Afinitor and Sutent for Pancreatic Neuroendocrine Tumors

Today saw two positive votes for new therapies for the treatment of pancreatic neuroendocrine tumors from FDA’s ODAC.  Novartis’s Afinitor (everolimus) got the thumbs up by a 10-0 score.  Pfizer’s Sutent (sunitinib) “eeked out” an 8-2 win.

The ODAC approval for everolimus is limited to treatment of neuroendocrine tumors that are of pancreatic origin.   Novartis’ 274 patient trial compared everolimus to placebo + best supportive care.   PFS on everolimus was 11 months vs. 4.6 months on placebo (P<0.001).

Pfizer’s 171 patient Ph-III sunitinib 37.5 mg trial was stopped early at the behest of their DSMB. The trial was stopped after there were 81 progression-free survival events, which was just 31% of the events planned into the study design.

This is problematic because it leaves unanswered the true magnitude of the benefit that sunitinib offers vs placebo / best supportive care.  But the drug was clearly prolonging PFS, so it wouldn’t be reasonable not to recommend its approval.  The median PFS was 11.4 months in the sunitinib group vs. 5.5 months with placebo (HR 0.418, P=0.0001).  6-month PFS on sunitinib was 71.3% vs 43.2% of patients on placebo.

 

Secondary endpoints included overall survival, overall response rate, time to response, duration of response, safety, and patient-reported outcomes. Overall survival had not been reached after a median follow-up of 10 to 11 months.  The six month survival on sunitinib was 92.6% vs  85.2% in the placebo group (HR 0.409, P=0.0204).

 

I had a chance to speak with an internationally recognized group of pancreatic cancer thought leaders a few months back.  Here are some of their thoughts on pancreatic NETs and the new therapies to treat them:

  • Pancreatic neuroendocrine tumor (NET), even combining functional and nonfunctional tumors, is still much smaller of an indication than is pancreatic ductal adenocarcinoma.  The clinical pipeline for pancreatic NET is more robust than for ductal adenocarcinoma.  The classes of compounds that most appear worth pursuing are VEGF/PDGF, mTOR, combinations of VEGF + mTOR, and hedgehog.

 

Afinitor (everolimus / RAD-001; Novartis)

 

“Let’s turn towards the NETs.  What would be your top one or two developmental candidates at this point and what is the basis? It is a really rapidly moving field from having literally no definite standard say five years ago.  We have now I have seen there are several promising agents, which will get approved or are in the approval phase.  There is bevacizumab.  There are the mTOR inhibitors.  There is a combination of the two.  So I think that clearly we are going to have new standards of care in this disease beyond somatastatin analogs.  Does it matter whether or not these tumors are productive or not? Actually it doesn’t seem to matter that much if they are productive or not.  Most of the tumors that we see don’t have a classic syndrome in the sense of overwhelming hormone production like carcinoid or so.  But most of them have some pancreatic polypeptide, a little bit of chromogranin and they are not terribly functional in that sense.  So we see a lot of activity with small molecules.  Certainly we are, fortunately part of several of these trials.  It is a little difficult for me to discuss all of these trials, but I think it is an area kind of which will see rapid changes in standards.  And just to be clear the key class of compounds you would focus on for NETs? I would think right now antiangiogenic agents and the mTOR inhibitors are probably in the forefront”. 

 

 

“Now, if I had an mTOR inhibitor that is what I would do.  So mTOR inhibitor and angiogenesis inhibitor and hedgehog.  I would have trouble.  I think the hedgehog is unknown so that would probably be number three, but if I had a new VGEF inhibitor or PDGFR inhibitor I would do that in neuroendocrine”.

