XL-281 (Bristol-Myers Squibb; Exelixis); BRAF for Melanoma

Posted by Jeff Berk, BOLT International:

 

Two more weeks and we’ll be in the midst of another ASCO fiasco.  This year I’m going to be prepared.  I’ll bring my own pens and a notebook (okay, not really.  Thanks Steve Jobs, for the ipad) because Lord knows, Henry Waxman sure doesn’t want me to be biased by some Pharma giving me a pen.  I might say something nice for once.  JK.  BTW, how many of you physicians from Minnesota stare bitterly at the Boehringer-Ingelheim or Lilly booths as they give some nibble out to everybody else but YOU?!  Personally I could get fat (JK) on Merck’s frozen yogurt.  There ya go Henry, go ahead and call a hearing or something (what?  you’re in the minority now?!)  I put in a free plug for Merck.  MERCK MERCK MERCK.  Good Yogurt.  MERCK MERCK MERCK.  So here’s today’s cactus, a Sulcorebutia arenacea, and then on to melanoma –  the disease that I personally think will be the Belle of the Ball.  (okay, there should be some good lung stuff, but BOLT is doing a Lung Thought Leader panel right now, and all that dirt is being embargoed until after we get paid for a  while).

 

So tonight I’m going to “pick” on BMS and Exelixis… (because THEY DON’T GIVE OUT YOGURT!)

 

 

XL-281 (Bristol-Myers Squibb; Exelixis)

 

 

  • BMS is running a Ph-I study of ipilimumab + XL-281.  This is not necessarily the best BRAF inhibitor, but it is the one that’s in BMS’ portfolio.  The rationale for the combination is to control the tumor with the small molecule and release the antigen, and use ipilimumab to mediate the immunologic response.

 

“Our ipilimumab study is with the XL281 RAF inhibitor because BMS has that now.  I don’t know that it is the best RAF inhibitor, but that is all we can get right now.  That is the one that came from Exelixis? Yeah, that is.  That is right.

 

“Yeah, I think the same strategy would make sense.  Control the tumor with the small molecule, release the antigen and then hopefully prolong the – you know because the RAF inhibitor by itself, the duration of response is limited, but with ipilimumab or drugs like PD1 we are seeing durable responses, which are immunologically mediated.  So yeah, that will also be done as well.  But the first trial is the ipilimumab combo? Correct”.

 

 

  • XL281 is a RAF kinase inhibitor under development by Exelixis.  Notably, the same phenomenon of squamous cell carcinomas developing in patients treated with PLX-4032 (RO5185426) was seen previously with XL-281.  But the squam cases in patients on PLX-4032 seem to be more dramatic (faster onset, multiple lesions) than those seen in patients on XL-281.  One speculative explanation for this is that PLX-4032 is more selective for mutant BRAF, and while BRAF V600E  inhibition is interfering with a survival pathway in melanoma, it is activating a survival pathway in these squamous tumors.

 

“I have been working with both compounds and I haven’t seen as dramatic development of this as in the Plexxikon drug.  I don’t know if…we are at fairly decent doses of the Exelixis drug too, so I am not entirely sure what the difference is”.

 

 

“We had this skin toxicity including the squamous cell skin cancer.  We also saw it with an XL281 inhibitor.  So that could be a class action, maybe C-RAF inhibition or something like that”.

 

 

“The XL-281 I thought was definitely something I would mention.  That drug seems to be very interesting with activity”.

 

 

“The increased cases of squamous that we have seen with the Plexxikon drug; we have seen this with the Exelixis drug as well-these squamous carcinoma. Yeah, I have personal cases of people erupting with these well-differentiated squams on targeted therapy. So what is causing it? It is important to think of one thing, which is the signaling pathways, that is like the postal service, whether you are delivering good or bad news is completely irrelevant-you are inhibiting the US Postal Service.  The signaling itself doesn’t deliver necessarily proliferative or anti-proliferative signals.  It is signaling.  And then at the other end of that signaling, and this is something I think that is under appreciated, is the composition of the transcriptional responses that dictate whether a cell stops dividing, undergoes apoptosis eventually, or differentiates into a fully differentiated keratinocyte or the T-cell needs to be stimulated somehow to get its response.  I think what you are going to see is that the same signaling pathways are being used by different cells for different purposes.  So whether it is delivering good news or bad news or it is delivering the growth news or the stop growing news that is going to become really vividly clear once you inhibit a pathway and something else develops.  It is going to be a true challenge if you inhibit BRAF and you develop squams because of it.  That is going to be an extraordinary challenge or you cripple the immune system.  It is going to be a major problem if they find that out.  I think there is no way to know that until it hits the animal or it hits the human”.

 

 

“Is there any role for a third BRAF inhibitor? I think there is.  We know that these tumors are dependent on BRAF, the BRAF mutants obviously.  We know that something has happened because when you block BRAF even though the drugs are equally potent at blocking BRAF and CRAF, but when you are dealing with a cell that has mutated BRAF then that is not true anymore.  But if you have a pan-RAF inhibitor that hits mutated BRAF as well, can you start developing a drug there?  So we know that the target is validated.  Can you model it some other way and maintain the high response rate and decrease toxicities, which are not too high but they are still important, or more importantly prevent resistance?  That is a big area I think.

Categories: CANCER, melanoma
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