MaverickNY | Pharma Strategy Blog

Highlights and lowlights from the ASH meeting #ASH2010

By MaverickNY on December 14, 2010

Since the pre-ASH review of what might be hot at the conference, a few people have written to me asking for a rundown on my highlights from the recent hematology and breast cancer conferences. In the end, I only made it ASH in person, but followed the tweets and news that flowed out of the AACR SABCS meeting, which will post either later today or tomorrow.

Here are a few observations that struck me from ASH. There were some genuine highlights from this meeting, both in lymphomas and leukemias:

Rituximab (Roche) was the only clinical abstract selected for the plenary session this year. I loved Dr Anas Younes’ summary of this data on his Facebook Page:

“Clearly, early treatment with rituximab improved the progression free survival and time to next therapy. It is too early to see any effect on survival. My guess is that watch and wait will disappear as patients and doctors will start recommending early use of rituximab instead of watch and worry!”

The results are therefore potentially practice changing and it’s good to see positive data in a difficult to treat subset.

Ponatinib (Ariad), a third generation tyrosine kinase inhibitor (TKI) had excellent phase I data in relapsed/refractory chronic myeloid leukemia (CML), both with and without the T315I mutation. The phase II trial (PACE) is now enrolling and it is my hope that patients who find the existing TKIs fail or develop the T315I mutation will have a new therapeutic option in the not too distant future if the results continue to hold up.

Brentuximab vedotoxin (Seattle Genetics and Millennium) was the real star at ASH this year though. We’ve covered some background on the blog here. Basically, it’s a novel conjugate consisting of a monoclonal antibody with a chemotherapy molecule bolted on. The data in Hodgkin Lymphoma (HL) was absolutely stunning and a nice follow up to the article published in the NEJM by Dr Anas Younes et al., earlier this year. The companies have since announced that they intend to file with the FDA in early 2011, so perhaps we might see this exciting agent approved in the second half of next year.

Unfortunately, there were also some disappointing lowlights:

Lenalidomide (Celgene) had some interesting data in several phases of multiple myeloma, but what shocked many observers was the results of the MM-015 trial. This was the third study to suggest that there may be a risk for secondary cancers with Revlimid. Previously, the data emanated from the IFM and CALGB cooperative studies, but this was the first company sponsored trial that may be considered a registration study.

Clearly, the trend is not good news at all, although it is known that:

Alkylating treatment for AML and NHL run the risk of secondary cancers later in life
The literature suggests that all three cancers have a higher risk of secondary cancers developing, which may or may not be drug related.

In the light of all this, the myeloma finding with Revlimid is not entirely surprising but one can see why investors panicked and sold off stock after the data was announced. Of note though is that patients in the maintenance arm (MPR-R), however, will clearly receive more exposure to the drug than those in the MPR arm, potentially exposing them to a slightly higher risk.

Bosutinib (Pfizer) is a 2nd generation TKI in phase III development for newly diagnosed CML. Much of the expectation surrounding this agent was whether is would be superior to imatinib (Gleevec) in terms of efficacy in the same way that nilotinib (Novartis) and dasatinib (BMS). Both have proven to deliver earlier and deeper responses than imatinib, albeit with the caveat that we won’t know whether survival and overall outcomes will be better until the 5-10 year data is available. There was also some suggestion from Pfizer evolving over the last year that bosutinib might also be cleaner given that it only inhibits BCR-ABL and Src and not other off-target kinases such as PDGF. Unfortunately, that turned out to be a complete misnomer.

Dr Carlos Gambacorti-Passerini (Milan) did an excellent job trying to put a positive spin on the data, but this was a resoundingly negative trial. The primary endpoint of confirmed complete cytogenetic response (CCyR) at 12 months in the intent to treat (ITT) population was not met, although the secondary endpoint of major molecular response (MMR) was met. The side effect profile was particularly disappointing with a lot of diarrhoea, nausea and vomiting being frequent and most unwelcome side effects, which are very similar to chemotherapy. Much of the goal of targeted therapy is to hit the cancer cells for six while leaving normal cells largely alone. Chemotherapy is highly untargeted and hits everything in it’s wake, leaving people well aware that they are undergoing treatment for cancer rather than living with a chronic condition. Sometimes a disconnect between scientific theory and reality happens.

