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What’s hot at ECCO 2013 – Preview of late breakers and PI3K abstracts

By on September 17, 2013

Next I’ll be off to the European Cancer Congress (ECC) in Amsterdam. This meeting alternates each year between ECCO and ESMO hosting the event at a different European city.

The last couple of years have seen some nice data that missed the ASCO deadline, other years can bring an update of the already familiar ASCO data. I suspect that this year will be one of those events, with updated PD-1 and PD-L1 data.

If you missed my colleague Pieter Droppert’s ECCO highlights yesterday, you can catch them here, including details of the iPad app and abstracts.

In addition, there were other abstracts of interest that caught my eye, including some solid late breakers:

1. T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician’s choice. H. Wildiers (Belgium) et al.

The study looks at advanced disease in patients who had received at least two prior regimens. This analysis looks like an interim one, given the full study timeframe is over 3.5 years. I’m particularly curious what the physician choices were to compete with Kadcyla and what the 1 year survival curves look like. It’s a wee bit early to hope that they might separate already, certainly I hope they do!

2. Evaluation of everolimus (EVE) in HER2+ advanced breast cancer (BC) with activated PI3K/mTOR pathway: Exploratory biomarker observations from the BOLERO-3 trial. G. Jerusalem (Belgium) et al.

Originally, I thought this had been presented at ASCO, but the biomarker abstract I found actually referred to BOLERO-2, where they noted that “efficacy was greater in patients with low PI3K expression”, which is an odd finding. The BOLERO-3 data from ASCO presented the initial phase III data for the combination of trastuzumab, vinorelbine and everolimus vs trastuzumab and vinorelbine alone in trastuzumab resistant HER2+ advanced breast cancer. This should be an interesting presentation worth attending.

3. FLT1 gene variation as a major determinant of recurrence in stage I-III non-small cell lung cancer. F. Innocenti (USA) et al.

Many of us familiar with FLT3 in leukemia, but FLT1 is an interesting concept with very little data (or drugs) out there. I will be curious to see if this is a druggable target and where this approach might lead.

4. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. F. Hodi (USA) et al.

If you look at five year survival curves for advanced melanoma in the literature, it’s historically around 20% or so when patients have received IL-2, which is where I would expect ipilimumab to be. Trials with DTIC have shown a much lower rate, at around 8-9%. Not every patient is suitable for IL-2 though, so we may be seeing similar survival rates irrespective of the immunotherapy given, but with very different safety profiles.

One of my favourite cancer pathways is PI3K-AKT-mTOR. It’s dysregulated in some 80% of cancers yet we haven’t really seen a major breakthrough with these agents in solid tumours outside of the stunning Afinitor data in relapsed ER+ metastatic breast cancer from the BOLERO-2 study presented at ECCO in Stockholm two years ago.

There are many different permutations out there from single to dual inhibitors and also specific isoforms of alpha, beta, delta and gamma.

One of the challenges with targeting PI3K is that it activates feedback loops. Thus inhibiting PI3K in advanced prostate cancer activates the androgen receptor, while single agent use in advanced breast cancer can lead to activation of HER3. In addition, there have been mixed results with biomarkers and specific mutations/tumour suppressors to date such as PIK3CA and PTEN. This increases the complexity tremendously and therefore speaks to more careful trial selection based on inclusion criteria and also logical combinations to try and shut down the compensatory pathway.

I was therefore pleased to see a few trials reporting early phase I/II data in this vein:

P017: Evaluation of tolerability and anti-tumor activity of GDC-0032, a PI3K inhibitor with enhanced activity against PIK3CA mutant tumors, administered to patients with advanced solid tumors.

D. Juric, J.R. Infante, I.E. Krop, C. Kurkjian, M.R. Patel, R.A. Graham, T.R. Wilson, J.Y. Hsu, J. Baselga, D.D. Von Hoff

According to the abstract:

“GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform.”

Several confirmed partial responses have been reported and further trials will continue:

“GDC-0032 is a next-generation PI3K inhibitor with promising anti-tumor activity observed in patients with PIK3CA mutant tumors. GDC-0032 is being investigated in combination with endocrine therapies such as letrozole and fulvestrant for patients with hormone receptor-positive breast cancer.”

P079: Hyperglycemia in patients treated with the pan-PI3K inhibitor buparlisib (BKM120): characterization, management, and assessment for pharmacodynamics

A. Azaro, J. Rodon, J.F. Vansteenkiste, Y. Ando, T. Doi, D. Mills, C. Sarr, E. Di Tomaso, C. Massacesi, R.W. Naumann

Source: Novartis

Source: Novartis

BKM120 is also an oral pan PI3K inhibitor that does not target mTOR. Aside from the activation feedback loop effects mentioned earlier, PI3K plays a key role in glucose homeostasis. A number of earlier trials with different PI3K and mTOR inhibitors have reported hyperglycemia as a class effect although they have varied in the degree to which the event occurred.

This study highlights the importance of a potential pharmacodynamic marker (C-peptide) in assessing the insulin response and I’m looking forward to seeing more detail in the poster.

P061: Factors predisposing to development of hyperglycaemia in phase 1 studies involving PI3K, mTOR, AKT and mTORC1 and mTORC2 inhibitors

M. Wong, K.H. Khan, K. Rihawi, S. Bodla, B. Amin, K. Shah, D. Morganstein, S.B. Kaye, U. Banerji, L.R. Molife

Related to the topic of hyperglycemia, the Royal Marsden mined their database for PI3K-mTOR trials and looked at factors that might influence the presence of the glucose spike in order to essentially try and predict which patients were more at risk and improve management. While most patients did not require intervention, but in those that did, metformin and insulin were usually preferred. Interestingly, the main factor emerging in this retrospective study was a prior history of diabetes, which is not totally unsurprising. It will be useful to see if these results can be validated in prospective future trials.

P227: Anti-tumour efficacy of the PI3K inhibitor GDC0941, the dual PI3K/mTOR inhibitor GDC0980 and the MEK inhibitor GDC0973 as single agents and in combination in endometrial carcinomas

O. Aslan, A.M. Farrelly, B. Stordal, B.T. Hennessy

Much has be written about the potential for a PI3K and MEK combination in different tumour types, but so far they haven’t proven to be the home run many of us hoped for.

This preclinical paper looks at cell lines to explore potential targets and synergies in endometrial cancer (EC). They concluded,

“Our data suggest that the mutational status of PIK3CA, PTEN and KRAS can be used as biomarkers to select patients for PI3K and RAS/RAF-targeted therapies. Further, the combinations of the PI3K inhibitors GDC0941 and GDC0980 with the MEK inhibitor GDC0973 are promising approaches for the treatment of patients with PIK3CA, PTEN and KRAS-mutated EC.”

