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Posts from the ‘Conferences’ category

Will combining custirsen and MDV3100 reduce resistance in advanced prostate cancer?

By on February 26, 2012

EAU-2012-Congress-Paris-View-of-Eiffel-Tower-By-NIght

Sights of 2012 EAU Congress

Greetings from the European Association of Urology (EAU) congress in Paris. Despite the grey drizzle typical of Europe in winter, this is actually quite an interesting meeting with lots of poster presentations.

One poster that caught my eye yesterday was from Martin Gleave’s group on clusterin knockdown synergising MDV3100 activity. Previously, we discussed on this blog how inhibiting clusterin with custirsen (OGX-011) potentiated docetaxel. At the AUA meeting last year, the issue of whether the same would happen with MDV3100 was suggested, as you can see in the short video blog.

Clusterin is also known as testosterone-repressed prostate message-2 or TRMP-2, and has been shown by Miyake et al., (2000) to be important in advanced prostate cancer. This is because the treatment of choice in hormone-sensitive disease, androgen deprivation therapy (ADT), can lead to clusterin upregulation, thereby causing castrate resistance.

The group’s latest study at EAU looked at whether clusterin knockdown sensitised MDV3100 activity and evaluated potential mechanisms for how this might work.

The results showed that:

  1. Neither MDV3100 or custirsen alone affected AR levels, but in combination, the AR protein levels were reduced.
  2. The combination synergistically suppressed LNCaP (human prostate cancer cell lines) in vitro and in vivo compared to monotherapy with either alone.
  3. Inhibition of the AR has been shown to activate the PI3K-Akt pathway, but the combination prevented this from occurring.
  4. Dual treatment also increased AR instability via decreased levels of the AR chaperone, FKBP52.
  5. AR degradation occurred with combination therapy via the proteasome, leading to synergistic repression of AR transcription.

While these data offer a very nice and logical preclinical rationale for considering a combination of MDV3100 and custirsen to overcome castrate resistance in advanced disease, we also need to see clinical evidence in advanced prostate cancer before getting too excited. I like the idea scientifically but Oncogenex, the manufacturers of custirsen, have not exactly been swift at moving their previous trials along, as Luke Timmerman noted his Xconomy article last year.

Ultimately, the proof is always in the (clinical) pudding.

References:

ResearchBlogging.orgMiyake H, Nelson C, Rennie PS, & Gleave ME (2000). Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer research, 60 (1), 170-6 PMID: 10646870

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The role of the Androgen Receptor in breast cancer

By on February 10, 2012

This week I have been in Orlando for the American Association for Cancer Research (AACR) Special Conference on prostate cancer chaired by Drs Arul Chinnaiyan (U. of Michigan) and Charles Sawyers (MSKCC).  It was a superb meeting, probably one of the best I’ve attended since the PI3K meeting that AACR hosted in February last year.  I wrote nearly half a Moleskine of notes that vaguely resemble chicken scratch – there were so many good talks that stimulated new ideas and explained a few scientific things I also didn’t know too well.  Learning is a continuous lifetime experience, after all.

During the meeting, I had a nice correspondence with one of our regular blog readers, the thoughtful Biomaven.  Peter mentioned some data on the androgen receptor (AR) as a potential target in breast cancer following Medivation’s recent conference call.  It’s an interesting topic and one well worth discussing.  Here’s a map of the AR pathway for reference:

Source: wikipedia

The AR is not something one naturally and immediately thinks of in women, since testosterone is usually considered a manly thing.  That said, it is present in women in both normal breast epithelial cells and ~70% to 90% of invasive breast cancers.

Until recently, the link, however between AR status and breast cancer survival is uncertain and perhaps a little controversial, but Hu et al., (2011) looked at the association between the AR status and breast cancer survival in the Nurses’ Health Study (NHS) – see references at the end for the link to the article.

What was the study about?

According to the authors:

“The NHS is a prospective cohort study established in 1976 when 121,700 female registered nurses from across the United States, aged 30 to 55 years, completed a mailed questionnaire on factors that influence women’s health.

Follow-up questionnaires have since been sent out every 2 years to the NHS participants to update exposure information and ascertain nonfatal incident diseases. Follow- up rate from 1976 to December 2007 is 98.9% in our study.”

Not to be confused with an population/epidemiology study from the NHS (National Health Service) in the UK!  The main goal of this study was to:

“… determine the association of AR status with survival outcomes adjusting for covariates.”

What did the research find?

Out of all the breast cancers followed (n=1467), 78.7% were AR+. Additionally, amongst the ER+ patients (n=1,164), 88% were AR+:

“AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47–0.99) and overall mortality (HR, 0.70; 95% CI, 0.53–0.91) after adjustment for covariates.”

The situation was very different in women who were ER- (n=303) though:

“42.9% were AR-. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94–2.68).”

In other words, AR+ confers a better prognosis in ER+ breast cancer.

Now, the relevance of all this research is potentially important when considering possible mechanisms of resistance to aromatase inhibitor (AI) therapy in ER+ breast cancer.  Recall that one mechanism of resistance to AI treatment is mTOR, which is why the BOLERO2 trial with an AI (exemestane) plus an mTOR (everolimus) in the relapsed setting did so well in ER+ women.  Not all of the women in the trial responded to the treatment though, suggesting that other factors may play a role in acquired or adaptive resistance.

What is the importance of AR to therapies for breast cancer?

