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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Melanoma’ category

Will vemurafenib receive early approval for metastatic melanoma?

By on August 9, 2011

A Reuters press release on vemurafenib (Zelboraf) caught my eye this morning, suggesting that it might be approved in BRAFV600E metastatic melanoma by the FDA might be “imminent” according to an unnamed source and much earlier than the expected PDUFA date in November October 28th (now confirmed by Roche/Genentech).

If so, that’s very good news.

However, what really caught my eye was a quote from a spokesperson at Roche Diagnostics, suggesting that the BRAFV600E test would could around $150.  That’s lower than I was expecting, although no doubt it will be considerably offset by the cost of vemurafenib itself.

It was also good to hear recently that Roche and BMS, the manufacturers of ipilimumab (Yervoy), have now met to discuss and finalise the much anticipated combination trial of Zelboraf and Yervoy.  It will be interesting to see if the combination will extend survival even further in patients with the V600E mutation.  There’s a long way to go before the results bear fruit, as an early dose finding and tolerability study will be the first step in the process.

Of course, pricing and reimbursement will be key, given that Yervoy was launched recently with a $120K price tag for four infusions.  On the 2Q earnings call the other week, BMS announced that the launch was going well and uptake was strong.  It is given as a 3mg infusion every three weeks for 4 cycles, over a 3 month period.  It will be interesting to see what the Zelboraf monthly price will be, assuming it successfully garners approval.   Should the combination work out in the future, the cost of treating metastatic melanoma will likely become even more expensive despite only small incremental survival benefits.

 

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European Hematology Association meeting 2011

By on June 8, 2011

Well, after just getting back from the American Society of Clinical Oncology (ASCO) meeting in Chicago, I’m heading off to Europe for the European Hematology Association (EHA) meeting – no rest for the wicked!

ASCO was a rather flat meeting this year – the stars were undoubtedly the imatinib 36 vs 12 month data in adjuvant GIST (clearly superior) and Roche/Plexxikon/Daiichi Sankyo’s vemurafenib in BRAF V600E metastatic melanoma. The ipilimumab data was strangely disappointing in the upfront setting – only 2 months improvement in survival when added to DTIC.

On the Sarcoma front, the catch-all nature of the study came back to haunt Merck with an improvement in PFS but no overall survival benefit for ridaforolimus as maintenance therapy after 1-3 cycles of chemotherapy. That filing will likely result in a highly charged ODAC meeting debating the merits of some awkward results.

Ovarian cancer data was a mixed bag – olaparib continues to look promising in this setting, although the Avastin OCEANS data caught a few people by surprise – yet another PFS endpoint met but no overall benefit in survival and the expected incidence in bowel perforations. I think this will likely be reserved for high risk women, if used.

There was a lot of interesting/promising data in phase II, which are too numerous to mention right now – check back as I will be adding some notes on some of the emerging compounds that I liked.

Meanwhile, I’m aggregating the tweets from the hematology meeting using the #EHA11 hashtag – you can track them in the widget below if interested in following along remotely. Most of the tweets from me will likely be on leukemias, lymphomas and multiple myeloma.

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BMS and Roche join forces in metastatic melanoma

By on June 2, 2011

Two of the most dynamic cancer markets at the moment are prostate cancer and metastatic melanoma, which is great news considering that neither has had much attention over the last decade compared to breast and lung cancers.

My colleague has posted an overview of what’s going on in advanced prostate cancer today, which you may be interested in checking out pre-ASCO.  However, what excited me this morning were announcements from BMS and Roche declaring their intent to pursue combination trials in BRAF metastatic melanoma with their therapies ipilimumab (Yervoy) and vemurafenib (PLX4032).

This is really great news, and a very logical approach that is well worth evaluating.

I’m delighted to see the two companies seeking to work together on this to see if the combination can improve outcomes further than what we have seen for vemurafenib alone, which already showed impressive responses in poor prognosis patients.

How vemurafenib works in BRAF V600E metastatic melanoma

Vemurafenib has been shown to target the BRAF V600E mutation, as you can see in the graphic.

Ipilimumab is an immunotherapy that targets the CTLA-4 antigen and was approved by the FDA in March as a treatment option for newly diagnosed patients with metastatic melanoma.