Translating data from simple cell lines to complex human bodies does not always predict response given the variable responses seen from patients with mutations and tumour suppressors in clinical trials. I think it will take a while to tease out what defines and predicts a response in each tumour type much in the same way we saw different effects in advanced melanoma when targeting BRAF with sorafenib versus BRAF V600E with vemurafenib or dabrafenib. The devil is in the details.

And finally, an oral presentation with a very different focus in the PI3K related field that I’m really looking forward to hearing:

#1859 PI3KCA mutations and correlation with pCR in the NeoALTTO trial (BIG 01-06)

J. Baselga, I. Majewski, P.G. Nuciforo, H. Eidtmann, E. Holmes, C. Sotiriou, D. Fumagalli, M.C. Diaz Delgado, M. Piccart-Gebhart, R. Bernards

The authors evaluated:

“The influence of PI3K pathway mutations (PIK3CA, KRAS, BRAF, AKT1) on sensitivity to trastuzumab (T), lapatinib (L), or both agents (L+T) in combination in early-stage HER2-positive breast cancer patients enrolled the neoALTTO trial.”

The goal here is to see the presence of any of the mutations were more likely to lead to resistance and enable better selection of therapy for patients. I will update on this study after the presentation.

More detailed posts and synopses will continue from the meeting itself on Biotech Strategy Blog, where we’ll be sharing our insights and analysis daily.

Transformative antibody technology in cancer research

By on July 30, 2013

Recently, I came across an exciting new development in a Nature publication and couldn’t resist teasing my Twitter followers with this terse statement:

Naturally, this mischievous tweet set off a lot of folks frantically trying to guess what I was referring to and the @replies came in thick and fast.

The National Science Foundation defines transformative as:

“Transformative research involves ideas, discoveries, or tools that radically change our understanding of an important existing scientific or engineering concept or educational practice or leads to the creation of a new paradigm or field of science, engineering, or education.  Such research challenges current understanding or provides pathways to new frontiers.”

Many suggestions came hurtling in, most related to a drug or company, but actually what I was referring to was a transformative technology – the biggest clue was in the question 🙂

Bispecific antibodies, to be more precise.

I was completely inspired by an article by a group of scientists in Nature Biotechnology by Speiss et al., (2013) – the link is included in the references below and is well with reading. It’s one of those things you read and think, “Wow, wish I had thought of that!”

Genentech kindly gave me access to one of their scientists involved, Dr Justin Scheer (gRED), who explained the rationale behind their approach and what they hope to do with this technology.  More on that in a moment, but first it’s a good idea to understand where I’m coming from.

Let’s take a look at both the potential and limitations of the various types being developed as cancer therapeutics, and the basics underpinning monoclonal and bispecific antibodies in more detail.

What are monoclonal antibodies?

Essentially, a monoclonal antibody is a manufactured molecule that’s engineered to attach to specific defects in cancer cells. They mimic antibodies the body naturally produces as part of the immune system’s response to invaders.

The immune system is trained to attack foreign invaders in the body, but it doesn’t always recognize cancer cells as enemies because they are formed from massive proliferation of the body’s own cells i.e. not foreign, unlike bacteria and viruses.

Monoclonal antibodies are usually directed to attach to certain parts of a cancer cell. An easy way to think of it is that the antibody ‘marks’ the cancer cell and makes it easier for the immune system to find and destroy.

How do monoclonal antibodies work?

The majority of currently available monoclonal antibodies are monospecific, i.e. having a single specific target e.g. CD20 or CD19, for example. The classic example in oncology is rituximab. Rituximab attaches to the CD20 protein found on B cells, which is associated with some types of lymphomas. When rituximab attaches to CD20, it makes the lymphoma cells more visible to the immune system, enabling them to be attacked and destroyed.

Treatment with rituximab lowers the number of B cells, including healthy B cells. The body will produce new healthy B cells to replace them and ensures that the cancerous B cells are less likely to recur.

While results with this approach have been impressive in some cases, there are limitations because cancer is highly complex and more than one target may be need to be addressed. This means that drug combinations are needed, increasing the complexity of clinical trial design especially in dose finding and MTD studies, risk of added or overlapping toxicities, increased costs etc.

Monoclonal antibodies such as rituximab have some other limiting factors though, as Speiss et al., (2013) observed:

“They lack natural Fc regions, they cannot bind to the neonatal FcRn receptor; binding to FcRn delays antibody clearance and improves pharmacokinetic (PK) properties.”

The lack of an Fc region also means that monoclonal antibodies typically cannot activate T-lymphocytes – because this type of cell does not possess Fc receptors – so the Fc region cannot bind to them.

A new potential solution exists

Antibodies that target two antigens are known as bispecific antibodies. Only one is currently available commercially (catumaxomab, Removab) and binds to CD3 and EpCam, although there are several in late stage development, including blinatumomab (Amgen) in ALL. The latter is interesting because it is part of the new generation of antibodies known as bi-specific T-cell engagers (BiTEs).

A bispecific monoclonal antibody (BsAb) is a manufactured protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen.

Manufacturing a monoclonal antibody, while more complex than an oral tyrosine kinase inhibitor (TKI), is easier than a bispecific antibody. Much of the limitations seen so far with bispecific antibodies have been technological rather than clinical. What the Genentech scientists set out to do is succinctly described by Dr Scheer in the short Soundcloud below:

What are the advantages of bispecific antibodies?

The main advantage of bispecific antibodies is the ability to combine a cytotoxic cell (e.g. CD3) or ADC with a tumour specific protein target (e.g. CD19 or CD20) although a number of different combinations could be considered. In other words, you would get the ability to home in on the specific tumour target together with enhanced cell killing.

This could be a potent combination, except that technology-wise, they are difficult to engineer as Speiss and colleagues noted:

“… bispecific-antibody design and production remain challenging, owing to the need to incorporate two distinct heavy and light chain pairs while maintaining natural nonimmunogenic antibody architecture.”

There are some technological difficulties in engineering bispecific antibodies, though.  Blinatumomab was mentioned as one example by Speiss et al., (2013) because:

“… some bispecific antibody fragments (e.g., the anti-CD19-CD3 single-chain fragment blinatumomab) are expressed as a single polypeptide chain they include potentially immunogenic linkers.”