Pfizer announced at the meeting that they plan on pursuing an EU filing, but would hold discussions with the FDA about the relapsed/refractory setting, suggesting they will not file in the US for newly diagnosed CML, unless the FDA do a U-turn on the secondary (MMR) endpoint. The chances of that are rather slim, I suspect. I’m not entirely sure how the filing might be suitable for the EMA and not the FDA, unless the primary endpoints agreed with the Health Authorities were different. That said, given the good choices already available to people with CML, bosutinib is not going to appeal to many, I’m afraid. Certainly the CML KOLs I spoke to at the meeting were largely unenthusiastic about the agent.

Like many of the attendees, the thing most remembered from Orlando will be the bitter cold, both outside and in the presentation halls! Overall, it was really a rather quiet meeting this year, except for the excellent data in brentuximab.

1 Comment

Disclosures

By MaverickNY on December 13, 2010

IMGP2338 After the recent cancer conference and travel schedule, I’m a bit pushed for time today as the consulting work we’re doing at Icarus is frantically busy at the moment.

This is a great thing of course, but not so good for blogging 🙂

Still, I get a lot of questions about what we do job-wise, during the day, so you can head over to our new business website and check that out, if interested.

Meanwhile, some housekeeping updates here on Pharma Strategy Blog:

A disclosures tab has also been added to the top of this blog and going forward, all information relating to this will be curated there rather than on individual posts. It will save me forgetting 🙂
Our first cancer conference newsletter is almost ready to go out, so if you haven’t already subscribed and would like to, just add your name and email to the sign-up form at the top of the right hand column —>. Be warned – regular blog subscribers will not automatically receive the reports unless you choose to sign up.

Have a great day, everyone – the Holidays will soon be upon us.

Some additional thoughts on Zometa in early breast cancer

By MaverickNY on December 10, 2010

Yesterday’s news from the AZURE trial at the San Antonio Breast Cancer Symposium generated a lot of buzz. I posted the data after the press briefing in the afternoon here but have received a lot of questions from people confused by the press coverage of the data. To be fair, the physician presenting the data, Dr Robert Coleman, didn’t help matters by stating:

“Clearly our results are very different from those published by the ABCSG investigators”

when referring to the previous study published in the NEJM in February last year, without elaborating clearly on the differences. Dr Coleman also stated that it was “a negative trial”.

Interestingly, in the panel disclosures only Dr Giordano from MD Anderson revealed nothing to declare; Drs Coleman (Novartis and Amgen), Chlebowski (Novartis and Amgen) and Gnant (Novartis, Amgen and AstraZeneca) all received industry funding of some kind.

For those of you interested in the detail, I included the journal reference and the differences between the two trials in the post yesterday.

But to simplify – they are actually two very different trials – involving different stages of disease, menopausal status and different base treatments, so in reality, we should not expect them to be the same, since the populations are different.

Here’s a quick summary in the table below:

Recent Zometa trials in early breast cancer-2012-01-07
What we can see from this is that the stage II/III premenopausal women who received chemotherapy did not do well on zoledronic acid, but the other two groups did. I should point out that the post menopausal subset group who did benefit were typically more than 5 years post menopause and amounted to around one third of the study participants, so it was not an insignificant number. Lumping both menopausal ER+ subgroups together for the purpose of an overall analysis is fraught with challenges given the potential heterogeneity if the two behave differently, thereby effectively cancelling each other out.

We can also see that comparing the premenopausal groups in the two trials is not an easy comparison since one received hormonal therapy and the other chemotherapy. Taking hormonal therapy essentially induces early menopause, so this means that the ABCSG trial participants may actually model the AZURE postmenopausal women closer than people realise.

The whys and wherefores will not doubt follow in due course from the breast cancer oncologists.

My only surprise in all this is that Novartis have already stated they are withdrawing the filing, which may be a little hasty given that they have 2 out of 3 positive subsets of women with breast cancer who appear to significantly benefit from zoledronic acid treatment.

Ah well, time will tell where this controversy will lead!

2 Comments

Zoledronic acid did not improve disease free survival in early breast cancer

By MaverickNY on December 9, 2010

Wow, every now and then, something unexpected turns up and makes you stop, listen and most importantly, think. This was the headline from an American Association of Clinical Research (AACR) news release that I received from the San Antonio Breast Cancer Meeting (SABCS) this afternoon.

The result is totally unexpected. Why?