A phase I/II trial is planned initially, which is a relatively low risk study – if the results look good we will hopefully see a larger scale phase III trial emerge.  If not, at least we will know a quick answer on the combination.

Meanwhile, these two drugs will be presented in the plenary session at ASCO this weekend comparing either to the current standard of care, dacarbazine (DTIC), in advanced newly diagnosed metastatic melanoma.

I’m really looking forward to writing more on those trials on Monday morning – so do check back then for an update of the phase III data!

 

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What's hot at ASCO 2011?

By on May 31, 2011

This weekend I’m heading off to Chicago for the annual meeting of the American Society of Clinical Oncology (ASCO).  I’ll be writing some in depth pieces and daily highlights from the conference, but in the meantime, many of you will be wondering what might be interesting amongst the 5,000 or so abstracts.

Here’s a quick snapshot of some data I’m looking forward to catching up on – there’s no clapperboard or guy with a teleprompter behind the camera, just a few ideas and some things to watch out for:

http://youtu.be/TNwQvV4aYl8

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Roche files vemurafenib for metastatic melanoma in Europe and US

By on May 12, 2011

Yesterday, Roche/Genentech announced that they have submitted the New Drug Application (NDA) filing for PLX4032 (vemurafenib) in BRAF V600E mutation-positive metastatic melanoma, based on BRIM2 and BRIM3 trials to both the FDA and EMA.

I’ve posted quite a bit on BRAF inhibitors such as vemurafenib on this blog – check out the related posts feature at the bottom if you want to learn more about the history of this class of drugs.

Interestingly, Roche have also submitted the companion diagnostic, cobas 4800 BRAF V600 Mutation Test, which means that oncologists in the community will be able to more easily test patients for the mutation, since these patients are more likely to respond to therapy with BRAF inhibitors such as vemurafenib.

Source: wikipedia

Although melanoma is treatable in the early stages, unfortunately once it becomes metastatic, it becomes more difficult to contain.

Roche have conducted two large-scale clinical trials (BRIM3 and BRIM2) to evaluate the safety and effectiveness of vemurafenib in mestatatic melanoma patients who have the V600E mutation. According to the Company:

“BRIM3 is a global, randomised, open-label, controlled, multicentre, Phase III study that compared vemurafenib to dacarbazine chemotherapy, a current standard of care, in 675 patients with previously untreated BRAF V600 mutation-positive, unresected or locally advanced metastatic melanoma.

The study met its two co-primary endpoints and showed that participants who received vemurafenib lived longer (overall survival) and also lived longer without their disease getting worse (progression-free survival) compared to those who received dacarbazine chemotherapy.

The safety profile was consistent with previous vemurafenib studies.”

The BRIM2 study also formed part of the global filing:

“BRIM2 is a global, single-arm, multicentre, open-label Phase II study that enrolled 132 patients with previously treated BRAF V600 mutation-positive metastatic melanoma. The primary endpoint of the study was overall response rate as assessed by an independent review committee.

The study showed that vemurafenib shrank tumours in 52 percent of trial participants. People who participated in the trial lived a median of 6.2 months without their disease getting worse (median PFS).”

Like many of us, I’ve known family and friends or friends of friends who have been lost to this devastating disease.  Six months doesn’t sound very long, but when you look at many of the oncologic filings over the last decade, very few have actually shown six months improvement in overall survival.  In that context, this represents a dramatic advance for patients.

Of course, we can still do better, and as we learn more about the biology of the disease, so we can develop smarter therapeutic strategies for overcoming malignant melanoma.  This could take the form of new combinations or other BRAF inhibitors that do not target CRAF as well as BRAF, for example:

“The most frequent Grade 3 adverse event observed in clinical trials of vemurafenib was cutaneous squamous cell carcinoma, a common skin cancer treated by local excision (minor surgery done in a physician’s office).

The most common adverse events were rash, photosensitivity, joint pain, hair loss and fatigue.”

It has been shown that activating CRAF, for example, is most likely responsible for the squamous cell proliferation on the skin in some patients.  It appears to be reversible once treatment is stopped.  However, that said, this is still a huge advance and should be applauded as such.

