This is newsworthy because I expect trials like this to fail in GBM, and I'm very biased against single agent kinase inhibitor trials for GBM, but this one showed regorafenib to actually be superior to lomustine in a randomized phase 2 trial.
Can I just say, it is my impression that larger doses of chemotherapy, achieve better results, in terms of progression. Typically toxicity is the limiting factor, so lomustine is taken once every six weeks, whereas TMZ once every 4 weeks. The dosage with TMZ is neither here or there, I was being prescribed 400mg/day, other times 300mg/day but nothing had ever changed and my blood were always the same (good), just that the oncologist calculated wrongly or differently a couple of times. I think you can take more if you can, as long as your bloods are good. On the same dose sometimes I spent 2-3 days in bed (during the on times) and other times I was at the seaside swimming. So I think if I had more TMZ I could have taken more, or for a few more days. It seems those alternate protocols end up giving you more TMZ/28 days overall, much more. If I were to do this again I might add a few more days to the 5/28 or maybe at a reduced dose for the extra days. Back on this trial we see worse side effects for the Regorafenib group - maybe then they took "more" chemo than the lomustine group and thus achieved better results ?
Regorafenib has a completely different mechanism of action versus lomustine or TMZ or other genotoxic chemos. The fact that it worked at all is impressive, because I've seen failure of trial after trial testing single agent kinase inhibitors. This is why I posted it, I was surprised to see any kinase inhibitor performing better than a conventional chemo, regardless of the dose.
The doses of both drugs used in this trial are the standard doses approved by the FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf
Not necessarily, because it's impossible to predict how two drugs will interact with each other until they actually try it clinically. But I do expect that they will try regorafenib + TMZ for newly diagnosed GBM on the basis of this phase 2 trial.
The 2 patients in the regorafenib group with IDH1 mutation and 2 more MGMT methylated patients in the regorafenib group versus lomustine group would be presumed to have better prognosis, but not enough to account for the large differences in OS at 12 months in my opinion.
The survival differences were highly statistically significant between groups (HR 0.50, p=0.0009). They didn't provide a statistical analysis of prognostic factors between groups, but the differences didn't seem to be great, a matter of only a few percent.
In any case I expect there will be a larger phase 3 trial on the basis of this trial, to provide more definitive proof.
But you have noticed the much increased toxicity? Also as regorafenib acts completely differently, it is not a substitute for CCNU. Toxicities aside, they would work synergistically. Is it not a bit like Avastin?
Yes I saw the toxicity data. More grade 3-4 adverse events with regorafenib, but drug related side-effects leading to dose reductions occurred in 17% in the regorafenib arm and 18% in the lomustine arm, virtually the same number of dose reductions.
On your second point, I totally agree. I expect to see a phase 3 trial combining regorafenib with standard TMZ chemo for newly diagnosed GBM.
Regorafenib is similar to Avastin in the sense of targeting VEGF/VEGFR axis, but it is a multi-kinase inhibitor and has broader activity than Avastin. Avastin binds specifically to VEGF-A which interacts with VEGF receptors 1 and 2.
Regorafenib inhibits VEGF receptors 1,2,3 as well as PDGF receptor beta, and RAF-1 and some others. So it has potential to be active even in tumors that are not primarily VEGF-A dependent where Avastin would be ineffective.
It would be possible to try it, but there's no evidence of how effective it would be. There are not many drugs that have been effective after failure on Avastin.
Stephen, do you think Regorafenib would inhibit a patient for other future trials, like Avastin did? Surgery, at this juncture, didn't work out for my husband. Perhaps later. Thanks, Candy
I think the only sorts of trials that regorafenib would make a person ineligible for would be trials testing other antiangiogenic therapies (targeting VEGR/VEGFR) or other RAF inhibitors.
My husband has recurrence with possibly 2 new tumors. I posted his scenario under "Tumor Monorail". If he ends out not being a candidate for surgery this time, his NO wants him to try the Regorafenib. It's expensive and I don't think insurance will cover it yet. However, he says he thinks they will because of this Italian Trial for GBM. Right now trying to get evaluated to see if surgery is possible.
If Regorafenib doesn't interest us, then NO recommends trying VP-16. Do you know much about that Stephen? I don't see anything on site here about it. Also the "Tumor Monorail " looks interesting but not available. My daughter is also wanting us to ask about NeuroBlate device which was recalled but she thinks now on the market. What do you know about that Stephen? Thanks, Candy
VP-16 is etoposide. I don't have a lot of confidence in this. There's a reason they don't use this until the standard chemotherapies have failed. NeuroBlate can be used especially for tumors that are inaccessible to conventional surgery.
The old Monteris website used to show a list of locations where NeuroBlate was available: Brain surgeons using the NeuroBlate technology are currently located in Cleveland OH, Philadelphia PA, New Haven CT, Richmond VA, Dayton OH, Winston-Salem NC, Charlotte NC, St Louis MO, Rochester MN, Atlanta GA, Jacksonville FL, Winter Park FL, Orlando FL, Kansas City MO, Kansas City KS, Dallas TX, Houston TX, San Antonio TX, San Diego CA, and Vancouver BC (Canada).