 

“The pipeline is looking better, but a lot of people don’t want to go there because they don’t think it is a very big market, but it actually is.  You hit the nail on the head.  It is slower growing.  Some guys get transplants, like Steve Jobs, and so you have got more time to work with it.  But there are some big announcements in the recent months that Sutent is active.   So platelet derived growth factor receptor antagonists.  They are very active-Sutent.  The other drug mTOR inhibitors are very active.  Avastin is very active.  I think there is a lot of room there yet because again these are more chronic diseases.  I think it is a very fertile field.  It is more common than people think.  The prevalence keeps going up because you can control it for longer periods of time.  Some of them are functional, so they are making some hormone and sometimes it gives you terrible diarrhea and these are phases all refractory.  I think it is a very fertile field for somebody who has got an angiogenesis inhibitor, mTOR inhibitor and some newer mechanisms.  But mostly antiangiogenics, mTOR would be a good place to start.  I think by the way the other place is the hedgehog inhibitors too.  Nobody is tackling hedgehog inhibitors in these tumors.  Why not? They think it is a small market to be frank.  That is interesting that you say that because I think about, for example, CML. That is a small market. You have no argument from me.  You just asked me why they think.  It is interesting they just haven’t gotten yet.  I totally agree with what you are saying.  I mean come on, it is what nine billion dollars for Gleevec.  It is unbelievable.  Sometimes it takes a while to sink in”.

 

  • RADIANT-3, everolimus in pancreatic NET is expected to be a key topic of conversation at EORTC Berlin (November 2010).  The study was reported to be positive in June.  This update will provide 6-months longer data.  The only contraindication we heard for an mTOR inhibitor being used in a patient with a pancreatic NET in pneumonitis from a prior reason.  We expect everolimus to become part of standard of care for pancreatic NETs.

 

“For mTOR inhibitors there are fewer absolute contraindications.  I would be I guess a little apprehensive if someone had pneumonitis from a prior reason but again I can’t think of a clear-cut reason why they wouldn’t be considered as a class of drugs in general for most people”.

 

“I don’t know if you have heard this from others, but I think that of any disease that GI oncologists treat neuroendocrine cancer is probably the one where there is the least consensus and the most options in that medical oncologists, surgical oncologists, interventional radiologists and gastroenterologists are all referred these patients.  Internally here, it is a little bit who you are referred to as to what your initial treatment course is.  That is really an important point.  So take me through – specifically I have been very focused on the pharmacotherapies.  When is a VEGF inhibitor going to be used before an mTOR inhibitor, for example? I think that will definitely be in the hands, at least as of now, for medical oncologists.  So some of these patients are considered for debulking procedures via surgical oncologists, some for debulking procedures via hepatic artery embolization or radiolabeled TheraSpheres.  So both of those considerations would be sort of secondary.  In terms of medical oncologists, yeah, I think that two emerging classes of drugs are VEGF inhibitors and the mTOR inhibitors.  But how do you choose how you sequence those? We don’t have any clear data as yet and neither of these are in an on-label use setting.  So here at Memorial all those drugs are administered in the context of clinical trials.  We don’t have an option to prescribe them again outside of clinical trials for our treatment considerations.  But I do think that both classes here are going to become established treatments for pancreas neuroendocrine cancer and I guess the RADIANT-3 data will be fully updated at the EORTC meeting and that is likely to lead to generate some further discussion on this topic”.

 

“(In pancreatic NET) mTOR inhibitors are very active”.

 

“So the RAD-001 is Novartis’, otherwise known has everolimus.  Oh that is approved for renal cell carcinoma. For renal, right, but it is also an incredible drug in neuroendocrine tumors, really incredible”.

“How do you think about targeted therapy differently if you are treating a patient with a functional or non-functional NET? At this time I do not know if that makes any difference.  Again, I don’t.  The patients who have a functional thing the hormonal aspect of it can be controlled by giving sandostatin in addition to what else you want to give.  At this time, to my knowledge the functionality has not been linked to any particular pathway, although I may like to think that mTOR inhibitors are better in that sense but I don’t have any evidence to go by proving that”.

 

 

“I think one notion is that aggressive local management improves outcome, so resection of these tumors as much as possible.  We continue to treat them with a variety of chemoembolization, radiofrequency ablation and some other type of things.  But not really – perhaps the mTOR inhibitors – is the strongest new data that we have.  But nothing really else”.