More BRAF and RAF inhibitors are on the way

BRAF inhibitors

Interestingly, Bayer also announced yesterday that their multi-kinase RAF/VEGF/Tie2/RET/KIT inhibitor, regorafenib, was granted Fast Track designation by the FDA for the treatment of patients with metastatic and/or unresectable gastrointestinal stromal tumors (GIST) whose disease has progressed despite at least imatinib and sunitinib as prior treatments.  This is an incredibly small population so I don’t expect the trial to accrue speedily.  GIST is largely KIT or PDGF rather than RAF driven.  The trial began enrolling in January this year and accrual is still open – in all, Bayer plan to enroll 170 patients.

I will be interested to see whether regorafenib also activates CRAF as well as RAF – if so, we can expect some squamous cell proliferation in the adverse events – while multi-kinase inhibitors can be effective, we also have seen some off-kinase side effects, as shown with sorafenib and sunitinib.

What does this data mean?

The vemurafenib filing is excellent news for patients based on the data and pictures I have seen of responses in various conference presentations to date.  It’s a great success story of finding an aberrant mutation, developing a diagnostic to enable widespread testing for it and matching the patient to the treatment.

What I also like is the fervour with which the melanoma scientist-physician community is researching the methods of resistance and looking at new combinations with BRAF inhibitors almost as soon as they detect them – a great showcase for what to do.

We can also expect update on the BRIM2 and 3 trials at the forthcoming annual meeting at ASCO next month – I can’t wait to see how the data is maturing!

Assuming that vemurafenib is approved, it will also be interesting to see what happens post-approval, since Daiichi Sankyo bought Plexikkon, complicating the potential marketing and sales roll-out considerably.  One can wonder at the old adage that two’s company, but three becomes a crowd to manage.

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Update on PARP inhibitors including iniparib, olaparib and veliparib

By on May 10, 2011

A PSB reader wrote in asking whether an update on the PARP inhibitors and the clinical trials would be possible.   Following on from the last update in January that covered Sanofi’s negative iniparib phase III data in triple negative breast cancer and AstraZeneca’s decision in February not to pursue olaparib in hereditary BRCA1 and 2 positive breast cancers, it would be a good idea to see what’s left of this once highly promising class of compounds.

I first wrote about PARP inhibitors way back in 2006 and like many, I’m rather disappointed with the results we’ve seen so far.  However, all is not lost.  Abbott’s veliparib is going strong, while Pfizer (PF-01367338) and Cephalon (CEP-9722) are just getting started with their programs.

Iniparib was probably the weakest inhibitor of the class and perhaps not potent enough, since there was no increase in toxicities in the TNBC study (that can be a good and a bad thing), while olaparib has proven to be potent but challenging to combine with chemotherapy.  It doesn’t mean that a different compound or clinical approach will be unsuccessful.

The saddest thing about the iniparib trial is the lack of BRCA1 and 2 testing, given the heterogeneous nature of triple negative breast cancer. We will likely never know which different subsets responded and why from that trial, it probably could have been better designed and included more rigorous biopsies for biomarker analysis, but once done it is too late.  This is one of the dangers of applying old-style chemotherapy trial designs to targeted therapies – first know your molecular targets – or potential targets – and evaluate the biomarkers over time in response to therapy.  Otherwise, it’s a bit like blindfolding an archer and asking him to hit a target s/he can’t even see.

I don’t think all is lost with AstraZeneca’s olaparib yet, but we will have to wait and see what the current ongoing studies bring in terms of answers.  Certainly, both AstraZeneca and Abbott have a broad range of clinical trials that may yield some interesting results. We shall see.

I took a quick look at the clinical trials database and sifted through the available data for PARP inhibitors. This is what we have so far:

Parp Inhibitors

One trial I’m eagerly awaiting the results of is the ISPY2 trial in neoadjuvant breast cancer, which included veliparib as one of the treatment options in a molecular based approac,h much in the same way the BATTLE trial worked in lung cancer.  For those interested in the background to this approach in breast cancer, you can find the details in an interview with Sue Desmond-Hellmann (UCSF), when the trial was first announced.  It will be a while before we know the results, but one that is very eagerly awaited in the breast cancer community.

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An overview of mechanisms of resistance to BRAF

By on May 5, 2011

A new paper has just been published on the mechanisms associated with BRAF resistance by Corcoran et al., (2011).  One of the things I liked about this paper, other than it’s clarity and simplicity, is that you can find it in OncoTarget, an open access cancer journal (see references below), with a prestigious editorial board including Carlo Croce, Bert Vogelstein, Pier Palo Pandolfi, Wafik El Deiry, and Brian Druker to mention a few of the researchers.