Normally, knowing whether a particular situation has a better or worse outcome isn’t particularly helpful for patients, since it doesn’t predict which therapy might be more appropriate. However, there is some other AR and breast cancer research from Cochrane et al., (2011) which was presented to the Endocrine Society Peter referred to that tells us a bit more of the AR story:

“We postulate that ER+ breast cancers that fail to respond or become resistant to current endocrine therapies (tamoxifen or AI) may do so because they have switched from growth controlled by estradiol (E2) and ER to growth controlled by liganded AR.

We therefore sought to determine if blocking AR activity could serve as a therapeutic intervention for such tumors.”

What did they do?

Cochrane et al, (2011) stated that:

“We used breast cancer cells that express ER and AR such as MCF7 cells and a cell line that we recently isolated that contains more AR than ER.

Our data indicate that although DHT does slightly inhibit E2-mediated proliferation, DHT alone is proliferative in cells such as MCF7 with both ER and AR, and is even more proliferative than E2 when AR is more abundant than ER.”

What did the results show?

The results were a) interesting and b) a little surprising:

“We found that while both the anti-androgen bicalutamide and the triple acting, non-steroidal, AR antagonist MDV3100 block DHT and R1881-mediated proliferation of breast cancer cells, we made the novel observation that MDV3100, but not bicalutamide, inhibits E2-mediated proliferation of breast cancer cells.”

These results led the authors to conclude that:

“Anti-androgens, such as MDV3100, may be particularly useful to treat patients whose tumors fail to respond to traditional endocrine therapy despite being ER+, or who have ER-/AR+ tumors.”

Not surprisingly, Medivation announced on their recent conference call this month that they will be seeking to explore this phenomenon in clinical trials.  I think this is a logical and exciting development that is well worth a shot on goal.  We know that not all the women in the BOLERO2 trial responded to exemestane and everolimus, so other mechanisms must be at play here.  This is certainly worth exploring.

The question with the study design of me for me though, is patient selection.  How do we determine which women whose initial AI therapy leads to relapse should go onto an mTORor an AR antagonist?  I’m guessing that maybe biopsies will be part of the answer.

In conclusion…

On the positive side, it would be pretty cool if we could uncover two mechanisms of resistance to AI therapy in ER+ breast cancer and have some viable therapies to offer women once relapse or acquired resistance sets in.  It would start to offer a) hope and b) potentially prolong outcomes further as we determine ways to shut down the various escape routes and signaling pathways.  If the concept works, given that up to 30% of women with ER+ breast cancer may have AR+ signaling, then it would also be good news for Medivation and Astellas with MDV3100’s potential upside.

References:

ResearchBlogging.orgHu, R., Dawood, S., Holmes, M., Collins, L., Schnitt, S., Cole, K., Marotti, J., Hankinson, S., Colditz, G., & Tamimi, R. (2011). Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women Clinical Cancer Research, 17 (7), 1867-1874 DOI: 10.1158/1078-0432.CCR-10-2021

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ASH 2011 Update #3 – Multiple Myeloma

By on January 4, 2012

Most new developments in cancer research tend to occur in increments, thus we see a fair number of improvements in survival (whether PFS or OS) in the 1-4 month range over the existing standard of care. However, as we saw recently at European Conference for Clinical Oncology (ECCO) in September and the San Antonio Breast Cancer Symposium (SABCS) last month with the BOLERO-2 nad CLEOPATRA trials, every once in a while something comes along that shifts the efficacy curve by six or seven months and people rightly get very excited about this.

Imagine then, an improvement in median overall survival by 13 months? Or rather, 13.3 months to be precise? That’s both very exciting and huge for patients and physicians alike.

What was the drug that produced this stunning seismic shift?

Velcade.

VISTA in newly diagnosed elderly patients with MM

At the 2011 American Society of Hematology (ASH) meeting, Professor Jesús San Miguel (Salamanca, Spain) presented the five year results of the VISTA (VELCADE as Initial Standard Therapy in Multiple Myeloma) study. This trial compared triple therapy with bortezomib, mephalan and prednisone (VMP) to the current standard of care, melphalan plus prednisone (MP) in previously untreated multiple myeloma (MM) patients (N=682) who were ineligible for high-dose therapy.

The analysis demonstrated that after a median follow-up of 60.1 months, the median OS was 56.4 versus 43.1 months for patients randomised to VMP and MP, respectively, giving a significant survival advantage of 13.3 months for the VMP arm (p=0.0004).

This is how the survival curves look:

Source: Image courtesy of Millennium

Unfortunately, I wasn’t able to see the actual presentation live as it clashed with so many concurrent presentations on the ‘manic Monday’ of the meeting, but I did talk to Prof San Miguel, who excitedly described the findings as “impressive” despite the fact that “the control arm did very well,” however, “we now know that VMP is the best option in this patient population.”

This was one of those rare times when I thought that ‘impressive’ was perhaps an understatement, especially as the majority of patients could be considered elderly, in the 65-75 age range. Based on this eagerly anticipated data and talking to several myeloma thought leaders at the meeting, there is no doubt that VMP will become the new standard of care for upfront treatment in those patients who are ineligible for high dose treatment and a transplant.  It’s a result that is full of win all around.

Secondary Primary Malignancies and Revlimid

The other interesting thing about the data was the incidence of secondary primary malignancies (SPM), a topic that was very much to the for last year for Celgene’s lenalidomide (Revlimid).

Dr San Miguel observed that the background incidence in this elderly population is 1.92, based on SEER data. He also noted that in the VISTA trial, the incidence of SPM was 1.66 SPM per 100-patient-years for the VMP arm versus 1.30 for MP alone. This difference wasn’t significant and in fact, both arms were lower than expected from the SEER data, which is reassuring.

