Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘ponatinib’

After a long lull on the targeted therapies front – outside of EGFR T790M in lung cancer – this year’s ASCO has plenty to be cheerful about with new data across multiple tumour types.  We can’t cover them all here, but more will be discussed in the Daily Live Blogs starting on Saturday.

Which drugs are going to be in roaring back after a quiet period?  Which ones will be having a more muted meeting?

ASCO16 Chicago 4For those of you who are working in the targeting therapy world, take heart, there is a future beyond cancer immunotherapy; it is not the universal panacea and will likely not cure every cancer, at least for now.

There’s still a market opportunity for targeted therapies in cancer, and as we mentioned in yesterday’s ASCO Preview, there is also potential for the combination of targeted therapies with immunotherapies, so long as the combined toxicity is manageable and doesn’t outweigh the benefits.

In this post we’re looking at a selection of targeted therapies in a variety of tumour types. There’s a lot to choose from at ASCO this year.

Here’s a few we think are worth highlighting upfront.

Subscribers can log-in to learn more or you can click on the Blue Box below to sign-up and become a member of the burgeoning BSB Community who appreciate the value of education, information and, even occasionally, infotainment…

Oncology R&D is tough and there are many more failures than successes, despite the FDA approving more than they’ve rejected over the last two years. That’s quite unusual in my experience.

Dr Mario SznolAs Dr Mario Sznol (Yale) told us at SITC recently, sometimes these things are sometimes more whimsical. He was referring to different types of modalities that can be used in conjunction with cancer immunotherapies, but the sentiment is also highly relevant to the FLT3 AML space.

The critical questions we need to think here about are:

  1. What’s different about the various approaches?
  2. What can we learn from the FLT3 experiences to date that give us clues about the changing landscape in AML?

To learn more about FLT3 AML and where this field is going, subscribers can login below or you can sign up to receive our commentary and insights in the box…

Many years ago, I used to work in the sarcoma and GIST space, which is a very interesting and fascinating disease to explore from a biology perspective. There are many different subsets of sarcoma, several different histologies, as well as numerous targets such as KIT in gastrointestinal stromal tumours (GIST). Some of these subsets are sensitive to chemotherapy such as doxorubicin, while others such as GIST are sensitive to targeted therapies including imatinib, sunitinib, regorafenib etc. Imatinib (Gleevec) is particularly effective in GISTs with exon 11, while the less common exon 9 has been shown to be more sensitive to sunitinib (Sutent), for example.

Often pharma companies will work with the Sarcoma Alliance for Research through Collaboration (SARC) cooperative group to undertake a phase 1 allcomers trial to evaluate which subsets might be appropriate for a given therapy, before exploring a narrower inclusion/exclusion criteria in a larger phase 2 or 3 study.  You can check out their current clinical trials in sarcomas here.

Overall, people with malignant sarcomas tend to be seen by specialist centres where there are usually clinical trials available, representing a way to determine which of the agents in development are superior to the current standard of care.

Dr Margaret von Mehren

Dr Margaret von Mehren

One of my favourite moments at ASCO this year was escaping the heavily mobbed poster halls to sit down for a quiet ‘fireside chat’ and catching up with an expert in this field to learn more about the latest new developments in sarcoma.

I’m delighted to publish another thought leader discussion today on Biotech Strategy Blog (BSB), where we have an in-depth interview with Dr Margaret von Mehren, the Director of Sarcoma Oncology at Fox Chase Cancer Center.  She has spent spent her career trying to identify new therapeutics for gastrointestinal stromal tumours (GIST), as well as soft tissue sarcomas (STS).

To learn more about the latest insights on soft tissue sarcoma and GIST, you can log in or sign up in the box below.

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

Catherine-Smith-MD-UCSF-PLX3397-AML-ASH-2011-PresentationIn 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

Catherine-Smith-MD-UCSF-Ponatinib-AC220-ASH-2011-PresentationIn 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:

  1. Will FLT3 inhibitors be more effective in the maintenance setting after induction therapy to prolong CRs and outcomes?
  2. 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.

ResearchBlogging.orgShen, 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

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.

European Hematology Association (EHA) Congress London 2011At the 16th Congress of the European Hematology Association (EHA) that was held in London this past weekend, the educational sessions were extremely well attended.

The reason for this was the quality of the thought leaders who presented on science and emerging treatments.

The quality of the education sessions and the fact they are repeated twice, so you can avoid schedule clashes, is one of the things I particularly like about both the American Society of Hematology (ASH) and European Hematology Association (EHA) annual meetings.

As I have written before while at EAU in Vienna, I’m not a fan of promotional satellite symposia.  As an example on the Thursday before EHA, attendees interested in CML could attend the Novartis symposia in the morning about how nilotinib was better than imatinib, then in the afternoon attend the BMS sponsored symposia to hear how dasatinib was also better than imatinib.  Indeed, two of the speakers were identical in both symposia, but with entirely different messages.

Two other satellite symposia also had speakers talking about second-generation tyrosine kinase inhibitors.  What, of course, was on everyone’s mind was when to use one second-generation TKI over the other?  Also given that imatinib is reimbursed in many countries, while nilotinib and dasatinib are often not yet available in that setting, the issue of how to treat patients second-line with these therapies was also a hot topic.

However, just attending the individual company-sponsored symposia, to me, meant that it was hard to put together a big picture of exactly what to do when.  Perhaps a better way to handle it would have been to have one CML satellite symposia sponsored by all the companies with a dog in the race (Novartis, BMS, Ariad, Pfizer). We might have heard what the experts really thought that way. 🙂

The other issue that arose during the meeting is how data is presented when looking strategically at one treatment or trial to another in the same indication.  Are you truly comparing apples with oranges?

M Baccarani European Hematology Association Congress London 2011As Professor Michele Baccarani pointed out, there is a big difference between data that shows a cytogenetic or molecular response “BY” a certain time as compared to “AT” a certain time.

“BY” can include patients who had a response then went in remission, so could present a higher number than “AT” data that shows only those patients who have a response at that cut-off date.  This is an important distinction, for example, when comparing data from the BMS DASISION trial and Novartis ENESTnd trials to long-term survival data for imatinib versus interferon-alpha from the IRIS trial.

So, it was left to the EHA education symposia to provide some practical guidance.  In an excellent presentation, Hagop Kantarjian M.D. from MD Anderson provocatively presented his CML treatment guidelines, and discussed when you would use one drug over the other along with the importance of routine monitoring to evaluate how well a patient was doing on therapy.

Webcasts from the EHA education sessions will be available online soon and are well worth watching if you were unable to be in London this past weekend.


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