Well, we know the drug is effective in Stage IV metastatic disease and a previous trial from the Austrian group (study ABCSG XII) had positive results in stage I pre-menopausal women with breast cancer (see reference below). Early last year that trial was hailed as an important landmark study in The New York Times.

The current trial (AZURE) with zoledronic acid (Zometa) as adjuvant therapy in women stage II/III breast cancer was therefore expected to be positive, sitting neatly in the middle of the two previously published and positive settings.

Let’s take a look at the trial design.

3,360 women from several countries (the majority from the UK, Eire, Australia and Spain) were randomised to receive standard chemotherapy (physician’s choice), with one group receiving zoledronic acid and the other not. The women either had node positive (N+) adjuvant or T3/T4 or confirmed N+ neoadjuvant disease. They had undergone tumour resection, but not received bisphosphonates over the previous year or had any evidence of metastases. In the zoledronic acid arm, it was given as a 4mg infusion over a total of 5 years – ie 6 doses every 3-4 weeks with chemotherapy, then 8 doses every 3 months followed by maintenance therapy every 6 months for 5 cycles.

The primary endpoint of the study was disease free survival (DFS) with invasive DFS (IDFS) as a secondary endpoint. According to my notes, the planned final analysis was due to take place at 940 DFS events with an anticipated 3 year DFS of 75%, allowing for a 3 year recruitment period and 6 years of follow-up. The study was powered at 80% (two sided) to detect a 17% hazard reduction in DFS (HR=0.83) i.e. from 75% to 78.7% for DFS at 3 years. There was an original interim analysis in 2008 but the Data Monitoring Committee (DMC) did not recommend stopping the trial at that point. A second analysis was proposed (accepted) to the DMC given the low event rate for the whole study with a 3-year DFS rate of approximately 85%. The patients in both arms were well balanced for the key factors (lymph nodes, T stage, ER and menopausal status):

The groups were also well balanced for prior treatment, including chemotherapy:

The median follow-up period was similar in both groups (58-60 months), as was time since last follow-up (approx. 6 months). There was little difference between the groups in adverse events, with the exception of osteonecrosis of the jaw (ONJ), a known side effect of bisphosphonate treatment:

At this point, things started to get interesting. Here’s what happened in the ABCSG XII trial from Gnant et al.; you can see the clear separation of the DFS survival in their large (n=1803 ) trial in premenopausal women:

This is exactly what the investigators hoped to see with zoledronic acid in the AZURE trial. Instead, the survival curves virtually surprisingly overlap:

Just in case anyone is wondering whether prior bisphosphonate therapy affected the results, the analysis suggested otherwise:

As Rob Coleman, the British PI of AZURE stated in the AACR press conference, the results between the two studies are essentially ‘chalk and cheese’, meaning polar opposites:

When they looked at the AZURE subgroup analysis, they found something interesting. While the premenopausal patients saw no benefit from zoledronic acid therapy, there was a significant difference for older women (>60yo) who were postmenopausal:

Given the disparity between the ABCSG XII and AZURE trials in premenopausal women, it is hard to imagine bone studies essentially being right, creating an interesting controversy as to why there is a disparity. Bear in mind that the Austrian study was in women with stage I breast cancer without chemotherapy, while AZURE was stage II/III disease with chemotherapy. Zoledronic acid in the Austrian trial was given at the same dose (4mg), but on a much simpler schedule (every 6 months) because there was no chemotherapy involved, only endocrine treatment.

Clearly something interesting is going on in the tumour microenvironment rather than the host and further research is likely to be ongoing to try and explain the science behind these findings.

Coleman speculated that there might be increased turnover and endocrine changes going on associated with menopausal and bone cell function, but that is just a hypothesis at this stage. My initial reaction is this does not explain the ABCSG XII results in stage I premenopausal women.

Impact of the AZURE results:

Given the resoundingly overall negative outcome in DFS, it is likely that Novartis will withdraw the expanded Zometa approval to prevent breast cancer relapse. Meanwhile, there will be much controversy and discussion to try and reconcile the results of the AZURE vs ABCSG XII trials in the premenopausal setting.

I think that it is unlikely that the guidelines will support routine use of zoledronic acid in this setting, although the findings in postmenopausal women will no doubt deserve further analysis in the coming months.

Disclosure:

I’m a former employee of Novartis and also a consultant, but have never worked on Zometa.