What was fascinating about the Nature Biotech paper was that they reported on a new process they had developed to manufacture bispecific antibodies:

“We present a bispecific-antibody production strategy that relies on co-culture of two bacterial strains, each expressing a half-antibody.  Using this approach, we produce 28 unique bispecific antibodies.”

One thing I thought was particularly cool about this novel approach is that bacteria are easier to manipulate and having a foreign component in the antibody will potentially mean that the human body’s immune system will hopefully pick it up more easily. Essentially, these new chemical structures could act as a powerful cancer homing device against specifically chosen targets.

The example used in the paper was a new bispecific antibody they engineered from co-cultures of EGFR and MET. Remember that Genentech/Roche already has a TKI against EGFR (erlotinib) on the market and a MET antibody (onartuzumab) in development. Neither of these drugs hit both targets and yet as Speiss and colleagues noted:

“MET and EGFR drive the growth of a marked proportion of non-small cell lung cancer tumors. MET and EGFR are often co-expressed and co-activated, and MET signaling can compensate for loss of EGFR signaling and vice versa.”

Image Courtesy of Roche's gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

Image Courtesy of Roche’s gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

As Dr Scheer observed, we don’t know yet is where the company will go with this exciting technology, but if the approach shows promising efficacy in future clinical trials, then it’s easy to see how multiple new bispecific antibodies could be easily developed for different tumour types, with far more potency and utility than single targeted therapies alone.

Stop and think about that possibility for a moment.

Transformative science isn’t always about finding a new target, sometimes the breakthrough is in removing the technological limitations to create a much more robust platform with enormous therapeutic potential.  At that point, the biology, targets and imagination become the limitations, not the technology itself.

I have a feeling that this platform is a much more exciting breakthrough than many realise – it’s the sort of approach where you can see, to paraphrase a famous watch company’s ad – some day all antibodies will be made this way.

References:

ResearchBlogging.orgSpiess C, Merchant M, Huang A, Zheng Z, Yang NY, Peng J, Ellerman D, Shatz W, Reilly D, Yansura DG, & Scheer JM (2013). Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies. Nature biotechnology PMID: 23831709

Update on iNHL and CLL – idelalisib, obinutuzumab and ibrutinib

Yesterday, Gilead announced on their 2Q Earnings Call that they plan to file their PI3K delta inhibitor, idelalisib (formerly CAL-101), with the FDA later this year in indolent non-Hodgkin’s Lymphoma (iNHL). Discussions with both FDA and EMA have already been initiated based on the phase II results in CLL and iNHL.

Many of you will recall the CLL data presented at ASCO by Dr O’Brien (MD Anderson) and Jennifer Brown (Dana Farber), followed by the iNHL data update presented in Lugano by Dr Salles (Lyon Sud).

The single arm NHL study 101-09 evaluated idelalisib (150 mg BID) in patients (n=125) who were refractory to rituximab and alkylating agents. In other words, there is a high unmet medical need for a new alternative therapy option.

As background, recall that previous trials with ofatumumab (4 prior regimens) and bendamustine (2 prior regimens) demonstrated an overall response rate (ORR) of 22% and 76% respectively, with a duration of response (DOR) of around 5.8 and 10 months.

In study 101-09, patients received approximately 4 prior regimens (maximum was 12) and are therefore more comparable to the ofatumumab study in terms of prior therapy. Interestingly, 65% also received bendamustine in addition to rituximab and alkylating agents, while 63% received an anthracycline.

Instead of an ORR in the expected 20-30% range, the actual number was an impressive 53.6%.

What about the DOR you may be thinking? 11.9 months.
Progression-free survival (PFS) was 11.4 months.

The waterfall plot tells a bigger picture:

Idelalisib iNHL study 101-09

Source: Gilead

 

Side effects were similar to those previously reported, with diarrhea, fatigue, cough and nausea being the most common. The only grade 3 event in double figures was diarrhea (10%). Almost half (48%) saw raised liver enzymes (ALT or AST), with 13% experiencing grade 3 or more. Hematologic events were mainly decreased neutrophils (53%) with a quarter (26%) experiencing grade 3 or more.

The company also has three phase III trials in CLL ongoing.

In particular, Study 116 (idelalisib plus rituximab versus rituximab alone in patients unfit for chemoimmunotherapy) is nearly enrolled. The interim analysis is expected in the fourth quarter this year.  This trial is a similar population to the German CLL11 study in patients with co-morbidities that compares obinutuzumab and rituximab with chlromabucil to chlorambucil alone.

No doubt if the interim analysis is promising, then further Health Authority discussions will ensue with regards to the CLL approval path for idelalisib.

What does all this mean?

Gilead have gathered solid phase II data for idelalisib in refractory iNHL, an area of high unmet medical need.  Whether this would be considered for Accelerated or full approval isn’t yet clear, since there are no surrogate endpoints.  It will be interesting to see how the FDA view the data and make an informed decision.  No doubt we will hear more later in the year pending discussion with the FDA and their perspective on the data.

My experience from extensive market research and KOL interviews in CLL is that patients with co-morbidities tend to be treated with either chlorambucil or rituximab, both as single agents. Thus having two new therapies ie obinutuzumab and idelalisib (in different combinations) potentially available in the near future would transform this particular disease segment, create new standards of care, offer more therapeutic options and raise the bar for future entrants.

Pharmacyclics and J&J are also in the mix in CLL and NHL with their BTK inhibitor, ibrutinib, having Breakthrough designation and FDA filings have also begun for that compound.  These markets will soon become very competitive and it will be interesting to see how the landscape plays out given the lack of biomarkers available to help with decision making.  Obviously, the labelled indications will drive initial usage.  After that, no one is clear yet on how oncologists will ultimately decide on three different therapies, each with good data.  I do think it’s good to see clear progress, that’s ultimately the important thing from a clinical perspective.

Roche/Genentech have Priority Review and a PDUFA data of December 20th for obinutuzumab in front-line CLL, as well as Breakthrough Designation.  This could be very timely for the company given the ASH meeting in early December.  Pharmacyclics’ ibrutinib is expected to receive rapid approval for CLL and refractory mantle cell lymphoma (MCL).  In the meantime, if Gilead file for iNHL by year end, then idelalisib could be commercially available in the first half of 2014.

In addition, both idelalisib and ibrutinib appear to have decent efficacy in CLL patients with 17p deletions, a small subset that tend to have a poorer prognosis.

All of these exciting developments will make it more challenging for other possible agents in development by demonstrating good activity in areas that might have previously appeared attractive as a fast track to market strategy.  For patients and oncologists, a surfeit of riches is no bad thing!