Talking of SPMs, I attended Dr Antonio Palumbo (Torino, Italy) presentation on the last day on a retrospective multifactorial analysis of newly diagnosed patients with MM (N=2,283) who had received Revlimid in European clinical trials (N=9).  They sought to try and address if we can anticipate when SPMs were most likely to occur and in which combinations. The median follow-up time for in their analysis was 29 months and the median age was 69 years.

Overall, they found 48 secondary cancers including 10 blood cancers and 38 non-blood cancers.

The data clearly showed that the incidence of SPM with IMiDs was higher in melphalan-based regimens than others:

Revlimid:
Dexamethasone ± cyclophosphamide 0.40
Melphalan                                             0.95

Thalidomide:
Melphalan                                             1.05

Melphalan only:                                     0.42

We can see from this analysis that while the IMiDs per se don’t appear to cause SPMs, there is clearly an interaction occurring between the IMiDs and melphalan that increases the risk, although the mechanism for this phenomenon is unknown.

The future is bright for MM

Multiple myeloma is now becoming a very dynamic area of clinical research beyond Velcade, thalidomide and Revlimid.

Other emerging agents include carfilzomib, pomalidomide, MLN9708, perifosine, HDACs (panobinostat, romidepsin, vorinostat) and many others.

No doubt we will hear more about these new agents in development going forward either as new combinations or sequencing of multiple therapies, all of which may lead to a cumulative increase in survival for patients with multiple myeloma.

 

 

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ASH 2011 Update #2 – Non Hodgkins Lymphoma

By on December 21, 2011

I’ve been busy with other things offline since the last blog update from the American Society of Hematology (ASH) meeting in San Diego, but will be catching up on my notes from the conference over the next few days.

In addition, my colleague Pieter Droppert has already posted his topline impressions of the meeting on the companion Biotech Strategy Blog, which readers may be interested in:

  1. Ponatinib in CML
  2. Update on new advances AML and FLT3
  3. Interesting posters – BTK and PI3K

Meanwhile, I thought it would be a good idea to look at the pipeline developments in non-Hodgkin’s lymphomas (NHL) that I particulalry liked at ASH:

PI3K inhibitors

Pieter’s choice of PI3K as a hot topic turned out to be rather prescient given that:

a) Intelikine announced last night that the company is being bought by Millennium-Takeda in a deal worth $190M upfront with $120M in additional milestone payments. This is a great transaction all around, enabling clinical development to now begin for Intellikine’s two remaining PI3K-mTOR and selective isoform inhibitors and since Takeda have research facilities locally in San Diego, this will enable work to continue with minimum fuss and relocation.

b) As of this morning, Exelixis announced they have licensed their PI3K-delta inhibitor in preclinical development to Merck. This deal features an upfront payment of $12 million, but the company will be eligible for potential development and regulatory milestone payments for multiple indications of up to $239 million in the future.

Another PI3K inhibitor in the news is Calistoga’s CAL-101 (now owned by Gilead), a delta selective isoform inhibitor being evaluated in indolent NHL. At this meeting, the phase I data was presented in a poster. The patients enrolled to date (n=37) included those with follicular lymphoma, small lymphocytic leukemia and marginal zone lymphomas, all of whom had received prior therapy for their disease. In this study, CAL-101/GS-1101 was given in combination with rituximab and/or bendamustine to determine the safety profile.

The big question is whether the combination with chemoimmunotherapies would lead to added or overlapping toxicities – the authors, de Vos et al., concluded that answer was no and a good efficacy signal was seen:

“GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy.”

On the basis of this study and a prior phase I trial that determined the dose (150mg/BID), further continuation of the program in this indication appears warranted:

“The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with iNHL.”

 

Anti-CD20 monoclonal antibodies

Rituximab was the first targeted cancer drug following its approval back in 1997 and has shown how important targeting CD20 has been in lymphomas and more recently, chronic lymphocytic leukemia (CLL). At this meeting, we saw an interesting new development in lymphomas from Roche/Genentech in GA101 (obinutuzumab). This is essentially a follow-on biologic to rituximab. In a previous post prior to ASH, I looked at the key questions that need to be addressed in order to displace rituximab, namely more activity in rituximab refractory patients, more efficacy/better side effect profile up-front or broader activity across several diseases.

What are the key differences between rituximab and obinutuzumab you might ask and does this impart any clinical benefit?

Well, rituximab is a humanised type I monoclonal antibody, whereas obinutuzumab is a humanised type II glyco-engineered antibody, both target CD20. What’s the difference between Type I and II? Well, according to Robak, 2009:

“GA-101 binds with high affinity to the CD20 type II epitope, resulting in the induction of antibody-dependent cytotoxicity that is 5- to 100-fold greater than observed upon treatment with rituximab.”

The proof of the pudding is always in the clinical data, especially randomised head-to-head trials. There were over a dozen abstracts on GA101 at ASH, but the most important one in this context was a phase II GAUSS trial from Sehn et al., which randomised patients with indolent B-Cell NHL to receive either rituximab or obinutuzumab in the relapsed setting:

Gauss trial schematic courtesy of Roche

And the result? The authors concluded that:

“Treatment with GA101 in patientss with relapsed NHL resulted in higher response rates compared to rituximab as assessed by both investigators and the IRF at an early time point.

GA101 was well tolerated, although a higher rate of IRRs was noted, the majority were grade 1/2 in severity and did not result in significant differences in treatment discontinuation.”

Where IRR is infusion related reactions.

This data is promising for obinutuzumab, but still very early – we will still need to see what happens in a larger scale phase III trial with more patients before we can draw more definitive conclusions. That said, I found the GAUSS trial data very encouraging indeed.