{UPDATE}

Novartis have announced that they are indeed with drawing the filing for Zometa, with the following statement:

“Last year, Novartis filed supplemental marketing authorization applications for the adjuvant treatment of premenopausal women with HR+ early breast cancer in conjunction with hormonal therapy in the US and European Union (EU) based on the results of ABSCG-12. Novartis is currently reviewing the data from the AZURE trial results, which were expected to be added to the submission. In the meantime, Novartis will withdraw the current marketing applications and discuss next steps with health authorities.”

References:

Gnant, M., Mlineritsch, B., Schippinger, W., Luschin-Ebengreuth, G., Pöstlberger, S., Menzel, C., Jakesz, R., Seifert, M., Hubalek, M., Bjelic-Radisic, V., Samonigg, H., Tausch, C., Eidtmann, H., Steger, G., Kwasny, W., Dubsky, P., Fridrik, M., Fitzal, F., Stierer, M., Rücklinger, E., & Greil, R. (2009). Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer New England Journal of Medicine, 360 (7), 679-691 DOI: 10.1056/NEJMoa0806285

2 Comments

Risk of lung cancer after treatment for breast cancer

By MaverickNY on December 9, 2010

There was an interesting paper published recently in The Lancet Oncology, which looked at the increased risk of developing lung cancer after women had experienced prior breast cancer (see ref below). Over the years, there has been much debate about the potential impact of different treatment regimens, whether chemotherapy or radiotherapy, on the development of secondary cancers, but what about other factors such as lifestyle and health issues?

Yet in many ways, it’s almost a catch 22 situation, because improvements in treatment for breast cancer also means that women are living longer, and therefore at a greater risk of developing a second malignancy with the passage of time. This study set out to see which variables might possibly be important. According to the authors:

“We review data on the effect of treatment factors (ie, surgery type, radiotherapy technique, and adjuvant chemotherapy) and patient factors (ie, age and smoking) on the risk of developing a subsequent lung cancer.”

The results suggested that:

“Older radiotherapy techniques were associated with a substantially increased risk of developing lung cancer in the ipsilateral lung, but there is no clear evidence of an increased risk with modern techniques.”

Several factors had an unclear effect, e.g. age at treatment, while others such as adjuvant chemotherapy, were not a risk factor.

Unsurprisingly, smoking was found to be an critical risk factor, with the risk also increasing in those women who smoked and received prior radiotherapy.

Overall, the simple message of this story is those women with breast cancer who have smoked and received radiotherapy will be at a greater risk of getting secondary lung cancer later in life than those who did not.

References:

Lorigan, P., Califano, R., Faivre-Finn, C., Howell, A., & Thatcher, N. (2010). Lung cancer after treatment for breast cancer The Lancet Oncology, 11 (12), 1184-1192 DOI: 10.1016/S1470-2045(10)70056-5

5 Comments

AACR San Antonio Breast Cancer Symposium #SABCS

By MaverickNY on December 8, 2010

Sadly, a nasty ear infection has grounded me and I’m unable to attend the San Antonio Breast Cancer Symposium after all :(.

However, I’m aggregating the Tweet commentary from the various attendees and will be following remotely in the back channel. Various breast cancer specialists such as enthusiastic and enigmatic Dr Naoto Ueno will be tweeting live, so it should be a good meeting! Today is mostly the education symposia.

You can see all the tweets, posts and comments from the meeting in the widget below:

<a href="http://www.coveritlive.com/mobile.php/option=com_mobile/task=viewaltcast/altcast_code=5fff5fd716" >SABCS</a>

Highlights of #ASH2010 – Day 1

By MaverickNY on December 5, 2010

Yesterday was an unusually quiet day at the conference, with no formal oral abstract sessions, although there were various educational symposia running in a number of topics. Depending on what’s happening in the particular disease and who is presenting, sometimes these can be exciting when the deep thinkers present the data in an interesting way and advance the field by asking the audience to consider things more strategically.

This year, there was no new data or ideas expounded in the sessions I chose, they were basically a run through of the old data with a couple of slides at the end listing a few compounds that are in development. The pipeline in for hematologic malignancies is gradually gaining more attention from Pharma, which is great news, although they are probably a lot less crowded than the main solid tumours.

The Leukemia press briefing was informative and a number of abstracts were selected for discussion. All of the presenters did an excellent job of summarising their data, which is embargoed until after the Plenary or Oral sessions on Sunday and Monday.