Exciting times in CLL: an ASCO 2013 interview with Dr Susan O’Brien

At the recent ASCO 2013 meeting in Chicago, I had the great pleasure to interview Susan M. O’Brien, MD who is the Ashbel Smith Professor in the Department of Leukemia at the University of Texas, MD Anderson Cancer Center in Houston, and someone who is making a difference to the lives of CLL patients.

ASCO 2013 Dr Susan O'BrienI first met Dr O’Brien over ten years ago when I was at Novartis Oncology in new products working on bringing to market what was then known as STI571, and subsequently became Gleevec.

In the same way that tyrosine kinase inhibitors forever changed CML, the treatment of Chronic Lymphocytic Leukemia (CLL) is set to undergo a major transformation over the next few years.

I hope you will enjoy this video interview in which Dr O’Brien discusses some of the CLL data presented at ASCO ’13 and shares her perspective on several of the new targeted agents in development. It’s an exciting time in CLL!

After several months of free/open access, this video is now viewable on Biotech Strategy Blog Premium Content.

ASCO 2013 Highlights Part 2

It’s that time of the year when the annual meeting of the American Society of Clinical Oncology (ASCO) hurtles around with alarming speed out of nowhere and everyone in Pharmaland goes, “ASCO, what already? Is it really June?!” Suddenly the month becomes the focus for many frantic hives of activity.

Immunotherapy

The last two years have seen some unprecedented changes in new therapies emerging to treat several different tumour types, both liquid and solid.  One of the new trends that has begun to emerge is the new class of immunotherapy agents called checkpoint regulator inhibitors.  These include:

  • CTLA-4 (ipilimumab)
  • PD-1 (nivolumab and lambrolizumab)
  • PD-L1 (RG7446)
  • OXO-40 inhibitors (more about those in another post).

This year at ASCO brings forth a lot of new data from the four compounds mentioned. In the video preview we have also attempted to explain how these antibodies work and why they are an important development beyond melanoma. There are data in several tumour types including melanoma, RCC and head & neck cancer at Chicago. In the recent thought leader interview with Dr Robert Motzer (MSKCC), he mentioned PD-1 as a hot topic to watch out for in renal cancer. However, I’m particularly looking forward to seeing the lung cancer data, which has the potential to be really stunning.

In this year’s ASCO video preview, we have included some graphics and an MOA video explaining how these immunotherapies are thought to work. Check it out below!

CLL

Another area that I’ve been watching for a while is chronic lymphocytic leukemia (CLL), which has languished a little in the shadow of it’s CML cousin. Not for long though!

There are a lot of exciting developments here beyond Pharmacyclics BTK inhibitor, ibrutinib. These include new CD-20 antibodies such as Roche’s GA-101 (obinutuzumab) and SYK inhibitors (whatever happened to fostamatinib, one of the hematology highlights of the 2010 ASCO?) where Gilead are now developing an early compound, potentially for combining with their PI3K-delta inhibitor, CAL-101, now known as idelalisib.

In addition, Infinity also have a PI3K-delta inhibitor, although they are further behind in development. We don’t know yet whether greater in vivo potency will translate to the clinic or whether also targeting gamma will add to the efficacy or introduce off-target kinase toxicities.  Either way, it’s good to see so many targets and exciting new agents being explored for this disease.

Breast and Lung Cancers

On the solid tumour front, I was delighted to see new data in HER2+ breast cancer and ALK+ lung cancer.  Interestingly, in both of these cancers, Pfizer and Novartis in particular are making inroads with a number of compounds including everolimus (Afinitor), palbociclib (PD-0332991) a selective inhibitor of cyclin dependent kinases (CDK) 4 and 6, LDK378 and PF-05280014, a trastuzumab biosimilar.

Pancreatic Cancer

My final topic that has some interesting developments is pancreatic cancer.  Since the phase III Abraxane data from the MPACT study was presented at ASCO GI, Celgene have filed with the FDA and received Priority review, with a PDUFA date of September 21st.  An update is expected at ASCO, along with tumour marker data and prognostic biomarker data.  Threshold are presenting their phase III study design for TH-302 in the Trials in Progress section, but given the standard of care may well have changed by the time the data is mature, this may well be a day late and dollar short.

All in all, a good year can be expected for new data emerging at this year’s ASCO.

You can learn more about these topics, including insights on how PD-1 and PD-L1 immunotherapies work from the video highlights by clicking on the image below:

ASCO 2013 Preview Video

My ASCO preview video was freely available for several months but is now part of Biotech Strategy Blog Premium Content.

 

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ASCO 2013 Highlights PD-1 and PD-L1 immunotherapy

One of the hot topics at this year’s annual ASCO meeting is clearly going to be PD-1 and PD-L1 immunotherapies, following on from the success of BMS’ PD-1 agent highlighted in my ASCO video last year.  By now, we know that it has a generic name, nivolumab, and is being studied in combination with ipilimumab (Yervoy) in metastatic melanoma. You can find the many nivolumab abstracts here.

Understanding how PD-1 and PD-L1 immunotherapy works.

Source: Roche

Interestingly, BMS also now has competition from other big pharma companies, including Roche’s PD-L1 antibody, MPDL3280A, and Merck’s lambrolizumab.  Roche appear to be developing a companion diagnostic, which could mean the responses are different for PD-L1 positive and negative patients.  At least, that would be an intuitive conclusion and a potentially good way to preselect patients who are most likely to respond to the therapy.

In addition, the FDA have already picked up on this class of agents, conferring the almost ubiquitous Breakthrough Therapy status on some of them already, so solid data in the next year or so could mean a fast track to market strategy is possible in this category.

In the battle of the abstracts and sheer depth of data in the PD-1/PD-L1 segment, you can see that Merck are already the poor cousins to BMS and Roche in execution. Just one?  That’s pitiful!  Never a good sign.

What factors need to be considered in looking at the immunotherapy data?

Last night I was searching the abstracts on my iPhone after the local broadband inconveniently went down and also watched the conversations on Twitter, usually a fun experience fishing for and discussing the diamonds in the rough. A couple of things struck me, however, around the immunotherapy data mining and chatter:

Firstly, there’s way too much focus on ORR (overall response rate) and the minutiae of the differences between the different PD-1/PD-L1 agents. It’s far too early to tell much, as we all know that what matters are the randomized phase III trials, trial design and patient selection (specific, catch-all etc). These can all have a huge impact on the final outcomes in large scale randomised studies.