The article essentially describes ERK and non-ERK dependent methods by which resistance occurs to BRAF inhibitors such as PLX4032 (vemurafenib).  These are summarised in the table below:

Mechanisms of resistance associated with BRAF

As a result of these findings on the underlying biology to date, the authors suggest that different treatment strategies can be considered:

Potential treatment strategies for overcoming BRAF resistance

As our knowledge of the science of metastatic melanoma improves, so do our opportunities for therapeutic intervention and improvement in outcomes.

Metastatic melanoma is likely to be a hot topic at the forthcoming ASCO annual meeting next month with updated data from the vemurafenib and ipilimumab clinical trials.  I will add a more detailed post once the new data has been presented.

In the meantime, this paper is well worth reading – check it out!

References:

ResearchBlogging.orgCorcoran RB, Settleman J, & Engelman JA (2011). Potential Therapeutic Strategies to Overcome Acquired Resistance to BRAF or MEK Inhibitors in BRAF Mutant Cancers. Oncotarget PMID: 21505228

 

 

 

MEK mutations confer resistance to MEK and BRAF inhibitors in melanoma

By on April 21, 2011

The other day, we discussed resistance in melanoma and how COT can reactivate BRAF signalling through MAPK reactivation.  Previously, we reviewed how MEK inhibitors may potentially be useful when combined with BRAF inhibitors in overcoming resistance due to cross-talk.  There are also other methods of preserving this oncogenic activity, which are highly relevant to current clinical development.

At the recent American Association for Cancer Research (AACR) meeting, Levi Garraway (Dana Farber) presented at the plenary session on “Navigating the interface of tumor biology and therapeutic development through integrative genomics.” He first discussed the history and context of targeted therapy, then focused on the progress in metastatic melanoma, highlighting some dramatic responses to the BRAF inhibitor PLX4032 (vemurafenib) using before and after pictures of his patients.

The talk was very well done indeed and I was so engrossed in following the story, I forgot to make notes – that’s how good it was!  The good news is that AACR captured the excellent slides and audio in a free webcast.  If you have 20 minutes, please do take some time to check this one out – it was one of my highlights of the meeting.

Dr Garraway also drew the audience’s attention to a poster from Wagle et al., (2011) based on new research from his lab looking at a new mechanism of resistance in melanoma, namely mutations in MEK.  Unfortunately, I missed the poster that morning, but the group kindly referred me to their publication in Journal of Clinical Oncology last month (see references below), which offers more detail for discussion here.

Essentially, they used a genomics approach to see if they could advance our understanding of mechanisms of de novo and acquired resistance to RAF inhibition, which are poorly understood.  To put things in context, the same patient that Dr Garraway refers to in the webcast above was also the subject of the genomics profiling in the paper:

“We performed massively parallel sequencing of 138 cancer genes in a tumor specimen from a melanoma patient who developed resistance to PLX4032 after a dramatic initial response.”

Initially, the patient responded to therapy:

“A profound clinical response ensued, including nearcomplete regression of all subcutaneous tumor nodules at 15 weeks on drug.”

The pictures of the patients torso in the webcast were dramatic.  There were several involuntary sharp intakes of breaths from the audience around me in the session.

Unfortunately, it wasn’t all good news:

“After 16 weeks on PLX4032, the patient experienced widespread disease relapse, which by 23 weeks involved most previous sites of visceral and subcutaneous disease.”

The pictures in the webcast also showed the physical impact of this sad news.  The key question then, is why did the patient relapse?

The genomic profiling undertaken by the group addressed this question and uncovered something unexpected:

“The resulting profile identified a novel mutation in the downstream kinase MEK1 that was absent in the corresponding pre-treatment tumor.

This MEK1 mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro.”

What are the implications of this research?

This was a very nice piece of work that sought to uncover the reason for a responding patient becoming resistant to treatment with PLX4032.  The researchers found a downstream MEK1 mutation was responsible for inducing resistance.

The implications of the finding, however, are slightly scary.

Why?  Because as the authors concluded in their paper, the MEK1 mutation found in this patients is cross-resistant to allosteric MEK inhibitors (eg AZD6244), even though the patient has never been exposed to a MEK inhibitor.  It also implies a mechanism by which melanoma may become resistant to combination RAF and MEK inhibitors (eg PLX4032 + AZD6244) with just a single mutation.