The leukemia highlights comprised:

Dr Fielding: imatinib in Ph+ pediatric ALL
Dr Rosti: nilotinib in Ph+ early phase adult CML
Dr Cortes: ponatinib in advanced phase CML
Anna Jankowska and Prof Maciejewski: TET2 mutations in myeloid malignancies

I will write more about the data after the embargoes have been lifted.

A number of people were tweeting snippets from the meeting and quite a few bots were posting various press releases. There are a number of tools out there for showing the big picture around conferences and hashtags, which we’ve shared in the past on this blog. The latest one I came across was shared by Greg Mathews (@chimoose) who kindly put this TPS (tweet positioning system) dashboard together:

Screen shot 2010-12-05 at 7.03.11 AM

You can check it out for yourselves by clicking on the tool link here.

The Highlights of the Day for me weren’t any of the education sessions, but rather took on a more human element, ie catching up with Twitter buddies in person. It is always nice to chat with the excellent Jan Geissler (@jangeissler), who was diagnosed with CML in his late twenties and now does sterling work in CML advocacy and Silja Chouquet (@whydotpharma), who also used to work at Novartis like myself, but we never met until afterwards. I love this photo taken during the conversation:

203139505 Later in the poster session, I tracked down Michael Becker (@mdbpartners) at the Semafore poster he was hosting for SF1126, a dual PI3-kinase-mTOR inhibitor being investigated in a phase I trial for B-cell malignancies. Michael and I have been exchanging tweets during and after conferences for some time now but never actually met in person, so it was great to finally put the face to the Tweeter, so to speak. A great guy!

Here he is at the SF1126 poster:

203149060 If you’re not watching Semafore and another PI3-kinase company, Calistoga, that I mentioned in my What’s Hot at ASH 2010 post, then check them out as they both have novel and interesting compounds that may be eventually licensed by pharma or biotech companies. You can also read more about the background behind PI3-kinase as a valid cancer target here.

Strange goings on at #ASH2010

By MaverickNY on December 4, 2010

One of the highlights for me in attending this American Society of Hematology meeting is the increasing number of science presentations. This is important because ultimately, as our understanding of the underlying biology of diseases such as hematologic cancers improves, so does our skill and knowledge in figuring out ways to overcome those quirks and potentially develop new therapeutics that improve outcomes.

This is what this blog is really all about – the science and biology of cancer and how research from bench to bedside is making any impact on people’s lives. I’m a Ph.D scientist, so this is what interests me most. We may not be able to cure most cancers, but we are starting to shift some of them from an acute to a chronic disease. This is progress indeed.

It was therefore with some dismay to discover that the one of the sessions here I was most excited about, I actually cannot attend! That is a first at any conference I’ve actually received registration for.

Imagine, I was really excited by the thought of attending the Monday session entitled:

“DNA-repair pathways: cancer syndromes to novel therapies”

After all, I’ve been writing about the science of DNA repair, synthetic lethality and PARP inhibition on this blog since 2006 and most of the data has emerged in solid tumours, especially breast and ovarian cancers. The idea that it might have some application in hematologic malignancies is therefore new and potentially ground breaking, so well worth covering from a science and news perspective.

But take a look at this – while putting my schedule together, the small print in the program clearly says:

“The Education Spotlight Sessions are restricted to medical professionals only; no businesspersons or media will be admitted.”

Here’s a photo of the statement:

This rather unfriendly and unexpected policy raises several questions:

Why are only medical professionals included and how are they defined?
What about MD’s working for pharma companies as businesspeople?
What about Ph.D’s, RN’s, pharmacists who are working for a company or who are members of the media like myself?
What about medical professionals working for patient advocacy groups?
Why do this at all? It’s not something that I ever recall seeing at ASH in the 15 years I’ve been coming to this annual event.

A quick look at the ASH website didn’t help much as I have to run around over 1,000 posters to catch up on the hot new things, I don’t have much time to surf for policies etc when there are more important things to do.

That said, one of the huge advantages of oncology science and medical conferences is the multidisciplinary and collaborative approach that has evolved over the last decade to everyone’s benefit, not least the speeding up of bench to bedside therapeutic development that has led to improved outcomes for people living with many different hematologic cancers.

Limiting access to only select individuals, rather than the greater good for all who wish to attend does none of us any good in the long run – it’s a backwards, not a forwards step, sadly.