Bruton’s Kinase Inhibitors

In the first update, I highlighted how Bruton’s Kinase inhibition (BTK) was one of the exciting new emrging pathways in chronic lymphocytic leukemia (CLL), but new data was also presented on the leading BTK inhibitor, PCI-32765 (Pharmacyclics/J&J), in lymphomas.

The preliminary phase II data in mantle cell lymphoma (MCL) presented by Wang et al., in 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) with a median of two prior treatment regimens (range:1-5).

Initial efficacy data was reported:

“The objective response rate (ORR) is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort.”

The side effect profile seen to date was also described:

“Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765.”

I thought these results were encouraging – with good tolerability and encouraging signs of efficacy – certainly worthy of exploring in a randomised phase III trial in this indication. This is an agent we are probably going to hear a lot more about in the near future.

And finally…

There were a lot of new developments emerging at this meeting, particularly in the poster sessions and also in both phase I and II trials. It was impossible to keep up with everything, so this post is just a flavour of some of the abstracts either of us did manage to take in.

The challenge, as always, with ASH is their insistence of holding all the critical oral sessions on biology and therapy in leukemias, lymphomas, myelomas and myeloproliferative diseases almost on a single day, making it absolutely impossible to see/hear all the new and exciting data. Monday is, therefore, always a manic day. It’s a strange contrast from the long lulls on the Sunday where some of the oral sessions could have been hosted, perhaps the biology sessions, thereby freeing up a more flexible schedule for the clinical data on Monday. There is some weirdness and also dismay in seeing a biology and clinical session for the same topic (eg CML, Multiple Myeloma, Lymphomas or FLT3 in AML) clashing. Not everyone is a specialist, certainly the community oncologists who attend are not. This is silly scheduling and means that people presenting in a biology session often miss the clinical update for a trial they were a PI in, while attendees like me are regretably forced to choose from one or the other.

Sadly, not everyone can stay until Tuesday morning when a few more key oral sessions that include new data are held, for a meeting that began on Friday. This is issue compounded by no virtual meeting facility, one of ASCO, AACR, ECCO and even the NY Chemotherapy Symposium’s great online service whereby you can catch up with sessions you missed later. For me, this is a critical and integral part of modern cancer meetings.

I hate missing out on great or important data and hope that ASH will seriously consider virtual meeting access for future meetings – it really does help attendees – otherwise if you didn’t catch the sessions they are gone forever!  Personally, I was still watching (and enjoying) presentations I missed at AACR and ASCO in July, long after both meetings finished, and really appreciated their excellent webcasts/virtual meetings.

One of the sad things for me was it turned out to be the first time in many years that I skipped the Plenary session as there were some odd choices this year that simply didn’t resonate with me. For example, making Mylotarg, a drug withdrawn by the FDA recently, one of the meeting highlights made little sense to me because:

a) it will have no immediate clinical or even scientific impact for the practising oncologist and
b) there were far more dramatic results that I thought were worthy of broader dissemination

Overall though, this was a good ASH meeting from the point of view of exciting new data in phase I and II trials; clearly the oncology pipelines are beginning to show some early promise, but it was disappointing not to see more of them prominently highlighted. There were quite a few other abstracts I liked, but this overview should give a good flavour of some of the novel agents emerging for the treatment of NHL.

For those wanting information on Hodgkins Lymphomas, I’ll cover those in a separate post as there was too much data to cover both in one post.

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ASH 2011 Update 1: Bruton’s Kinase Inhibitors (BTK)

By on December 15, 2011

This year’s American Society of Hematology (ASH) meeting heralded a wealth of new information on pipeline compounds in early development. Although a lot of people were excited about myelofibrosis and the battle between Incyte’s ruxolitinib and YM Bioscience’s CYT387 (more on these in a separate update), the area that intrigued me most was the Bruton’s Tyrosine Kinase (BTK) inhibitors in B-cell lymphomas.

Background on the science behind the BTK pathway:

I’ve been following these novel agents for a while and was fascinated by two abstracts from the ASCO and ASH meetings last year. It became clear that BTK is a valid target in B-cell lymphomas after Advani et al., (2010) demonstrated at ASCO the effect of BTK inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL.1

Later that year, Ponader et al., (2010) showed that PCI-32765 abrogates BCR- and nurselike cell-derived activation of CLL cells in vitro and in vivo.2

Between them, these two abstracts offered a solid rationale for investigating BTK inhibitors in B-cell lymphomas and CLL.

Where are we now with clinical development?

Fast forward to ASH this year, Dr Susan O’Brien presented the initial phase I/II data in chronic lymphocytic leukemia (CLL), which was well worth waiting for the last day of the conference to hear.  She took us through the concept of the how the BTK pathway fits into B-cell malignancies:

BTKSource: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission 3

Essentially BTK is a critical part of the BCL pathway that leads to proliferation, so targeting it leads to cell death or apoptosis:

“BTK is a Tec family kinase that is required for B-cell activation mediated by BCR signaling.  The essential role of BTK in normal B-cell development is evidenced by the clinical syndrome X-linked agammaglobulinemia, in which BCR signaling is abrogated by mutations in BTK.

Signaling from the BCR is also believed to be required for the maintenance of cell division and survival in B cell malignancies, presumably via downstream phosphorylation of PLC-gamma by BTK, ultimately leading to the activation of the anti-apoptotic transcription factor NF-kB and the kinase ERK.

Additionally, BTK may also play a role in the pathogenesis of B-cell malignancies by regulating integrin-mediated migration and adhesion, through regulation of malignant cell response to lymph node-derived chemotactic factors, such as CXCL12 and CXCL13.”

What does the latest data show?