Secondly, ORR is a measure of disease control – it tells us how much shrinkage there is going on at the time of measurement and is based on RECIST. This is partly a hangover form old chemo days, and partly a lack of available biomarkers of response. Let’s not also forget that immunotherapies usually have a delayed effect and while waterfall plots at six months or so are useful, they don’t tell us what the long term effects will be.  How durable will the responses be beyond 6-8 months?  Is there adaptive resistance developing?  What sort of logical combinations and sequencing options can be considered? So many questions to which we have no answers yet.

Thirdly, be very careful when interpreting the abstract data for ORR – sometimes the data is given for all the patients, irrespective of whether they responded or not, and sometimes it is given as a percentage of the patients who actually had some sort of response. You need to compare apples with apples when looking across studies or the conclusions drawn can end up being a little off.

Fourthly, I don’t think ORR is the ideal endpoint.  So what?  What really matters is how long do patients live, do they feel better (or worse) and will they have a better quality of life as a result of taking the medication?  Other obvious but important questions we need to evaluate going forward include:

  • How much of a prolonged effect with PD-1/PD-L1 immunotherapies have over 5 years?
  • What will be their effect on subsequent therapies?
  • Will they boost or hinder sequencing and in which tumour types?
  • Is there a biomarker of response?
  • Is a diagnostic necessary?

Fifthly, combination studies are nice if they lead to improved outcomes, but at what cost will this be achieved? By this, I mean both in terms of safety (remember ipi and vemurafenib were thought to be a logical combo in melanoma until the unexpected AEs scuppered that concept) and also cumulative cost of treatment. None of the new oncology therapies can or will be considered inexpensive these days, especially when the benefit might be measured in only a few months or less.

Overall:

I’m really looking forward to these presentations on PD-1/PD-L1 and will write about them in more detail at the meeting.  It continues to be an exciting area in oncology, as long as the results live up to the expectations.  It’s still unclear which tumour types will benefit most and what the durability will be.  Right now, I have more questions than answers, but as a concept it’s definitely one well worth watching over the next couple of years.

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Reflections of a Medical Oncologist on AACR 2013

Continuing my series of posts about the 2013 annual meeting of the American Association for Cancer Research (AACR), I am delighted to publish today a guest post from Philippe Aftimos, MD (@aftimosp) a medical oncologist at the Institut Jules Bordet in Brussels.

Blog readers may recall that Philippe wrote a guest post last year from AACR 2012 in Chicago. Since then he has been promoted from clinical research fellow to the position of medical oncologist and clinical research physician specializing mainly in early clinical trials (phase 1 and 2), new drug development and breast cancer. Congratulations!

It is impossible at large medical and scientific meetings to cover all sessions of interest, so while I followed the theme of resistance, Philippe focused on biomarkers and clinical trial design. I hope you will enjoy reading his reflections on AACR 2013.

Philippe Aftimos, MD writes:

Reflections of a Medical Oncologist on AACR 2013

Washington DC Cherry Blossoms on display for AACR 2013 Picture: Philippe Aftimos

I attended the American Association for Cancer Research Annual Meeting held this year at the Walter E. Washington Convention Center in Washington, DC, April 6 to 10th 2013. I was happy once again by @MaverickNY ‘s invitation to write a guest blog post once the effects of jet lag subsided.

18,000 participants (researchers, scientists, hematologists, medical oncologists, biotech specialist, bio-informaticians,…) conveyed everyday to the convention center and we were all blessed by a beautiful weather and the Cherry Blossoms that bloomed late this year.

Dozens of sessions ran in parallel and the word on every mouth was “sequencing”.  I was instinctively attracted as a clinician to the sessions tackling new drug development, novel biomarker discovery and future clinical trials design. It was clear that the scientific committees did a great job in tailoring a program that could please all of the different participants in the fight against cancer. This was mainly illustrated by the plenary session “From Discovery Science to Precision Medicine: Paving the Path to Progress”:

  • First, a subject with many clinical aspects: “Immune checkpoint blockade: Unleashing the immune system against cancer” presented by Suzanne Topalian. Targeting PD-1 and PD-L1 was also featured in last year’s plenary session.
  • The second subject was translational: “The therapeutic implications of genome sequencing and expression analyses for breast cancer” presented by Charles Perou.
  • The last subject came straight from the bench: “Wnt signaling, Lgr5 stem cells, and cancer” presented by Hans Clevers.

The subject I would like most to discuss is novel biomarker discovery.

Novel Biomarker Discovery

Treatments that do not work are responsible for “wasted” toxicity: wasted resources and, most importantly, “free “ side effects and wasted quality of life to patients. The advent and future “democratic” prices of next generation sequencing and high-throughput technology should help pave the way to “Precision Medicine”, the term that is set to replace “personalized medicine” [1].

Predictive biomarkers of response and/or resistance to anti-cancer therapies are explored at all levels: genome, “transcriptome”, “signalome”, proteins and even imaging. The way to achieve this goal is focusing on individual patients, consecutive sampling, real time science and implementation in therapy.

This is a non-extensive list of what was presented of AACR 2013:

  • PD-L1: the Programmed Death-1 Ligand 1 was presented as a predictive marker of response to anti-PD1 and anti-PD-L1 antibodies at the AACR 2012 plenary session. At the AACR 2013 plenary session, this IHC biomarker was presented as a good prognosis marker, mainly in melanoma and Merkel cell carcinoma.
  • RET fusions and response to cabozantinib (Cometriq, BMS-907351, XL184) in NSCLC: RET fusions are present in 1-2% of cases of Lung adenocarcinoma. 2 of the first 3 patients treated with the RET inhibitor cabozantinib achieved partial response and the third patient had stable disease [2].
  • BRAF(L597) and response to MEK inhibitors in metastatic melanoma: BRAF(L597R) is a somatic mutation in exon 15. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Subsequently, study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitors [3].
  • MAPK1 mutation and sensitivity to erlotinib: a head and neck cancer patient with bi-allelic missense mutation of MAPK1(E322K) presented a complete pathological response after a brief treatment with the anti-EGFR TKI erlotinib. Complete response is still persisting without any adjuvant treatment 1 year later [4].
  • TGF-ß and response to bevacizumab: RNA-seq was performed on core biopsies of 50 breast tumors exposed to bevacizumab in the neo-adjuvant setting. A TGF-ß gene signature was linked to response to bevacizumab. Finally a predictive biomarker to bevacizumab? [5]
  • P-S6 level and response to RAF or MEK inhibitors in melanoma: decreases in ribosomal protein S6 phosphorylation measures TORC1 activity suppression in sensitive melanoma cells. This information can be gathered by sequential and minimally invasive biospies before and early after start of treatment [6].
  • Dynamic BH3 profiling and apoptosis: this concept was difficult for me to understand and I am still not sure that I did understand all the subtlety of the technique. BH3 profiling is a tool designed to measure mitochondrial ‘priming for death’, essentially the proximity of a cell to the threshold of apoptosis. BH3 profiling on cell lines from multiple tumors performed following 16 hours of drug exposure was predictive of cell death. The authors believe in the ability of this technique to identify niche populations sensitive to an individual agent [7].
  • HER-2 mRNA expression and PICK3CA and response to T-DM1: Jose Baselga presented the lessons learned from the EMILIA trial in metastatic HER-2 positive breast cancer (phase 3 trial: T-DM1 vs capecitabine + lapatinib). The tested biomarkers included EGFR, HER-2 and HER-3 mRNA, PIK3CA mutations and PTEN loss. HER-2 mRNA level was correlated with PFS in both treatment arms. PIK3CA mutations were linked to lower efficacy with capecitabine + lapatinib. There was no treatment effect with T-DM1.
  • Predictors of response to BYL719, a PI3Kalpha-specific inhibitor: massive parallel sequencing covering either a panel of 182 cancer-related genes at Foundation Medicine or the whole exome at the Broad Institute of DNA obtained from pre-treatment specimens helped find markers of “insensitivity” to BYL719. Alterations in TP53 and KRAS were identified as statistically significant negative predictors of BYL719 sensitivity while mutations in the APC and PTEN genes were associated with a trend towards lack of benefit from treatment with BYL719 [8].

These markers will still need prospective validation. However, designing trials to achieve that goal will be very challenging. Most of these aberrations are very rare: the MAPK1 (E322k) mutation conferring sensitivity to erlotinib is found in only 1.4% of head and neck cancer patients. Collaborations should be built between institutions and patient referrals cannot remain a taboo. New trial designs such as “umbrella” trials and “basket trials” should be adopted.

Molecular screening programs are being developed in many institutions and smaller trials will eventually be initiated. Smaller trials mean more accurate conclusions, the ability to answer multiple questions and, sometimes, better care for patients.

It is also important to look at previous failures in order to identify the causes. Some of these failures will be explained by our inability to identify predictors of response and resistance. Indeed, very few tumor responses were recorded in a trial testing everolimus in metastatic bladder cancer. Whole-genome sequencing of the tumor of an exceptional responder helped identify TSC1 mutations as a basis for everolimus sensitivity [9].

The US National Cancer Institute (NCI) in Bethesda, Maryland, is launching an “exceptional responders” program [10] to help understand why a few patients benefit from particular treatments that failed the large majority of patients. This program represents, in many researchers’ opinions, a huge step towards “Precision Medicine”.

References:

1-    Momentum grows to make ‘personalized’ medicine more ‘precise’ http://www.nature.com/nm/journal/v19/n3/full/nm0313-249.html

2-    Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas. Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens PJ, Ross J, Miller VA, Ginsberg MS, Zakowski MF, Kris MG, Ladanyi M, Rizvi NA. Cancer Discov. 2013 Mar 26.

3-    Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle PL, Hicks DJ, Bozon V, Glaspy JA, Rosen N, Solit DB, Netterville JL, Vnencak-Jones CL, Sosman JA, Ribas A, Zhao Z, Pao W. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012 Sep;2(9):791-7.

4-    Lui V, Allen E, Li H, Zhang F, Zeng Y, Johnson J, Garraway L, Mills G, Grandis J. Whole exome sequencing links MAPK1 mutation to exquisite sensitivity to brief erlotinib monotherapy in head and neck cancer [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4565.

5-    Varadan V, Miskimen K, Kamalakaran S, Janevski A, Banerjee N, Williams N, Abu-Khalaf M, Sikov W, Dimitrova N, Harris L. RNA-seq identifies a TGF-β signature that predicts response to preoperative bevacizumab in breast cancer [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4566.

6-    Corcoran R, Rothenberg S, Hata A, Faber A, Winokur D, Piris A, Nazarian R, Brown R, Godfrey J, Mino-Kenudson M, Settleman J, Wargo J, Flaherty K, Haber D, Engelman J. Rapid assessment of TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF mutant melanoma [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4568.

7-    Montero J, Letai A. Personalizing cancer therapy using dynamic BH3 profiling [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 4569.

8-    Rodon J, Juric D, Gonzalez-Angulo A, Bendell J, Berlin J, Bootle D, Gravelin K, Huang A, Derti A, Lehar J, W�rthner J, Boehm M, van Allen E, Wagle N, Garraway L, Yelensky R, Stephens P, Miller V, Schlegel R, Quadt C, Baselga J. Towards defining the genetic framework for clinical response to treatment with BYL719, a PI3Kalpha-specific inhibitor [abstract]. Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. Abstract nr 2278.

9-    Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012 Oct 12;338(6104):221

10-Cancer researchers revisit ‘failed’ clinical trials http://www.nature.com/news/cancer-researchers-revisit-failed-clinical-trials-1.12835

Overcoming drug resistance in lung cancer

On the final day of the annual 2013 meeting of the American Association for Cancer Research (AACR) in Washington DC, Jeffrey Engelman (MGH) hosted an excellent plenary session on “Cancer Evolution and Resistance” with a series of superb talks not only from himself, but also Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands CI).

If this session is included in the webcast, I would highly recommend watching the whole thing several times, as it was one of the meeting highlights for me. Despite being on the very last day, the large hall was pretty packed and well worth waiting for. You can check availability of the AACR 2013 webcast talks here.

I’m going to focus on some of the specifics in NSCLC from Engelman’s talk for this update.

Where are we in the quest to improve outcomes in lung cancer?

Jeff Engelman, courtesy of MGH

Jeff Engelman, courtesy of MGH

Engelman discussed the basics of what we know about adaptive resistance to TKI therapy in solid tumours – most of them (EGFR and ELM4-ALK in lung, BRAF in melanomas, HER2 in breast, and cKIT in GIST) typically being in the range of 8-11 months, with only GIST seeing an impact for nearly 2 years (20 months).

Thus we can see that the resistance develops over time as mutations and amplifications in the tumour evolve in adaptation to the initial efforts to inhibit the target. Indeed, approx. 50% of EGFR lung cancers develop the T790M mutation, while ~33% of resistant ELM4-ALK cancers show new mutations (e.g. L1196M, G1269A and others).