</rant>

It isn’t often that I’ve attended a medical oncology conference and actually felt like a second class citizen or a need to rant at the unfairness of something, but that day finally arrived this morning :(.

17 Comments

American Society of Hematology meeting #ASH2010

By MaverickNY on December 3, 2010

The annual American Society of Hematology (ASH) meeting has come around all too quickly this year and starts today in Orlando.

I’ll be tweeting snippets from the event (wifi permitting) and also curating the tweets from the event below for those following remotely, based on the official Twitter hashtag #ASH2010, as well as other likely ones that may be in use.

The ASH organisers have a Twitter account (@ASH_Hematology), if anyone is interested in following them. They seem pretty helpful and responsive.

If you have any questions about the scientific presentations at the meeting, do feel free to tweet me or add them in the comments below. I’ll do my best to answer them or find someone who can.

Dr Anas Younes (@dranasyounes), a lymphoma specialist from MD Anderson, will also be tweeting and he has posted some of his top abstracts on his awesome Facebook page – check it out here.

To follow the meeting tweets, click on the play button below. The event runs through from Friday 3rd until Tuesday 7th.

What’s Hot at ASH in 2010?

By MaverickNY on December 2, 2010

Here’s my 2010 list of a few pipeline and approved products that I’ll be watching out for at the upcoming American Society of Hematology (ASH) meeting , which begins tomorrow and runs over the weekend. Some of them will not the expected hot ‘news’ items so beloved of the medical media who often seem to delight in over-hyping things.

Saturday and Sunday typically embrace the posters, education and plenary sessions, while Monday and Tuesday heralds the oral sessions.

In no particular order, and by no means extensive, these are agents I personally find interesting and worth checking out at the meeting:

1. ARRY-520 (Array Biopharma)

There is still no cure for multiple myeloma, although a wealth of new therapies and combinations has definitely improved survival and outcomes for this disease. It is always good to look out for new agents in development in the relapsed/refractory setting.

ARRY-520 is interesting because it’s a kinesin spindle protein (KSP) inhibitor. KSP is required for cell cycle progression through mitosis and inhibition of KSP has been shown to induce mitotic arrest and cell death, in a similar fashion to taxanes and vinca alkaloids. The company has a number of small molecule compounds in development for cancer:

Source: Array Biopharma

ARRY-520 has been researched specifically in hematologic models such as myeloma, so this will a poster I’ll be looking out for.

What I love about this compound:
While ARRY-520 may target the spindle like taxanes, it appears to do so without the associated peripheral neuropathy and hair loss.

2. SGN-35/brentuximab vedotin (Seattle Genetics/Millennium):

I wrote about the recent promising data from the NEJM by Dr Anas Younes and colleagues. At ASH the same group are presenting on SGN-35 in relapsed/refractory Hodgkin Lymphoma including adverse events and ORR (Mon 6th, 7am) and another group is looking at the agent in Anaplastic Large Cell Lymphomas (Tues 7th, 7.30am) where they will be presenting data on complete remissions.

What I love about this compound:
The concept of a monoclonal antibody combined with chemotherapy as a drug conjugate is an exciting new disruptive biotechnology with a lot of promise.

3. CAL-101 (Calistoga)

Most (but not all) of the other PI3-kinase inhibitors in development seem to have been focusing primarily on solid tumours with mixed results to date. There is also a potential role for the delta form of PI3 kinase inhibitors in B-cell signalling, which encompasses Non Hodgkins Lymphoma (NHL), Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL). Calistoga have been looking at CAL-101 specifically in hematologic malignancies and 7 abstracts are being presented this year either alone or in combination.

What I love about this compound:
When everybody zigs, zag.

4. Crizotinib (Pfizer)

This year, we’ve all heard a lot about ALK rearrangements in non-small cell lung cancer (NSCLC), but such translocations also occur in anaplastic large cell lymphoma (ALCL). It would be most logical to see if crizotinib has any effect in these people with this uncommon form of lymphoma, so I’m looking forward to seeing what the data looks like in the poster session on Sunday evening. I’m expecting/hoping it will show some positive signs in this particular subset who are chemorefractory.

What I love about this agent:
It’s highly and specifically targeted to ALK, a constitutively active translocation (and occasional mutation) that appears to be driving some lung cancer, lymphoma and other rarer cancer subsets.