Here’s a quick overview of the preclinical and clinical data I managed to see at ASH. There were over 2,000 posters over three days, plus a day and a half of simultaneous oral sessions, so it was quite hard to keep up with the sheer volume of it all!

In mantle cell lymphoma (MCL) the preclinical data looked encouraging:

Ponader et al., (2011) provided a nice overview of the initial PCI-32765 preclinical data in mantle cell lymphoma (MCL) in a poster presntation.4

They concluded that MCL cells express surface IgM and BTK, which is involved in BCR signalling. In this study, PCI-32765 successfully blocked BTK function and inhibited MCL proliferation, except in resistant cell lines. The former explains why there were responses in patients, while the presence of the latter suggests that additional BTK independent pathways exist and need to be elucidated.

I think that figuring the mechanisms of resistance out is important because it will help suggest possible rational combinations with BTKi therapy in advanced disease.

In CLL, the initial phase I/II clinical data is early, but promising:

Over the last 18 months, patients with CLL (n=117) have been enrolled into five trials, although the interim data was reported in the two relapsed/refractory arms (asterisked arms) at this conference, at two different dose cohorts of PCI-32765, given orally daily at either 420mg (n=27) or 840mg (n=34):

PCI

Source: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission5

The overall response rate (ORR) of 67-68% for both doses in the relapsed, refractory setting showed impressive activity and a clear sign that the BTK target is a valid one in this setting. Although the CR rate was low (<5%), the majority of patients saw PRs in this setting. Those with bulky disease (common in advanced disease) tended to do better.

There were also dramatic changes in the tumour burden, with the majority of patients seeing a greater than 50% change from baseline. Sustained improvements in blood counts were also reported. What particularly caught my attention was the activity in patients with known poor risk factors such as 11q and 17p deletions, who tend to have noticeably poorer outcomes. Obviously this is only a small phase I/II trial and we will have to see what happens in a larger scale randomised phase III study to see if the results are reproducible.

Typical side effects were diarrhea, cough and fatigue (any grade and grade 2+). The most common grade 3 adverse events were pyrexia, fatigue and diarrhea. Bearing in mind this was a heavily pre-treated population, many of whom had received prior immunotherapy, I thought the results were promising. The downside of immunotherapy is that while it has shown effectiveness, it does leave patients, especially the elderly, rather beaten up. The lack of grade 4 events in CLL was especially encouraging in this group.

What are the main BTK inhibitors in development?

Johnson and Johnson announced they were licensing Pharmacyclics PCI-32765 compound for nearly a $1B just prior to the meeting.6

Based on the data seen over the last two years, I thought they got a steal – this looks like it will be a very promising agent indeed. However, while they are clearly the leading BTK inhibitor, based on the sheer breadth and depth of their program, they aren’t the only one in this niche.

Avila Therapuetics also have a BTKi in early development, AVL-292, but they only have one phase I trial ongoing that I could find. The initial phase I data in B-cell malignancies was also presented in a poster at ASH.7

You can see why J&J licensed the Pharmacyclics agent – it’s much more advanced in the clinic than the others:

BTK
What does all this data mean?

Emerging data on BTK inhibitors has started to show that they produce consistently effective and well tolerated agents in B-cell malignancies such as NHL, MCL and CLL. I think this is a new class we are going to hear a lot more about over the next few years, either alone or in combination with other therapies.

  1. ASCO 2010  ↩
  2. ASH 2010  ↩
  3. ASH 2011 PCYC  ↩
  4. ASH 2011 MCL  ↩
  5. ASH 2011 CLL  ↩
  6. J&J licensing deal  ↩
  7. ASH 2011 Avila  ↩
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What’s hot at SABCS – Update 2 – advanced breast cancer

By on December 10, 2011

After a number of basic research and science sessions over the last two days (see the Update 1 post on the science that intrigued me for more details), but the last two days heralded some excellent clinical sessions, in both oral and poster forms. These included the presentation of the much anticipated update to the BOLERO-2 trial, which was also published in the New England Journal of Medicine online and the CLEOPATRA study, also published in the same journal.  One of the more impressive posters that caught my eye was the ENCORE 301 study, which provided an update to the entinostat data in ER/PR+ HER2- advanced breast cancer.

Many of you will have read the wire and news articles released in a barrage on Wednesday evening with the NEJM publications ahead of the presentations on Thursday and Friday, but I wanted to put them in context of what we know so far and why these studies are both elegant and important.

Why am I fascinated by these particular studies?

Drug resistance can develop either upfront or is acquired in response to treatment over time.  The latter is also known as adaptive resistance, as the tumour evolves certain strategies to ensure it’s survival.  This is one reason why many people will have a different response to the same treatment.

In simple terms, if we can figure out ways to:

  1. Either delay the development of resistance up-front in treatment naive patients by enabling more comprehensive pathway suppression
  2. Or switch to a new logical combination regimen once resistance has developed

then we may be able to prolong patient outcomes and survival further.  To me, these kind of rational approaches make much more sense than merely throwing random chemotherapy doublets of choice at the problem.  These two strategies are very much at the heart of the three impressive studies mentioned above.  Let’s look at them in a little more detail.

BOLERO2

BOLERO-2 is the acronym for the breast cancer trials of oral everolimus and the updated safety and efficacy data were reported here at the San Antonio Breast Cancer Symposium (SABCS), although it should be noted that the NEJM article is based on the phase III ECCO data previously presented by Jose Baselga in September.

The trial design, though, remains the exactly same – patients were randomised to receive with everolimus plus exemestane versus placebo plus exemestane to determine whether the mTOR added anything to the AI alone.