In other words, we still have a ways to go figuring out all the potential combinations and methods of resistance that could take place in this disease.  The good news is that research into mechanisms of resistance is running parallel with clinical development in metastatic melanoma and will hopefully continue to do so.

References:

ResearchBlogging.orgWagle, N., Emery, C., Berger, M., Davis, M., Sawyer, A., Pochanard, P., Kehoe, S., Johannessen, C., MacConaill, L., Hahn, W., Meyerson, M., & Garraway, L. (2011). Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling Journal of Clinical Oncology DOI: 10.1200/JCO.2010.33.2312

GRIN2A gene may be a new target in metastatic melanoma

By on April 19, 2011

This is turning out to be quite a week for posts on interesting and new things happening in melanoma.

Source: Wikipedia: metastatic melanoma that has invaded the pancreas

Yesterday, we discussed novel mechanisms of resistance to BRAF inhibitors such as PLX4032 and tomorrow we will review new findings associated with MEK resistance, but today I wanted to draw your attention to more basic research, that is, the identification of a new mutation in melanoma.

In a fascinating Letter to Nature Genetics, Wei et al., (2011) described how they used exome sequencing to systematically look at alterations in the DNA seen in the disease in 14 matched normal and metastatic tumours:

“Using stringent criteria, we identified 68 genes that appeared to be somatically mutated at elevated frequency, many of which are not known to be genetically altered in tumors.”

This is crucial, because when we consider therapeutic intervention down the road, we want to find targets that are aberrant in cancer, but preferrably, do not exist in people without cancer.  The reason for this is that many unwanted side effects are reduced by having a clear and obvious target.

What did the research show?

According to Wei et al., (2011), they found

“We discovered that TRRAP harbored a recurrent mutation that clustered in one position (p. Ser722Phe) in 6 out of 167 affected individuals (~4%), as well as a previously unidentified gene, GRIN2A, which was mutated in 33% of melanoma samples.”

The emphasis is mine, but what I found interesting was that TRRAP may be a new oncogene and GRIN2A may offer a druggable target in the same way that BRAF currently does for BRAF inhibitors.

Now, there are some limitations to this excellent piece of research:

  1. Small sample size
  2. Extrapolation to a wider population cannot be assumed
  3. Further research is essential to validate the targets

Implications:

The limitations aside, the findings are very important and do provide some useful clues for researchers to home in on and consider new studies to advance both the field, and our understanding of the biology of melanoma, further:

“Our study provides… the most comprehensive map of genetic alterations in melanoma to date and suggests that the glutamate signaling pathway is involved in this disease.”

This may a little bit of a surprise to the uninitiated.  Glutamate is an essential amino acid and a transmitter in the mature mammalian nervous system, but glutamate antagonists have been shown to limit tumour growth, as you can see in a PNAS article from Rzeski et al., (2001).

Overall, I think we will be hearing more about TRRAP and GRIN2A in metastatic melanoma going forwards.

References:

ResearchBlogging.orgWei, X., Walia, V., Lin, J., Teer, J., Prickett, T., Gartner, J., Davis, S., Stemke-Hale, K., Davies, M., Gershenwald, J., Robinson, W., Robinson, S., Rosenberg, S., & Samuels, Y. (2011). Exome sequencing identifies GRIN2A as frequently mutated in melanoma Nature Genetics DOI: 10.1038/ng.810

Rzeski, W. (2001). From the Cover: Glutamate antagonists limit tumor growth Proceedings of the National Academy of Sciences, 98 (11), 6372-6377 DOI: 10.1073/pnas.091113598

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COT drives resistance to PLX4032 through MAPK reactivation

By on April 18, 2011

At the recent annual American Association for Cancer Research (AACR) meeting, Keith Flaherty from Mass General Hospital discussed the latest developments in metastatic melanoma in a plenary session.

Much of the talk focused on progress to date with existing therapies, new mechanisms of resistance in BRAF V600E driven melanoma relating to COT, based on a recent Nature publication at the end of last year (see references below) and the potential for new compounds in the pipeline.

