Lung Cancer, But First… Props to Zelboraf (vemurafenib)

Posted by Jeff Berk; BOLT International

Boy oh boy!  One of the fundamental tenets of quantum physics was demonstrated this week.  I am just stunned, but IT’S TRUE:  FDA approved Zelboraf (vemurafenib) for the treatment of BRAF V600E mutation-positive, inoperable or metastatic melanoma, as determined by the cobas 4800 BRAF V600 Mutation Test.  So there you have it… Given enough shots on goal, even a committee of grey-footed boobies gets one right now and then.

 

I’ve posted a bunch of times recently on vemurafenib, and I’m not going to rehash those.  They’re there for you to find.  And besides, there are a couple of pharma companies that still have to buy BOLT’s recent Melanoma Thought Leader Panel before we dump any more free stuff.

 

So…  Instead today we’re going to talk a little bit about lung cancer therapy.  Eventually.  But first we’re going to talk about you buying our upcoming Lung Cancer Landscape!  We’re really REALLY excited to be coming to the end of production of BOLT’s first report in our new product format. The subject is lung cancer – non-small cell and small cell.  For those of you who are familiar with the BOLT Thought Leader Panels (that’s where a lot of my blog material comes from), “Hematology/Oncology Panel #27 – Lung Cancer Landscape” will include not only the excerpts of our Thought Leader interviews, but also a thorough medical and commercial analysis of the therapeutic category.  I blush when I say this, but this is the best report we’ve ever written.  We’re talking product profiles, company strategies, competitive intensity, unmet needs, launch timelines, habits and practices – the works.  My major co-author on this report is Eric Rowinsky (ex Imclone, ex-Lilly).  The deal-i-o is, however… THIS BLOG IS MY ONLY PRE-SALE ANNOUNCEMENT.  If you are a Pharma, and email me (jeff@boltinternational.com) with a PO# by September 5, 2011, it’s yours for $17,500.  After that, and we publish, we’re taking a page from Steve Jobs and no matter what, the price is $25 stacks.  If you have a pharma email address, and haven’t ever seen BOLT report yet (do you live UNDER A ROCK?  Mr. Geico Caveman?), email me and I’ll send you a really old one (in our old format).

 

So your free sample…

  • The progressively increasing clinically-relevant results pertaining to the dependence of stratified populations of NSCLC on “driving” targeting aberrations (e.g. EGFR activating mutations, EML4-ALK, KRAS (and mutant forms), RAF (and mutant forms) and HER2 (amplified in a small proportion of NSCLC), as well as the development of secondary, often gatekeeper, mutations following successful drug targeting continues to make HSP90 inhibition attractive for therapeutic targeting.  EGFR has long been demonstrated to be a “client protein” for HSP90, however, more recently EML4-ALK and C-RAS (a main  effector of mutant K-RAS signaling in NSCLC) have been shown to be more robustly “handled” (protein recycling and refolding) by HSP90.  Additionally, drug-resistant mutant variants of EGFR (i.e. T790 EGFR mutation) and components of the PI3K pathway (Akt, IGF-IR, others) have recently been demonstrated to also be client proteins for HSP90.  Therefore, it stands that is rational to assess HSP90 inhibition as a means to treat NSCLC with one or several activating mutations, irrespective of the development of secondary target mutations to kinase inhibitors and monoclonal antibodies, with HSP90 inhibitors.

 

“The list of client proteins for HSP90 inhibitor certainly is a mile long and includes every drugable target in every cancer type.  It is easy to pick out and say well clearly it hits EGFR so it is very important in lung cancer.  That is the first answer.  The second answer is I think like any…I actually think of the HSP90 inhibitors and most heat shock protein inhibitors in a category that is like chemotherapies, sort of non-targeted therapies in the end; because their toxicity profile is probably closer to non-target therapies and our ability to predict which tumor types are going to benefit from them is also similar to non-targeted therapies.  But I think they really deserve development because there is more in-vitro data than you can shake a stick at.  That being said I think they have been developed for at least 10 years and we are not much further along.  But, I think there is some potential out there with these, both alone and in combination, with conventional chemotherapy”.

 

“I think right now we are going to start to look at it because there is a lot of data that it will help in EGFR mutant lung cancer, so I think that would be the easiest place to establish proof of principle.  So take patients who had had Tarceva like you began the discussion with who had a good response and then started to progress and add in an HSP90 inhibitor.  Then you either show you stabilize the disease or hopefully see a certain proportion or aggressions that would then allow it to be approved for erlotinib failures and initially sensitive patients and then sort of go from there and see if one can apply it more ubiquitously”.

 

 

“I think HSP90 inhibitors will probably be used as second and third-line therapy.  I think right now people are trying to get it to have some response in patients that initially respond to Tarceva but subsequently relapse.  I think that is the population that people are going for right now.  As it gets approved obviously you are going to try to go up the stream and see you if we can treat untreated patients but right now that is the population that people are going after because there is a biological basis for that population”.

 

 

“I think those are potentially interesting because there is a fair amount of proteins that have been linked to requiring the proper folding and implicate HSP90.  It could essentially be a dirty mechanism to kill a lot of tumor cells.  Those agents have worked in EGFR mutants.  It is possible that other cells that have cryptic mechanisms that upregulate tyrosine kinase signaling or ras signaling or things like that would be preferentially killed by HSP90 inhibitor.  It may have the ability to have a little bit broader activity.  I have a feeling it will be used in combination to target certain pathways that are of interest or possibly being able to be used to overcome resistance to Tarceva-like drugs”.

 

 

 

  • The development of the first generation of HSP90 inhibitors, particularly the first generation inhibitor prototypic ansamycin classes — 17AAG and 17DMAG – were marred by various toxicological (primarily liver toxicity) and feasibility/pharmaceutical (solubility) issues.   Over the last several years, second generation HSP90 inhibitors, with improved solubility and potency over 1st generation compounds, have transitioned to early stage development in cancer.    Similar to 1st generation compounds, 2nd generation HSP90 inhibitors have demonstrated single agent activity in phase 1 studies (NSCLC, sarcoma, breast cancer), but appear to have a lower potential for liver toxicity.    Nevertheless, new toxicities, namely ocular toxicity (possibly due to the hyperdependence on retinal rod-cone recycling  for HSP90) has surfaced, particularly involving 2nd generation HSP90 inhibitors with a 17DMAG backbone including (SNX5422 (Pfizer – terminated due to ocular toxicity), AT-13387 (Astex), and AUY-922 (Novartis)).    Ocular findings have rarely been reported with 2nd generation HSP90 inhibitors with 17AAG backbones (ganetespib; STA-9090 [Synta]), IPI-504 [retaspimycin; Infinity]); diarrhea appears to be their principal dose-limiting and most common toxicity).  Despite a high incidence of ocular toxicity, Novartis is still in the game.

 

 

 

  • For the first time, the results of ASCO 2011 indicate clear robust single agent activity for at least one agent (ganetespib) in a molecular defined subpopulation (EML4-ALK translocation).  A phase 2 study with…

 

 

Oops…  The Free-Meter just expired.

 

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