The rationale behind this trial is that mTOR is a known cause of resistance to AI therapy, so the combination targets both the ER, which is driving the tumour proliferation, and mTOR targets the adaptive resistance pathway.  Shutting down both pathways should lead to improved survival, which we clearly saw at ECCO (6.5 months extra survival as measured by PFS).

The latest data presented by Dr Gabriel Hortobaygi (MDACC) confirmed that the responses continue to be durable, with an improvement in the PFS with the combination arm now up to 11.0 months, up from 10.6 months at ECCO. The results for the exemestane control arm remained the same at 4.1 months. This means that the improvement in survival with the mTOR now offers a median 6.9 months extra benefit.  OS had not yet been reached and therefore was not reported.

My view? These are excellent results from a well designed trial with a logical and elegant design given that we know mTOR is one of the adaptive resistance mechanisms to AI therapy and confirm that the original hypothesis was a valid one.

That said, what we don’t know is who will most benefit from the combination i.e. which women are more likely to respond. I’d love to know whether the really good responders had higher mTOR levels or overexpression or whether there is something else that would help us determine the likely responders for several reasons:

  • mTOR isn’t the only acquired resistant pathway to AI – there are others – so hopefully a way to determine who would be the ideal candidate for mTOR therapy will emerge from retrospective analysis.
  • A quarter (26%) of both arms received prior chemotherapy – did these women do better or worse when given the AI-mTOR combination compared with those who only received hormonal therapies?
  • This combination will not be cheap, considering the likely costs of everolimus alone without the AI could easily be ~$7K/month and the cost of exemestane must be added to that.

These points aside, I do think these results are impressive and good news for an advanced population of women who may not want to even consider chemotherapy – the current data suggests that many will get more time with this approach.  Expect to see Novartis filing for everolimus approval in advanced breast cancer with the FDA before the year is out.

ENCORE 301

In the same patient population of ER/PR+ HER2- women, there was an update to the phase II ENCORE 301 trial with the HDAC inhibitor, entinostat, that we blogged in more detail at the recent AACR Molecular Targets meeting.

What was new about the data here was an update on the overall survival (OS) data. Remember, in San Francisco the PFS for the entinostat arm (comparable to the everolimus-exemestane arm in BOLERO2) was 8.5 months in the women with high acetylation, an excellent predictive biomarker of response.

Now, I was wondering why the OS has still not yet been met in the BOLERO2 trial here and realised why with the updated entinostat data:

 

Entinostat OS in ENCORE 301

As you can see above, based on a medium follow-up of 23 months, the OS has improved in these patients in the phase II trial from 19.8 to 26.9 months, an improvement of 7.1 months of life.

We’ve all seen so many trials where the benefit is a mere 1-3 months, so to see several trials in advanced breast cancer where the survival is measured in 6-7 months is breathtaking.  Long may this trend continue with more rationally designed combinations and robust trial designs!

The entinostat phase II data certainly provides a good efficacy and safety signal to continue development and I was delighted to see that Syndax are moving forward to a confirmatory phase III trial in 2012.  I’m very much looking forward to watching how this study progresses, although we obviously won’t know the results for a while.

CLEOPATRA

The CLEOPATRA study looks at a completely different patient population than BOLERO and ENCORE.  In this situation, it’s looking at women were treatment naive, not refractory, who also needed to be HER2+ to enter the study.

As discussed in the What’s Hot at SABCS review prior to the meeting, pertuzumab is similar to trastuzumab in that it is a monoclonal antibody to HER2, but also differs in that it acts in a different part of the HER domain from Herceptin and also prevents pairing of HER2 and 3 dimersiation:

HER dimerization, source: NEJM

The idea behind combining pertuzumab and trastuzumab upfront is to enable a more comprehensive shutdown of the HER2 pathway and delay the resistance setting in.  By doing this, PFS should increase.

Dr Jose Baslega presented the results of the CLEOPATRA trial for the first time to a packed and highly excited audience in San Antonio.  Unfortunately, I wasn’t there as I was en route to the American Society of Hematology (ASH) meeting, but like many, I was eagerly reading the tweets and reactions from the attendees.

The Roche press release summed up the essence of the data nicely:

“The median PFS improved by 6.1 months from 12.4 months for Herceptin and chemotherapy to 18.5 months for pertuzumab, Herceptin and chemotherapy.

Overall survival (OS) data are currently immature, with a trend in favour of the pertuzumab combination.”

In short, another stunning six month leap in survival in an entirely different patient population of advanced breast cancer.  This is the sort of data those of us working in the industry live for and hopefully, things will continue to get better because clearly thought leaders such as Martine Piccart (at the the NY Chemotherapy Symposium) and Jose Baselga (at SABCS) are already dreaming and envisioning a world in which women with HER2+ breast cancer can be treated without chemotherapy at all.  Now that would be a wonderful thing indeed and I really hope to see it happen sooner rather than later.

One thing that hasn’t been factored into the equation is the antibody drug conjugate T-DM1 and how that relates to pertuzumab and trastuzumab.  The phase III trial MARIANNE is currently enrolling patients and may offer us an answer to that question in a couple of years time.

For those of you interested in some expert commentary, the NEJM published an excellent editorial from Dr William Gradisher (Northwestern, Chicago) accompanying the BOLERO2 and CLEOPATRA studies which is well worth reading (see references below).

In summary…

These three studies all show how rationally designed and elegant studies based on solid science can lead to large leaps in improvement in survival in the clinical setting.  Roche have already filed the BLA for pertuzumab and Novartis are expected to file everolimus in advanced breast cancer soon.  Syndax are already planning their phase III trial for entinostat.

