatinib inhibits Src-family kinases (SFK)

Dasatinib is approved for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL). It is a BCR/ABL, LYN and Src family tyrosine kinase inhibitor.

Src-family kinases (SFK) are involved with tumor proliferation and bone metabolism.

In the phase 1 & 2 clinical trials of dasatinib with docetaxel, many of the men with prostate cancer saw a decrease in PSA from baseline, reduction in tumor size and bone scan improvement and stabilization. Encouraging early results led to the start of a phase 3 randomized trial of dasatinib in combination with the chemotherapy, docetaxel.

However, the results for Src inhibitors in prostate cancer have been mixed to date, with not all agents generating positive data. Astra-Zeneca’s saracatinib (AZD0530), for example, showed little clinical effect on its own in a phase 2 prostate clinical trial.

It has been suggested by KOLs at numerous conferences that Src inhibitors may potentially be more effective in combination with other cancer agents. Data suggests that Src might be a resistance mechanism to enzalutamide (MDV3100), so it would be interesting to see whether a dasatinib/enzalutamide combination may be more effective than enzalutamide on its own.

Meanwhile, we await the data to see whether the combination of dasatinib with docetaxel generates a significant increase in overall survival over docetaxel alone. While some are “hopeful”, Dr Oliver Sartor, Professor of Cancer Research at Tulane Medical School noted in a prostate cancer session at ESMO 2012 that, “the docetaxel-combination graveyard is big!”

Update Jan 26 2013: Dasatinib Phase 3 Data at ASCO GU

Results from the dasatinib phase 3 prostate cancer trial are a late breaking abstract at the 2013 ASCO Genitourinary Cancer Symposium (ASCO GU) in Orlando. The data will be presented on February 14 by John Araujo MD PhD, Assistant Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

LBA #8: Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the phase III READY trial.

AB Science files for Pancreatic Cancer approval

AB Science confirms the filing for the Marketing Authorization Application to the European Medicines Agency of Masitinib in the treatment of Pancreatic Cancer.

Paris based biopharmaceutical company AB Science announced in an October 16 news release that the company has applied to the European Medicines Agency (EMA) for approval of masitinib in pancreatic cancer.

Masitinib is a tyrosine kinase inhibitor of PDGF, PDGFR, FGFR, FAK, c-KIT. A phase 3 clinical trial (NCT00789633) in pancreatic cancer is underway that compares masitinib with gemcitabine to placebo with gemcitabine.  The trial started in November 2008 with an estimated enrollment of 320 patients at 68 study locations. As far as I am aware no data has yet been presented for this trial.

The phase 2 trial results for mastinib in pancreatic cancer were, however, extremely promising.

Alain Moussy, CEO of AB Science in an interview on Pharma Strategy Blog, A leap of faith: AB Science & mastinib in pancreatic cancer, stated that masitinib “is unique its ability to resensitize the pancreatic cell that has become resistant to gemcitabine.”

Strangely, the AB Science news release today offers no top line results, and merely states the “communication of results was delayed to allow the filing for patent applications aimed at extending the period of marketing exclusivity.”

The presumption from the filing and today’s announcement is that the data for mastinib in pancreatic cancer is positive, which is good news for patients. I look forward to hearing more about the overall survival benefit for masitinib when more data becomes available.

This news also adds to the excitement building in pancreatic cancer, with the Celgene Abraxane data expected before year end.

Update November 1, 2012: Phase 3 Trial Results Announced

In an October 30, 2012 news release, AB Science finally shared the data for their Phase 3 clinical trial (NCT00789633): A Study to Compare Efficacy and Safety of Masitinib in Combination With Gemcitabine, to Placebo in Combination With Gemcitabine, in Treatment of Patients With Advanced/Metastatic Pancreatic Cancer.

I don’t plan to rehash the self-explanatory news release, but the results are mixed. The Principal Investigator, and leading pancreatic cancer experts I contacted (who were not involved with the trial) did not respond to requests for comment. This suggests that we will have to wait till the data is presented at the ASCO GI symposium in San Francisco next year to fully understand the implications for clinical practice.

Bad news: Study failed to meet it’s primary endpoint of showing that masitinib increased overall survival (patients lived longer) when used in combination with gemcitinabine versus gemcitabine alone.

  • Median OS was 7.7 months in the masitinib plus gemcitabine treatment arm versus 7.0 months in the placebo plus gemcitabine treatment arm (p=0.74; hazard ratio=0.90).

The company news release states:

“This finding of a non significant survival improvement in the overall population is explained by the fact that masitinib is not indicated when Gemzar® is highly efficient.”

However, there is some positive news for AB Science, and that is a subset of the 320 patients in the study did significantly live longer with masitinib.