Now they just have you type in location and email address, and will presumably tell you the closest location. https://www.monteris.com/find-a-physician/
Can I just say, it is my impression that larger doses of chemotherapy, achieve better results, in terms of progression. Typically toxicity is the limiting factor, so lomustine is taken once every six weeks, whereas TMZ once every 4 weeks. The dosage with TMZ is neither here or there, I was being prescribed 400mg/day, other times 300mg/day but nothing had ever changed and my blood were always the same (good), just that the oncologist calculated wrongly or differently a couple of times. I think you can take more if you can, as long as your bloods are good. On the same dose sometimes I spent 2-3 days in bed (during the on times) and other times I was at the seaside swimming. So I think if I had more TMZ I could have taken more, or for a few more days. It seems those alternate protocols end up giving you more TMZ/28 days overall, much more. If I were to do this again I might add a few more days to the 5/28 or maybe at a reduced dose for the extra days. Back on this trial we see worse side effects for the Regorafenib group - maybe then they took "more" chemo than the lomustine group and thus achieved better results ?
ReplyDeleteRegorafenib has a completely different mechanism of action versus lomustine or TMZ or other genotoxic chemos. The fact that it worked at all is impressive, because I've seen failure of trial after trial testing single agent kinase inhibitors. This is why I posted it, I was surprised to see any kinase inhibitor performing better than a conventional chemo, regardless of the dose.
DeleteThe doses of both drugs used in this trial are the standard doses approved by the FDA.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf
Stephen, does that mean Regorafenib + TMZ will be even better than
ReplyDeleteCCNU+TMZ
Not necessarily, because it's impossible to predict how two drugs will interact with each other until they actually try it clinically. But I do expect that they will try regorafenib + TMZ for newly diagnosed GBM on the basis of this phase 2 trial.
DeleteIncidentally, the regorafenib group in this clinical trial was slightly better in all characteristics.
ReplyDeleteThe 2 patients in the regorafenib group with IDH1 mutation and 2 more MGMT methylated patients in the regorafenib group versus lomustine group would be presumed to have better prognosis, but not enough to account for the large differences in OS at 12 months in my opinion.
DeleteThe survival differences were highly statistically significant between groups (HR 0.50, p=0.0009). They didn't provide a statistical analysis of prognostic factors between groups, but the differences didn't seem to be great, a matter of only a few percent.
In any case I expect there will be a larger phase 3 trial on the basis of this trial, to provide more definitive proof.
But you have noticed the much increased toxicity? Also as regorafenib acts completely differently, it is not a substitute for CCNU. Toxicities aside, they would work synergistically. Is it not a bit like Avastin?
ReplyDeleteYes I saw the toxicity data. More grade 3-4 adverse events with regorafenib, but drug related side-effects leading to dose reductions occurred in 17% in the regorafenib arm and 18% in the lomustine arm, virtually the same number of dose reductions.
ReplyDeleteOn your second point, I totally agree. I expect to see a phase 3 trial combining regorafenib with standard TMZ chemo for newly diagnosed GBM.
Regorafenib is similar to Avastin in the sense of targeting VEGF/VEGFR axis, but it is a multi-kinase inhibitor and has broader activity than Avastin. Avastin binds specifically to VEGF-A which interacts with VEGF receptors 1 and 2.
ReplyDeleteRegorafenib inhibits VEGF receptors 1,2,3 as well as PDGF receptor beta, and RAF-1 and some others. So it has potential to be active even in tumors that are not primarily VEGF-A dependent where Avastin would be ineffective.
It is interesting, is it possible to think about regorafenib after Avastin's failure?
DeleteIt would be possible to try it, but there's no evidence of how effective it would be. There are not many drugs that have been effective after failure on Avastin.
DeleteStephen, do you think Regorafenib would inhibit a patient for other future trials, like Avastin did?
DeleteSurgery, at this juncture, didn't work out for my husband. Perhaps later.
Thanks,
Candy
I think the only sorts of trials that regorafenib would make a person ineligible for would be trials testing other antiangiogenic therapies (targeting VEGR/VEGFR) or other RAF inhibitors.
DeleteMy husband has recurrence with possibly 2 new tumors. I posted his scenario under "Tumor Monorail". If he ends out not being a candidate for surgery this time, his NO wants him to try the Regorafenib. It's expensive and I don't think insurance will cover it yet. However, he says he thinks they will because of this Italian Trial for GBM. Right now trying to get evaluated to see if surgery is possible.
ReplyDeleteIf Regorafenib doesn't interest us, then NO recommends trying VP-16. Do you know much about that Stephen? I don't see anything on site here about it. Also the "Tumor Monorail " looks interesting but not available. My daughter is also wanting us to ask about NeuroBlate device which was recalled but she thinks now on the market. What do you know about that Stephen?
ReplyDeleteThanks,
Candy
VP-16 is etoposide. I don't have a lot of confidence in this. There's a reason they don't use this until the standard chemotherapies have failed. NeuroBlate can be used especially for tumors that are inaccessible to conventional surgery.
DeleteThe old Monteris website used to show a list of locations where NeuroBlate was available:
Brain surgeons using the NeuroBlate technology are currently located in Cleveland OH, Philadelphia PA, New Haven CT, Richmond VA, Dayton OH, Winston-Salem NC, Charlotte NC, St Louis MO, Rochester MN, Atlanta GA, Jacksonville FL, Winter Park FL, Orlando FL, Kansas City MO, Kansas City KS, Dallas TX, Houston TX, San Antonio TX, San Diego CA, and Vancouver BC (Canada).
Now they just have you type in location and email address, and will presumably tell you the closest location.
https://www.monteris.com/find-a-physician/