5. Imatinib/nilotinib (Novartis)

How low should you go? It is now clear from the evidence that people living with CML who attain a major molecular response (MMR) are less likely to relapse than those with a complete cytogenetic response (CCyR).

Ten years ago, the expected life span was only 3-4 years. Imatinib has dramatically shifted the paradigm for the treatment of CML, with people having a realistic goal of living for at least a decade after diagnosis with early chronic phase disease. It is likely that the baton will soon pass to the new second generation TKIs such as nilotinib and dasatinib, which can help achieve an earlier response into the ‘safe haven’ zone. They typically all achieve 90% response rates, but differ in their side effect profiles owing to the additional targets they inhibit.

It will be interesting to see what new data will be presented at this meeting in the annual IRIS trial update and other presentations in several sessions on Monday 6th.

What I love about this drug:
You can’t keep an old warhorse down!

6. Ponatinib (Ariad):

None of the TKIs currently approved for CML target the rare T315I mutation, which ponatinib does target, based on preclinical data. Initial phase I data in the relapsed/refractory setting including T315I mutations is due to be presented in Orlando in the oral session (Monday 6th, 8:15am).

What I love about this compound:
Resistance to all of the TKIs is not that common in CML, but I do think it would be good to have an option for those who find themselves in that unfortunate situation.

7. Rituximab (Roche/Genentech):

Most of the plenary presentations on Sunday afternoon are scientifically focused this year, but there is some preliminary clinical data on rituximab in follicular lymphoma (FL).

The randomised trial from the UK looks at rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky FL. The reason for this is that patients with asymptomatic, advanced stage, follicular lymphoma have shown no benefit of immediate chemotherapy when compared with a watchful-waiting approach, so chemotherapy is typically deferred until disease progression. Rituximab (when used with the CHOP chemotherapy regimen) has become the standard of care for NHL, so looking at it’s activity in another lymphoma subset makes sense.

What I love about this compound:
Anything that significantly delays disease progression without the side effects of chemotherapy would be a welcome addition to treatment options in FL.

8. Concomitant VEGF and MEK inhibition

There are a couple of novel approaches looking at new combinations at the ASH meeting. Thoughtful research studies can often inform us about a potential new approach that might be worthwhile considering in the clinic. One such example I came across was dual VEGF and MEK inhibition in pediatric 11q23 AML. In AML, it has been found that simultaneous activation of these pathways results in a poor prognosis, so this would be a logical therapeutic combination to consider in appropriate children. Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene at locus 11q23 are also associated with a poor outcome. These translocations represent approx. 15-20% of pediatric AML.

What I love about this concept:
As a result of the preclinical research, future studies looking at a VEGF-MEK combination are now being planned in pediatric AML and will be worth watching out for.

9. Panobinostat and everolimus (Novartis)

Believe it or not, I was actually trying very hard to avoid selecting another Novartis drug or combination, but they have a very broad portfolio in oncology and lots of interesting early data coming out. The reasoning behind this combination is that mTOR and deacetylase (DAC) inhibitors have demonstrated single agent activity in patients with relapsed and refractory lymphoma. Synergy between DAC inhibitors and mTOR inhibitors has also been observed in lymphoma cell lines in vitro. This is a phase I dose finding trial, so the results will be preliminary, but we should see whether the promise is possible from the early signals.

What I love about this concept:
HDAC and mTOR is a highly logical combination to explore in lymphomas based on the preclinical research to date.

10. TET2 mutations in myeloid malignancies

In case you’re thinking this might be a bit obscure, this presentation actually kicks off the Plenary session on Sunday and I have to say that it’s cool to see a Masters student present some really cool research.

“TET2 mutations are frequently found across broad spectrum of myeloid malignancies but how these mutations contribute to diseases is still unknown.”

I’m not going to spoil the presentation, but what I suspect they may have is a new therapeutic target in myeloid malignancies based on a mutation that occurs through epigenetic changes.

To check out some other top lists, take a look at Dr Anas Younes Facebook page, where he has posted his top 10 lymphoma clinical abstracts. I haven’t seen any other 10 ten abstracts for ASH yet, so we may well be the first two to stick our necks over the parapet 🙂

Disclosures:

– I own no stock in any of these companies (perhaps I should!)
– I’m a former employee of Novartis who worked on imatinib and my company has done consulting work for them.