Good news: a subset of pancreatic cancer patients with a novel genetic biomarker for tumor aggressiveness, identified using RNA expression from whole blood samples, lived significantly longer with masitinb.

  • Patients in the subset with this biomarker (65% of the study population) had a median overall survival (OS) of 5 months on gemcitabine alone, while those on masitinib and gemcitabine had an OS of 11.0 months (hazard ratio of 0.29, p=0.000038).

A survival advantage of 6 months with mastinib is a dramatic result!

If mastinib can be used in conjunction with a predictive biomarker that identifies those patients who may likely respond, it is hard not to imagine that some form of regulatory approval would be forthcoming, despite the failure of the trial to meet it’s primary endpoint. However, more clinical data and another clinical trial may be needed to validate the biomarker, if as it appears, the biomarker was identified retrospectively.

There are also many unanswered questions:

  • what is the technology needed to detect the biomarker?
  • is this a test that can be routinely performed?
  • is there a diagnostic kit available?
  • How might such a genetic biomarker be used in clinical practice by non-academic physicians?
  • What is the extent to which the biomarker has been shown to be valid and reproducible?

I look forward to hearing more about the masitinib data at the ASCO GI 2013 meeting.

Update November 6, 2012: Skuldtech identified as diagnostics partner

Another piece of the jigsaw has been provided in a November 3 news release from AB Science that french company, Skuldtech is the company they are working with on a companion diagnostic test for masitinib in pancreatic cancer. As usual, I found the news out first on Twitter:

The AB Science news release states that:

Skuldtech and AB Science plan to exploit these new markers for commercialization of a future companion test associated with masitinib, a molecule developed by AB science for treating pancreatic cancer.

It goes on to say:

“From a simple drop of blood, Skuldtech and AB Science were able to identify specific markers – transcriptomic markers – that can distinguish between the different populations treated during the phase III study and select the predictive markers for pancreatic cancer survival associated with masitinib treatment.”

We await further information on the cost, availability and validation of the companion diagnostic.

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ESMO 2012 Gefitinib in Esophageal Cancer – can we identify the responders?

At the European Society for Medical Oncology (ESMO) 2012 Congress in Vienna, David Ferry, Professor of Medical Oncology at New Cross Hospital in Wolverhampton, reported the results of the Cancer Oesophagus Gefinitib (COG) study, a UK 450 patient, multicenter, phase III clinical trial that looked at whether gefitinib (Iressa) could improve overall survival in esophageal cancer patients who had progressed after chemotherapy.

This is a disease for which there are no treatments that prolong life in the 2nd or 3rd line setting! Sadly, the trial results were negative; there was no difference in overall survival between the placebo and gefitinib study arms.

 

Placebo Arm (n=225): Median Overall Survival of 3.6 months

Gefitinib Arm (n=225): Median Overall Survival of 3.73 months

A non-significant difference. The data broken down by performance status shows:

  • PS0 – median OS = 6.03M
  • PS1 – median OS = 3.93M
  • PS2 – median OS = 1.97M

That you might think is the end of the story, just another negative trial, another example of the natural selection that takes place in the development of new cancer treatments.

“Gefitinib in Esophageal Cancer – just the beginning of a spicy story”

was the title given to the presentation by Arnaud D. Roth, MD Chief of Oncosurgery at Geneva University Hospital who discussed Professor Ferry’s paper at ESMO 2012.

There are a subgroup of patients who respond

Dr Roth pointed out that there were a subgroup of patients in the COG trial who responded well to gefitinib and lived longer as a result. In the waterfall plot he presented, you can see the partial response highlighted.

Using crizotinib as an example, (it is effective in only 5.5% of NSCLC patients), Dr Roth challenged the audience as to why we couldn’t identify the subset of esophageal cancer patients who might respond well to gefitinib.

He noted that 50-70% of esophageal cancers overexpress EGFR protein, suggesting some basis for using an anti-EGFR agent such as gefitinib.

To define this subset of esophageal patients, “we need to go deeper into the biology of esophageal cancer,” Roth said.

His recommendations:

  • Do not lose too much time at looking for discreet mutations predicting response to gefitinib
  • Analyze the responding subpopulation by genomic profiling and examine if they correspond to a particular subtype
  • Validate findings in relatively small clinical studies

Dr Roth concluded that:

“Better knowledge in molecular biology in this disease might help to select patients who might benefit from anti-EGFR TKI’s”

In summary, while the COG trial showed that gefinitib does not improve overall survival in second or third line treatment of esophageal cancer, there is hope that in the future we may be able to identify those patients who might respond, and live longer as a result.

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