The development of these changes essentially serves as a way to bypass tracks and and continue to allow downstream signalling of PI3K and MEK to occur, thereby driving growth and cell survival. What then happens is a myriad of other pathways become activated to help drive signalling, for example MET, HER2/HER3, IGF1R etc in EGFR driven cancers and EGFR and cKIT amplification in ALK lung cancers.

As an analogy, think of this process like a road traffic system – if the route into New York from New Jersey was cut off at the Holland Tunnel, so traffic would increase to the Lincoln Tunnel or Verrazano Bridge and if those were cut off, traffic would then flow onto the George Washington Bridge, as it adapts and seeks new escape routes from the original destination.

Eventually, the cancer evolves further with defects in growth arrest and apoptosis, as seen with transformation from NSCLC to SCLC in some patients with EGFR cancers, and even changes in the microenvironment through epithelial mesenchymal transition (EMT) and loss of BIM.

The key question is what can we do about overcoming or delaying resistance?

One strategy would be to evaluate more potent inhibitors e.g. LDK378 instead of crizotinib in ELM4-ALK cancers. Another might be to explore logical combinations to address shutting down the bypass tracks. A third might be to add in a new inhibitor to target the specific mutations that evolve e.g. T790M inhibitor in the case of EGFR driven cancers when it appears.

Some of these trials are already underway and we should have more data soon.

Another way, as we saw with the last post on metastatic melanoma, is to identify mechanisms of resistance using laboratory models and lab specimens. This approach can potentially lead to more rational drug development in the clinic. Traditionally, scientists have induced resistance in mice, looked for the mechanisms (a process that can take 1-2 years), validated them in lab samples of patients, and then treated with a new treatment strategy.

This process is obviously time consuming though and not every patient can wait that long for the answer. Engelman then explained how they are looking at ways to streamline the process in Boston. After the mouse resistance experiments are completed, they have added in a drug combination screen to look for logical treatment strategies i.e. what can be added to the original drug to overcome resistance?

A very elegant example was given for EGFR lung cancer where they evaluated 78 test drugs in a screen with and without gefitinib to determine those which led to cell death. Other examples were given for ELM4-ALK cancers.

The screen results suggested that most of the resistant models produced 3-6 hits. These might include adding a MET inhibitor to an EGFR inhibitor in EGFR mutant cancer, an EGFR inhibitor in MET amplified cancers and a SFK inhibitor in the case of ELM4-ALK cancers, for example.

These results are still early, but they do look very promising. Validation studies are still needed, but early studies they performed suggested that the hits are indeed showing efficacy in vivo.  A preclinical example for this concept was shown in vivo by adding ABT-263 (Bcl2 inhibitor) to gefitinib and seeing first a rise in tumour growth with the EGFRi and then a large drop in volume when either ABT-263 or AZD6244 (MEK) was added.

Based on the exciting initial concepts in animals, they are now moving to patient derived models since next generation sequencing (NGS) can help identify the mechanisms of resistance and combined with the drug combination screens, we may see more individual level treatments for patients on a case by case basis.  These might be based on large scale (over 100 cell lines) testing derived from resistant biopsies to identify effective combinations and match them to the relevant biomarkers.  It sounds easy and obvious, but few centres are doing this in practice.

This is true personalised medicine in action.

It is also pretty exciting to me as we know that cancer, even in different patient tumours, is very heterogeneous and requires a more personalised rather than a one size fits all approach. As Engelman observed,

“Heterogeneity of resistant clones within individual patients may pose additional challenges to overcome resistance.”

The second half of his really excellent talk focused on the use of sequential biopsies in patients to explain the heterogeneity and how it can lead to transformation from NSCLC to SCLC and back again in response to treatment with an EGFR inhibitor. That’s an in-depth discussion for another day though, but suffice to say it was a fascinating topic.

And finally…

I can see these novel and applied techniques eventually moving very fast and adopted in top level Academic centres where they have the resources and knowledge to marry basic and translational research with clinical practice in early stage trials, but for many Community or even regional Academic physicians, this will be virtually impossible without referral of patients to clinical trials in the Academic centres, at least for now.

Ultimately, we will see more improvements in treatment for lung cancer when we figure out not only the targets, but also how to overcome adaptive resistance, add logical new combinations, and select future treatment based on biopsies as the tumour evolves its response to each line of therapy. Treatment will essentially need to be chosen on an individual patient basis in the long run by evaluating adaptive resistance to each new combination over time.

The idea that we can use mouse models and drug combination screens with sequential patient biopsies to better understand the adaptive response to therapy over time is not new but few have managed to put processes and strategies in place to make this happen in real time. Patients often can’t wait 2 years or more for a new combination trial to open, but the Boston approach is very promising and I’d like to applaud all those at the Boston group (MGH, Dana-Farber, MIT/Broad etc) for their groundbreaking work in this field. Keep your eyes peeled for more updates in this exciting area of research!

Overcoming resistance to vemurafenib in metastatic melanoma

One of the interesting themes for that emerged for me at AACR this year was the amount of effort that is being expended on strategies to overcome drug resistance. This was particularly noticeable in metastatic melanoma and non-small cell lung cancer (NSCLC).  More on lung cancer in another post, as today I want to focus on melanoma.

In the advanced melanoma, vemurafenib is given to patients with the BRAFV600E mutation, which occurs in approximately 50% of patients. This oncogene drives activity of the tumour, but inhibition with vemurafenib (Zelboraf) has shown some remarkable effects, as the stunning before and after photos from Levi Garraway’s group demonstrate.

The challenge, however, is that adaptive or acquired resistance can occur in response to treatment and patients sadly find their melanoma returning after approximately 6-9 months on continuous daily therapy.

At last year’s ASCO, we saw that adding a MEK inhibitor such as trametinib to a BRAF inhibitor such as dabrafenib added around an extra 3 months over single agent BRAF therapy before the resistance set in and the disease returned, sometimes with a deadly vengeance.

I’ve written here on this blog about numerous mechanisms of resistance in advanced melanoma from MEK to COT and others (see related posts below for background reading).

The big question at this AACR was how is the field progressing with new research?

Sometimes, we have to go back to the lab to study animal models of resistance before returning to the clinic with new ideas.

Screen Shot 2013-04-15 at 2.54.50 PMThat’s what a young Novartis Postdoctoral fellow from NIBR, Meghna Das Thakur, did. She asked critical questions and attempted to answer them in a series of elegant experiments with mice as well as retrospectively test the concept in patient data. The cool thing is that while many of the oral sessions were taken up by the Major League researchers is that it’s also nice to see up and coming young scientists present some nicely done research.

