Biotech Strategy Blog

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

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PREVAIL trial EAU 2015We’ve been following the updates on the PREVAIL study evaluating enzalutamide (Xtandi) versus placebo in metastatic castrate-resistant prostate cancer (CRPC) in the pre-chemotherapy setting for a while now. It’s interesting to see how the data evolves over time as it becomes more mature.

The first presentation, back in January 2014 at ASCO GU by Dr Tom Beer (OHSU) reported on the first 540 deaths and was subsequently followed by an update of the survival data at AUA in May of the same year by Dr Chris Evans (UCLA).

This morning at the European Urology Association (EAU) in Madrid in the late breaking session on prostate cancer, the honour fell to Professor Bertrand Tombal (Leuven), who did a very nice job of reviewing the mature PREVAIL data (based on 765 deaths) and providing some context for how the CRPC landscape is being impacted by AR pathway inhibitors.

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At the last count, the renal cell carcinoma (RCC) space is quite competitive with five VEGF inhibitors (sunitinib, sorafenib, axitinib, pazopanib and bevacizumab), two mTOR blockers (temsirolimus and everolimus) and not forgetting IL–2, all approved by the FDA for the treatment of advanced disease.

Much of the recent focus has been on sequencing, exploring combinations (generally too toxic with little added benefit), and evaluating the potential for novel immunotherapies in development such as checkpoint inhibitors. Biomarkers are few and far between, making it hard to rationally decide which therapy each patient should get and in which sequence.

The key question is, why is this tumour type so challenging from a clinical and scientific perspective?

Screenshot 2015-03-23 12.44.32Recently, new data has begun to emerge that may help inform or enable us to switch to new approaches.  While the urologists are eagerly watching the live surgery on the EAU cam, we highlight research data presented at the European Association of Urology (EAU) in Madrid and take a look at how the underlying biology of RCC can elevate our knowledge about where the potential future strategies and blueprint might lie, if we want to facilitate exciting new developments in this field.

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Here’s something interesting and heart warming to reflect on at the end of a long week:

“Cellular therapy of Epstein-Barr virus (EBV)+ posttransplantation lymphoproliferative diseases (PTLD) in cord blood transplant (CBT) recipients is limited by lack of donor access and the donor’s naive neonatal immune system. We therefore used partially human leukocyte antigen–matched third-party in vitro expanded EBV-specific cytotoxic T lymphocytes (CTLs) to treat 2 CBT recipients with life-threatening, donor-derived monoclonal EBV+ diffuse large B-cell lymphomas with extranodal involvement developing in the context of graft-versus-host disease. Both patients had failed immunosuppression taper and rituximab. After 5 and 9 infusions of 106 EBV-CTL/kg, respectively, each patient achieved a sustained complete remission without toxicity or graft-versus-host disease. Each is alive without recurrence at 20 and 15 months, respectively, post–EBV-PTLD diagnosis.”

Barker et al., (2010) Blood

Viral reactivation post-transplant is potentially life threatening, yet here is a fascinating case study where two young patients were treated effectively and are still alive today.

Atara Biotherapeutics $ATRA announced yesterday (press release) that data from their collaboration with Memorial Sloan Kettering on cytotoxic T lymphocytes against Epstein Barr Virus (EBV-CTL) will be presented at the forthcoming AACR annual meeting. Readers will recall the therapy obtained FDA Breakthrough Designation earlier this month.

So what’s the real story behind this novel approach and how can T cells be used in ever more creative ways? Is there a market opportunity and who are the key players in this space?

Be warned this is a long read, and took us a while to put together. It contains insights from two thought leaders as well as our commentary and analysis. Grab yourself a cup of coffee……

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Over the last few years we’ve heard a lot about the evaluation of predictive biomarkers for checkpoint inhibitors, in particular the value of using PD-L1, whether on immune or tumour cells, as a way of separating responders and non-responders to therapy with anti-PD1 or anti-PDL1 blockers. The results to date have been mixed, with some KOLs concluding that smoking history or number of mutations was more useful in lung cancer and others believing that their assay has better utility.

Some cynical observers I’ve come across have even asserted that companies don’t want to see biomarkers emerge because that then limits their opportunity for patients being treated. Ouch! I don’t believe this to be true, it’s highly complex science and there is much about the healthy immune system that we still don’t know, never mind under more complex situations such as cancer. This is an ever-evolving field about which we still have much learn.

Eventually, we may see further refinement of these approaches, at least in some tumour types and I’m particularly looking forward to hearing more about those advances at ASCO and ASH later this year when the clinical and translational work is more mature.

Next month heralds the annual meeting of the American Association for Cancer Research (AACR). As we noted in our first AACR Preview on Immunotherapy last week, it’s the first time immunotherapy has literally dominated a largely preclinical and scientific program of this nature.

Over the next week or two, will be be highlighting and explaining some of the emerging trends in more detail.

On the important topic of biomarkers, one new approach particularly caught my eye in the abstracts that were released yesterday is worthy of further discussion since it could have important implications to future clinical approaches.

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One of my favourite meetings of the year in our conference calendar is the American Association for Cancer Research (AACR) annual meeting, which is held in the spring. In years past, the agenda at this event has set the scene for the rest of the year in terms of emerging new trends, particularly with regards to targeted therapies. In the last two years though, this hasn’t been the case, as adjusting to the brave new world of immunotherapies has taken some time.