It’s a very good period for ER/PR+ HER2- and HER2+ advanced breast cancers – from that perspective, this year’s San Antonio Breast Cancer Symposium was very uplifting and one of the more exciting meetings of the last five years.

References:

ResearchBlogging.orgBaselga, J., Campone, M., Piccart, M., Burris, H., Rugo, H., Sahmoud, T., Noguchi, S., Gnant, M., Pritchard, K., Lebrun, F., Beck, J., Ito, Y., Yardley, D., Deleu, I., Perez, A., Bachelot, T., Vittori, L., Xu, Z., Mukhopadhyay, P., Lebwohl, D., & Hortobagyi, G. (2011). Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1109653

Baselga, J., Cortés, J., Kim, S., Im, S., Hegg, R., Im, Y., Roman, L., Pedrini, J., Pienkowski, T., Knott, A., Clark, E., Benyunes, M., Ross, G., & Swain, S. (2011). Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1113216

Gradishar, W. (2011). HER2 Therapy — An Abundance of Riches New England Journal of Medicine DOI: 10.1056/NEJMe1113641

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Follow the American Society of Hematology ASH conversations!

By on December 10, 2011

It doesn’t seem a full year since the last American Society of Hematology (ASH) meeting took place, time has certainly flown by!

For those interested, I posted a review what I think will be hot topics at this meeting

In the meantime, to enable easy reading of the tweets and discussions here in San Diego for those both attending and following remotely, I’m aggregating the tweets around the official hashtag, #ASH11.

You can follow the conversations over the weekend through Tuesday in the widget below:

If you have any questions please do add them in the comments below or feel free to tweet me, @maverickny on Twitter.

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What’s hot at the American Society of Hematology 2011?

By on December 9, 2011

Palm trees in downtown San Diego

Greetings from the annual American Society of Hematology (ASH) meeting in San Diego!

The palm trees and warm sunshine here were a most pleasant welcome after the bitter chill in Texas.

Having just arrived here from the San Antonio Breast Cancer Symposium, I thought it would be a nice idea to do a quick preview of some of the new and interesting data that I’m interested in at this conference and share some of the hot topics that I’ll will be following over the weekend:

  • Ponatinib in refractory CML
  • In myelofibrosis, rixuluximib and CYT-387
  • Velcade and pomalidomide in multiple myeloma
  • Obinutuzumab, PCI-32765 and alisertib in lymphomas

Let’s take a quick look at these topics in turn.

CML

The updated phase II PACE trial is expected to be presented at this meeting. Ponatinib is a potent second generation BCR-ABL inhibitor that also targets FLT3 and FGFR. The initial indication is expected to be in relapsed, refractory CML after prior treatment with a minimum of two TKIs, although many are likely to have received imatinib, dasatinib and nilotinib, so a heavily pre-treated population. Patients with advanced CML or Ph+ ALL received ponatinib in a single arm open-label trial. The other thing to note is that this agent is the only TKI so far shown to target the rare T315I mutation and these patients were included in the study.

If the results continue to hold up for durability with no additional safety signals since FLT3 and FGFR may induce off-target side effects, then I’m expecting Ariad to file ponatinib for accelerated review with the FDA, based on phase II data in relapsed and refractory CML, sometime in 2012. This is an exciting new agent and it will good for patients with CML to have an additional option in this setting.

MYELOFIBROSIS

This year has seen a lot of interest in myelofibrosis with Incyte’s ruxolitinib (Jakafi) receiving FDA approval recently. The drug was approved largely on the basis of its ability to reduce spleen size, which is one of the complications of the disease. The updated phase III COMFORT-1 data is being presented on Monday and my assumption is that we will see an improvement in overall survival with ruxolitinib.

There has been a lot of interest in YM Bioscience’s agent, CYT-387, which caused a stir at ASCO after initial data suggested that it may be able to reverse anemia associated with the condition.

Now, I’m not sure of the exact mechanism behind this phenomenon, since both compounds target JAK1 and JAK2, so the anemia response may be an artifact or a real effect. If the anemia effect is real, then I’m expecting to see the hemoglobin levels to go up rather than down, as we saw with Jakafi. The poster on Monday may well tell us more about what’s happening here and also I’m hoping to speak to some myelofibrosis thought leaders to see what their perspective is.

MYELOMA

Multiple myeloma has seen real improvements in overall survival over the last 10 years with the introduction of bortezomib (Velcade) in the upfront setting and lenalidomide (Revlimid) in the refractory and maintenance settings. Currently, a new kid on the block, Onyx’s carfilzomib, is currently being reviewed by the FDA in the refractory population, although we likely won’t know the decision until 1Q next year. If approved, it may offer physicians a new option to extend outcomes even further in advanced myeloma.

There is another agent not far behind, pomalidomide, which is a third generation immunomodulatory agent similar to lenalidomide. Celgene are presenting key data at this meeting and I’m looking forward to seeing how the data is progressing. I’m expecting this compound to show good efficacy in advanced myeloma, as it is thought to be more potent than Revlimid.

The phase III multiple myeloma study that is of great interest is the VISTA trial, which will be presented on Monday and compares the combination of Velcade, melphalan and prednisone (VMP) with melphalan and prednisone alone (MP). The five year data in treatment naive multiple myeloma will inform us which combination has superior overall survival and side effect profile and what can be expected in terms of secondary primary malignancies (SPM) with the triple versus double combination over longer term follow-up.

LYMPHOMAS AND CLL

For me, the big lymphoma story at this ASH is probably going to be GA101, now named obinutuzumab. It’s a CD20 antibody similar to, but also different from, rituximab, making it ideal for testing in NHL since the proof of concept is already established for the CD20 target.