What Dr Thakur did was really interesting…

Her hypothesis was simple – that resistant tumours are ‘less fit’ than sensitive cells and have a selective disadvantage over sensitive cells in the absence of drug.

If this were true then we would expect to see dependence on drug for growth of resistant tumours in xenografts, much as we do in humans, with vemurafenib. The data clearly showed that vemurafenib resistant tumours were dependent on drug for growth. They also observed that:

1) p-ERK levels increased following withdrawal of vemurafenib in resistant tumours
2) There was a great deal of heterogeneity in the mechanisms of resistance

The key question then becomes how can we use this information to prevent resistance?

One way to explore this is to look at selective pressure, since vemurafenib is usually given continuously…

  • Treating continuously means that selective pressure enriches resistant cells
  • However, withdrawing the drug means that resistant cells suffer a fitness deficit

Essentially, the researchers noted that, “alternating the selective pressure prevents the emergence of a resistant population.”

In comparing continuous vs intermittent dosing, two things could be concluded from the model:

1) Resistant tumours emerge more rapidly under continuous dosing with vemurafenib
2) Intermittent dosing in multiple tumor xenograft models forestalled resistance

What can we learn from retrospective patient data?

What they did next was to look at computed tomography (CT) scans analysed for evidence of vemurafenib-dependence in patients treated with vemurafenib in the BRIM-3 and vemurafenib safety study, which were identified from the clinical trials database at the Royal Marsden Hospital. In particular, they focused on patients who stopped treatment because of progressive disease (PD).

Of 42 patients identified, 19 of these had CT scans performed after cessation of vemurafenib available for review, while 23 patients did not have a CT available for review and in 16 patients this was because of rapid PD.

For each of those 19 patients with a post-vemurafenib CT, the total tumour volume on three consecutive CT scans was recorded:

  • The CT performed prior to stopping vemurafenib
  • The CT performed when progressive disease was diagnosed and vemurafenib stopped
  • The CT performed after vemurafenib was stopped and prior to the initiation of further therapy

They found that 14 of the 19 patients experienced decreased tumour growth rate following cessation of vemurafenib, supporting the hypothesis that resistant tumours emerge more rapidly under continuous dosing with vemurafenib.

In this model, it is clear that intermittent dosing prolongs survival, but what is the underlying mechanism, and what does this mean for future treatment of patients and also clinical trial designs?

From this initial work it was clear that the MOA is not yet fully understood and further bench work will be needed to elucidate the mechanisms involved.  We don’t yet know, as the researchers point out, whether:

“Does resistance come from a clonal population or is it an adaptation or re-wiring of a selected few cells?”

What was clearer though, is that new clinical research will be needed to evaluate the potential for intermittent vs continuous dosing in patients, particularly in combination:

  • Will there be greater selective pressure from BRAF + MEK inhibitor combinations vs BRAF alone?
  • Identify combination partners that could be used during BRAF inhibitor holiday.

Overall…

I thought this was a very nice piece of well thought out research, perhaps one of my favourites from the AACR meeting this year.  Critically, we saw that the preclinical mouse xenograft model predicted a clinically-relevant resistance mechanism. Removal of drug from resistant cells leads to MAPK pathway hyper-activation and resistant cells experience a fitness deficit. Cycling the mice on and off therapy led to better outcomes than if they were dosed continuously, thereby giving us a new strategy to consider in melanoma patients.

The main impact of this preclinical study is that future clinical research in advanced melanoma should investigate the value of intermittent dosing strategies to improve patient outcomes.

The work turns the old concept of continuous dosing 365/24 on its head – suppressing the BRAFV600E oncogene continuously in melanoma may not necessarily be the best strategy in terms of superior outcomes.

This this does NOT mean that ALL tumours will behave in a similar fashion and intermittent dosing should be tested first in clinical trials where there is sufficient scientific evidence to warrant it.  If I were a patient, considering drug holidays without any evidence of effectiveness would NOT be a good idea.

I’m really looking forward to seeing the results of future combination trials with intermittent dosing to see if outcomes are indeed improved beyond would we currently see with continuous dosing either alone or in combination.

 

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AACR 2013 – some initial thoughts on the emerging trends

This year’s American Association for Cancer Research (AACR) annual meeting grew by 8% to approximately 18,000 attendees with 25% from 75 foreign countries, it is truly becoming a more global event for cancer researchers.

Over the next few days I plan to cover some of my highlights (basic, translational and clinical) in depth here on the blog and also with additional notes for email subscribers.  If you haven’t signed up for the PSB email alerts, there’s still time before the AACR notes go out.

Cherry Blossom in Washington DC by the Monument during AACR 2013With around 6,000 posters and many oral presentations from leading researchers, there is usually some interesting early data coming out from AACR.  This year was no exception.  My pile of poster handouts is over 6” thick with more already coming in my email!  My fervent wish for next year is that more scientists take to the QR code method of sharing their posters – aside from being green and saving trees, it’s also considerably easier on the back!  Another welcome development would be putting the posters online for later download as many of the European meetings already do.

I’m a little tired today as the event only just finished yesterday with a very good plenary session involving Jeff Engelman (MGH), Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands Cancer Institute).  More on this later, but what a way to end the meeting with a fairly packed hall despite it being the last day.

One of my favourite activities at AACR is talking with young researchers in the poster hall, and a few of these will be highlighted in separate posts.  Many took the time to explain some complex biology and answer my many questions on a variety of topics.  Some of this information was really helpful in improving my own understanding of why I don’t like some therapeutic approaches (e.g. targeting hypoxia) others reinforced my enthusiasm for some immunotherapies such as PD-1 and PD-L1 inhibition.

What about the emergent themes from this year’s AACR meeting?

Every year brings new developments in some shape or form, but here are some of the trends I observed based on the posters and oral sessions I attended:

  • Identifying and developing strategies for overcoming resistance was MUCH more noticeable this year
  • New combination strategies (including more novel-novel approaches) was also very much to the fore
  • Increased pace of research into biomarker identification for clinical trial design
  • Continuing rise of epigenetics as a viable approach for cancer therapeutics
  • New targets emerging (more about these later)
  • Second generation agents to CDK 4/6 and 7, chimeric antigen receptor technology (CART), Polo-like Kinase (PLK1) and many others.

Over the next few days I’ll be writing more about these topics after wading through my many pages of chicken scratch notes from the oral sessions (largely driven by ones I know likely won’t be on the webcast, which goes live for the majority of sessions on May 1st) and that huge poster pile – watch this space!

 

 

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