Remember that BRAF mutations are expressed in only 7% of cancers, but 60% of melanomas and mutant BRAF was seen as a poor prognostic factor until PLX4032 (now known as vemurafenib) came along and achieved some starting results in some patients.

Many of you may recall that we discussed other mechanisms of resistance to PLX4032. You can see in the kinase pathway how COT connects with RAF, so it is not entirely surprising to see an adaptive pathway emerge at this point.

Essentially, what happened is that the scientists looked for possible mechanisms of resistance that may offer new druggable targets to overcome BRAF resistance.  The Nature Letter is quite technical, but makes for an interesting read for those familiar with kinase screens and cell lines:

“Here we expressed ~600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor.  We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines.”

They then went on to explain what they found from this approach:

“COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling.  Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors.”

The good news is that COT is a tyrosine kinase, which means in theory it offers a new druggable target for therapeutic intervention, thus we may see chemists busy working on producing new kinase inhibitors that target COT, thereby offering a new combination down the road for melanoma clinical trials.

In the meantime though, there are some other promising new compounds in the pipeline that I have been watching, making advanced melanoma very much a hot topic of late, especially as much of the progress is based on translational research running in parallel. This may well be the future in cancer research – moving from bench to bedside in a seamless and ever evolving cycle.  It also speaks to the value of involving more scientist-physicians in the process to ensure that the learnings are reincorporated into research quickly and efficiently.  We need more of this sort of approach elsewhere for rapid progress to be made!

New therapeutic developments

Looking at the clinical trials database, there are many other compounds in development for metastatic melanoma, so all hope is not lost if PLX4032 primary or secondary resistance sets in, since sequencing or combination of different agents may be important in order to delay the onset of drug resistance.

As Dr Flaherty noted in his plenary talk at AACR, the next generation of inhibitors will seek to build on the success of PLX4032, offering further improvements:

  1. Increased potency and/or selectivity for BRAF
  2. Pan-RAF inhibitors with increased potency against CRAF
  3. Dimerization blockers

Some examples of the immediate melanoma pipeline for kinase inhibitors include:

  1. GSK2118432 (GSK) is a selective BRAF inhibitor similar to PLX4032
  2. PLX4720 (Plexxikon) next generation BRAF inhibitor, targets BRAF and CRAF
  3. RAF265 (Novartis) targets both BRAF and CRAF
  4. XL281 (Exelixis) similarly targets BRAF and CRAF
  5. AZD6244 (AstraZeneca) a MEK inhibitor
  6. GSK1120212 (GSK) also inhibits MEK

You can see more detail from Dr Flaherty’s talk given at the Targeted Anticancer Therapies Conference in March (PDF link, open access), which is similar to the AACR plenary talk we heard in Orlando:

Targeting BRAF in metastatic melanoma

The advantage of combining BRAF and MEK inhibitors is that you get increased PARP & caspase 3 cleavage at lower concentrations, at least when tested with PLX4720, suggesting that this may be a useful approach if the results are reproduced clinically.

In addition, as we learn more about the biology of the disease, so out knowledge of the importance of related and adaptive pathways also increases.  These include many we have discussed on this blog in other tumour types previously, including AKT, PI3K-mTOR, CDK2 and CDK4 as Dr Flaherty showed in this elegant slide:

New potential combination therapies in metastatic melanoma

What next?

My take on all of this is that it’s good to see new combinations emerge to combat various mechanisms of resistance that are evolving, and perhaps potentially reduce the squamous proliferation seen in some patients with PLX4032 due to CRAF being activated.

Overall, it does look like metastatic melanoma will be a hot topic at ASCO if there are some exciting new mature data available for presentation and discussion.

References:

ResearchBlogging.orgJohannessen, C., Boehm, J., Kim, S., Thomas, S., Wardwell, L., Johnson, L., Emery, C., Stransky, N., Cogdill, A., Barretina, J., Caponigro, G., Hieronymus, H., Murray, R., Salehi-Ashtiani, K., Hill, D., Vidal, M., Zhao, J., Yang, X., Alkan, O., Kim, S., Harris, J., Wilson, C., Myer, V., Finan, P., Root, D., Roberts, T., Golub, T., Flaherty, K., Dummer, R., Weber, B., Sellers, W., Schlegel, R., Wargo, J., Hahn, W., & Garraway, L. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation Nature, 468 (7326), 968-972 DOI: 10.1038/nature09627

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