My critical questions related to this agent’s development are:

  1. Will it overcome rituximab resistance and work in refractory patients?
  2. Will it work more effectively than rituximab earlier and prolong outcomes further?
  3. Will it have fewer side effects than rituximab?

If any of the above are true, how does obinutuzumab work differently than rituximab and does that explain any of the differences?

Not all of these questions will be answered here at this ASH meeting, but I’ll discuss these issues in more detail once the data is available.

Finally, there are a couple of other compounds in early development for lymphomas that I’m really interested in.

The first is PCI-32765 (Pharmacyclics), a bruton kinase inhibitor (BTK), while the second is Millennium and Seattle Genetics’s aurora kinase A inhibitor, alisertib. These are relatively new mechanisms of action in lymphomas and intriguing scientifically.

I’ll write more about these particular agents in depth as the data becomes available, but they’re worth watching out for over the weekend as the wires hit the news sites.

Meanwhile, you can follow the conversations at the American Society of Hematology meeting on Twitter using the official hashtag of #ASH11.

Do check back for daily updates here in the blog for the hot (and sometimes not so hot) data. I’ll also be posting a video review of the important news next week.

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What's hot at SABCS – Update 1

By on December 8, 2011

Yesterday evening brought a flurry of news around the New England Journal of Medicine articles for the BOLERO2 and CLEOPATRA trials, but out of respect to the presenters, I hate talking about the actual data before its being presented. Call me old fashioned if you like, but it seems odd moving up deadlines for the publication ahead of the presentations instead of releasing them on the day and is a little disrespectful of the journal towards the presenter and attendees.

I will therefore discuss the data for BOLERO2 and CLEOPATRA studies in detail after they have been presented today and tomorrow, respectively. For those of you interested in the study designs and their potential implications, you can check out my brief video highlights in the meantime.

Yesterday at the San Antonio Breast Cancer Symposium (SABCS) brought some really intriguing biology data that are well worth discussing:

  • Notch inhibition to reduce AI resistance
  • HER2 mutants
  • Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

Notch inhibition

Perhaps one of the most intriguing presentations (to me) yesterday at SABCS looked at combining a Notch inhibitor plus an AI to reduce breast cancer resistance in preclinical models.

This is an interesting idea that is worth exploring because resistance to oral therapies, including AIs, is a common problem. Understanding the potential mechanisms of resistance should therefore lead to new trial designs and logical combinations.

In this research, the presentation focused on early data on combining MK-0752 (notch) plus hormone therapy. Interestingly, it also finally mentioned the magic word, biomarkers! I think this is a combination we will here much more about going forward.

In his award lecture, Dr Carlos Arteaga correctly observed that the medical community has not done a good job with ER+ drug-resistant disease. This situation is slowly changing as the BOLERO2 data has shown and other mechanisms of resistance will no doubt follow now that more attention is being focused on it.

HER2 mutants

Dr Boulbes from MD Anderson presented the results of some elegant research identifying three mutants to HER2, namely:

  • D808N
  • V794M
  • L726F

All three phenotypes displayed aggressive tendencies. Both the V and L phenotypes showed a dramatic lack of phosphorylation and the latter may be related to the development of HER2 resistance. Data was shown in relation to lapatinib, a HER2 small molecule TKI, which is known to develop resistance to treatment over time.

This is the first time I think HER mutant phenotypes have been reported to my knowledge and if validated clinically, they will represent a breakthrough in our understanding of how HER2 resistance develops, but more importantly, suggest directions for potential therapeutic strategies to overcome it.

Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

HER3 has not received a lot of attention relative to its more popular HER2 cousin, largely because it is tricky to target. However, at this meeting, Dr Garner et al., showed that an anti-HER3 antibody (Novartis) nicely shrank breast cancer tumours in immunocompromised mice.

The presenter observed that the alpha-HER3 mAB recognizes and stabilizes HER3 in the inactive conformation. I was left wondering whether HER2 and 3 pairing / dimerization was shut off or something else was going on?

Dr Cook subsequently showed some clear data whereby HER3 is required for HER2 cancer growth in genetic engineering animal model. This was a very nice piece of research.

What was interesting was that Dr Garner also showed that alpha-HER3 can combine w/ trastuzumab plus a PI3K inhibitor to improve efficacy in trastuzumab-resistant settings. This caught my attention because earlier this year at the AACR PI3K special meeting, Neal Rosen (MSKCC) noted that targeting PI3K activated HER3 as one mechanism of resistance in the breast cancer model they were using and thus speculated that combined inhibition of HER3 and PI3K would lead to reduced resistance. Looks like his hypothesis was correct 🙂

And that was just the first full day of presentations with much more to come!

In the meantime, you can follow the conversations remotely using our tracking tool, accessible here on the blog.

Check back tomorrow for more updates on cancer biology and clinical trials from SABCS.

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Video preview of San Antonio Breast Cancer Symposium 2011

By on December 7, 2011

What’s hot at the 2011 San Antonio Breast Cancer Symposium?

There is a lot of exciting data coming out at SABCS 2011 over the next three days, including the BOLERO2, CLEOPATRA and NEOSPHERE clinical trial data.

I previously wrote about the exciting BOLERO2 results that were presented at the European Multidisciplinary Cancer Conference (ECCO/ESMO 2011) in Stockholm in September. More data is expected at SABCS to coincide with a publication in the New England Journal of Medicine (NEJM).

The following video outlines some of the data that I think is hot at SABCS and why it’s worth watching out for. I will be writing more about it as it’s presented.

http://www.youtube.com/watch?v=t7bnqslE6mc

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