The good news is that AACR has come roaring back in 2015 with a star-studded line-up that includes some of the big hitters and sluggers in the cancer immunology space.

What’s in store for this year, you may well be wondering, and where are we likely to see the new trends evolve?

We took an in-depth look at what’s hot in immunotherapies and where the new directions are going in this latest conference preview, the first one in series relating to the AACR annual meeting being held in Philadelphia from April 18–22nd (Twitter #AACR15).

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It’s time to answer some more subscriber questions. Several readers wrote in and asked about the anti-PD1 checkpoint data that was presented at the recent American Society of Hematology (ASH) meeting in classic Hodgkin’s lymphoma (cHL):

What did we think of it?

Well, for starters it was one of our highlights of the ASH 2014 conference (see quick write-up, open access), with an impressive 87% response rate for nivolumab in refractory cHL. Many of these patients had failed both autologous stem cell transplant and brentuximab (Adcetris), for which FDA granted breakthrough therapy designation.

ASH14 CHECKPOINTSOverall, I agreed with Ron Levy (Stanford) when he noted in the packed Special Session on Checkpoint inhibitors in Hematology that there were only 4 or 5 abstracts to actually discuss (he didn’t spend much time on the preliminary data) and that the results are still very early without seeing how good the durability will be.

As he observed in the session, which was standing room only, figuring out how best to integrate these new agents into clinical practice with other successful approaches will be most interesting.

That said, there are some new data that have emerged since ASH that are worthy of discussion in terms of potential future directions and how they could impact the checkpoint landscape in both hematologic malignancies and even solid tumours.

This is part of our ongoing immuno-oncology series on how we can manipulate T cells in creative ways to kill the cancer cells.  The findings discussed in this article are completely new and have not been discussed here before.

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We have been following the results of the checkpoint inhibitors for several years now, first with ipilimumab (Yervoy) and lately with anti-PD1 and PD-L1 inhibitors such as nivolumab, pembrolizumab and MPDL3280A. Irrespective of the antibody used, the best results we’ve seen have in melanoma, lung and bladder, but some tumour types such as colon and prostate cancers have barely been responsive at all.

Why is that?

Can we find ways to make non-responsive solid tumours responsive to immune therapies, and if so, what strategies could we employ to enable improved responses and outcomes?

At the ASCO Genitourinary (GU) meeting in Orlando this weekend there were some interesting hints of what might be possible in the not too distant future.

To learn more about this phenomenon, we conducted an interview with a leading cancer immunologist to find out what they are doing to make a difference in the GU space.

Interested?  Check out the interview by clicking on the link in the box below.

It’s now time to turn our attention to genitourinary oncology and, in particular, prostate, renal and urothelial bladder cancers. This week brings this ASCO GU meeting (#GU15), which is being held in Orlando this year and began this morning.

There are quite a few interesting topics being covered here, particularly in the poster sessions over the next three days. Hopefully, 2015 will also bring more good news in this space as 2014 was a rather dismal one on several fronts!

We decided to highlight some of the most interesting abstracts on castrate resistant prostate cancer and urothelial bladder cancer in our latest conference preview.

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After the intensity of gastrointestinal cancer, we now turn our attention to genitourinary (GU) cancers with the upcoming ASCO GU meeting later this week in Orlando.

Two of the big topics here will be prostate and renal cell (RCC) cancers.

Unfortunately, the long awaited data in adjuvant RCC demonstrated that early treatment with sorafenib or sunitinib did not improve outcomes in locally advanced kidney cancer after resection. According to the ASCO press release, the trial conducted by Dr Haas and colleagues at U Penn discovered that:

“The average period to disease recurrence was similar between those who received sorafenib or sunitinib after surgery (5.6 years) and those treated with placebo (5.7 years).”

We will therefore turn our attention to castration resistant prostate cancer (CRPC).

One of the recent and ongoing controversies is splice variants, especially AR-V7, which is thought by some research groups to confer resistance to the hormonal therapies, enzalutamide and abiraterone. The big question though, is does it, and how useful is an assay in helping to determine appropriate therapy? Are there other factors at play?

We looked at the latest data and put the findings in context with what we know from other published research.

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Continuing our series on the ASCO GI meeting, today marks the end of the conference coverage with an interesting look at overcoming resistance to EGFR therapies such as Erbitux and Vectibix.

One of the hallmarks of EGFR monotherapy in colorectal cancer is stable disease with eventual relapse, but few dramatic responses. This suggests that other factors may play a role in driving oncogenic activity.

Dr Tejpar, Leuven

Dr Tejpar, Leuven

Recently, patient derived xenografts (PDX) have begun to play an increasingly important role in helping to understand the biology of the disease and facilitate improved trial design.

Earlier this week, we discussed the molecular characterisation of the disease based on the keynote talk by Dr Sabine Tejpar. Her group in Belgium as well as others in Italy and Spain have been very active in European translational work in this area to identify and map the pathways influencing EGFR therapy in GI cancers.

What can we learn from the latest findings in this space?

The answer may well surprise you.

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