 

 

 

  • mTOR inhibition with either everolimus or with temsirolimus failed to improve outcomes in 2nd-line treatment of pancreatic ductal adenocarcinoma.  One possible reason for these failures is that because mTOR inhibitors block the pathway so much lower down and so distally they may actually might activate the feedback AKT loop, increase the AKT, and then downstream activation of other pathways; e.g. FOXO3.

 

“So the mTOR studies (in pancreatic ductal adenocarcinoma) have been negative.  I had an mTOR study on a compound which is published now, the RAD-001, and another of my colleagues here had a temsirolimus study.  So it didn’t really in the second line setting, it wasn’t efficacious and, in fact, because you inhibit the pathway so much lower down and so distally that you actually might revoke the feedback AKT loop and increase the AKT and then downstream activation of other pathways like FOXO3 and so on”.

 

 

 

Sutent (sunitinib; Pfizer)

 

  • Sunitinib has the most robust proof of efficacy of any VEGF inhibitor thus far in pancreatic  NETs.  Ph-III trial results show that median PFS was 11.4 months in the sunitinib arm vs. 5.5 months in the placebo arm (P=.0001).  Its progression-free survival was “convincing”, but Pfizer is struggling to make a compelling case for the quality-of-life data.

“The further maturation on the sunitinib data, I don’t think really anything new other than the quality of life data was presented.  There are some concerns in terms of the study conduct and interpretation, which I think are real ones.  Having said that, I think it is a drug that has demonstrated itself to have activity and certainly that progression-free survival endpoint was convincing”.

 

 

“Sutent had, I think, pretty good data at… Yes, just to prove the point.  There are many other VEGF or PDGF combinations, FGF combinations, the same kind of question I asked earlier about where in that pathway does it make most sense.  So as you look at many of these follow on antiangiogenic drugs and compare that to Sutent what is the profile going to be of an improvement on Sutent? Certainly a drug which may have less in the way of side effects.  How do you find the fatigue with Sutent? I think it is fairly prevalent.  And that is something which you would like to see less of it.  Again, hypertension, I doubt that is going to be eliminated with class of drugs.  Again, kinase inhibitors that have other kinases that they also target may also be of help.  So things like combination with FGF inhibition? Something like that, yeah.  I don’t want to put words in your mouth.  If you are thinking of other… I am just saying others but that might be one of them but I am not sure at this time which will be the better one to combine it with.  But what I am trying to say is that some of the kinase inhibitors have more than one or two or three targets in the same molecule, by the same molecule”. 

 

 

“I was still stay with anything that has got VEGF.  I don’t care what the other thing is; mTOR, as long as I got VEGF.  What the companies try to do is they try to emphasize oh it is not really a VEGF inhibitors, but it is a c-MET inhibitor.  It has got a little VEGF but c-MET.  That is exactly what Pfizer had going and then they see these responses and all of a sudden it is ALK drug.  It was really the off target.  If you are saying I had right now I would go out and buy one of these VGEF inhibitors and get it approved for patients with neuroendocrine tumors.  I don’t care what the other thing is that it does; I just care that I get VEGF.  VEGF inhibitors work in neuroendocrine”.

 

 

 

“There are some big announcements in the recent months that Sutent is active.   So platelet derived growth factor receptor antagonists.  They are very active-Sutent”.

 

 

 

Avastin (bevacizumab; Genentech); Nexavar (sorafenib; Bayer-Schering / Onyx)

 

  • Both Avastin (bevacizumab) and Nexavar (sorafenib) have positive Ph-II trials in pancreatic NET.  The key will be tolerability as part of combination therapy; the most interesting future combination being as part of an everolimus containing regimen.

“So is sunitinib going to be the best VEGF inhibitor we are going to have? No comparative data as yet.  Certainly, bevacizumab is likely to have a role and, as you know, some of the other VEGF inhibitors are entering development in neuroendocrine cancer.  I think what we do know that as a class they do have a role and are likely to become integrated in terms of future standard treatment options”.

 

 

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