Are you currently (or have you been) in a Clinical Trial?
Comments
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BlueGirl, It would be helpful to know what you have tried thus far, and how long the drugs have worked?
I assume you are talking about the phase 1 SERENA-1 trial? The advantage here is you would know exactly what you are getting, and of course that they are combining the SERD with Ibrance, Everolimus, Abemaciclib or Capivasertib.
One thing to understand is that at this point, pharma's goals are just to show that SERDs are as good as Faslodex, not necessarily better. So if one had progressed on a Faslodex-Ibrance combo, for example, you would not want to pick Ibrance- similarly, if you also progressed on Everolimus-Exemestane, you'd want to choose Abemaciclib or Capivasertib.
Either would be good options. Abemaciclib is significantly stronger than Ibrance, and hits additional kinases that mean it functions also a bit differently. But it would help to know if the cancer did response to Ibrance previously, if not it might be better to go with Capivasertib, an inhibitor of AKT kinase An earlier trial of Capivasertib with Faslodex on endocrine-resistant breast cancer showed a median progression-free survival for the combo of 10·3 months (95% CI 5·0–13·2) versus 4·8 months (3·1–7·7) for Faslodex alone.
Another trial to consider is the one Dee is on, for ARV-471- that drug might be better than Faslodex because it does degrade a lot more of the estrogen receptor in cell culture studies, however we are still waiting to see how well it works in people. Pfizer (maker of Ibrance) just paid 2.3B for that drug, even though they already owned a SERD and a SERCA, indicating that they might have seen some exciting data for ARV-471....
https://clinicaltrials.gov/ct2/show/NCT04072952
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BlueGirl, It would be helpful to know what you have tried thus far, and how long the drugs have worked?
I assume you are talking about the phase 1 SERENA-1 trial? The advantage here is you would know exactly what you are getting, and of course that they are combining the SERD with Ibrance, Everolimus, Abemaciclib or Capivasertib.
One thing to understand is that at this point, pharma's goals are just to show that SERDs are as good as Faslodex, not necessarily better. So if one had progressed on a Faslodex-Ibrance combo, for example, you would not want to pick Ibrance- similarly, if you also progressed on Everolimus-Exemestane, you'd want to choose Abemaciclib or Capivasertib.
Either would be good options at that point. Abemaciclib is significantly stronger than Ibrance, and hits additional kinases that mean it functions also a bit differently. But it would help to know if the cancer did response to Ibrance previously, if not it might be better to go with Capivasertib, an inhibitor of AKT kinase An earlier trial of Capivasertib with Faslodex on endocrine-resistant breast cancer showed a median progression-free survival for the combo of 10·3 months (95% CI 5·0–13·2) versus 4·8 months (3·1–7·7) for Faslodex alone.
Another trial to consider is the one Dee is on, for ARV-471- that drug might be better than Faslodex because it does degrade a lot more of the estrogen receptor in cell culture studies, however we are still waiting on trial results to see if its the case in people. Pfizer (maker of Ibrance) just paid 2.3B for that drug, even though they already owned a SERD and a SERCA, indicating that they have seen some pretty positive data....
https://clinicaltrials.gov/ct2/show/NCT04072952
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Cure-ious,
What's your take on whether or not Enhertu will be a possibility for those of us who have ERRB2 mutations? I don't see anything in the write-ups about that, but man, that would be something else.
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Cure-ious - what have I tried......... A long list since it is the 3rd episode of BC, twice left, now right. MO thinks each one has been a "new" cancer. Which options is the best? He thought this one, with oral fulvestrant I think it was 2 years into trial, so far positive results with minimal SEs. Fulvestrant, not a new drug, but it would be much more easily administered orally, and it sounds as if it might work better than injections. I have not tried fulvestrant. He might have only suggested ones he is involved with ? I will look at the ARV-471 you mentioned. Logistics will be an issue with any clinical trial since none are near-by.
This is the one that was recommended. https://clinicaltrials.gov/ct2/show/NCT03616587?te...
He did discuss two other trials, one with H3B-6545-A001-101, https://clinicaltrials.gov/ct2/show/NCT03250676?te...
The third one, my notes not good enought to find it, and was not recommended, described as a "poison" which can bind to the CD166 receptor on the cancer, It might be this one. https://clinicaltrials.gov/ct2/show/NCT04596150?term=CD166&recrs=ab&cond=Breast+Cancer&draw=2&rank=1
2009 - Left. Lumpectomy, radiation, tamoxifen 5 years
2016 - Left again. chemo, Bi-lateral (my choice), 2017 anastrozole initially, joint issues immediate switch to tamoxifen
2019 -Right, Ibrance, Arimidex....... became metastatic 12/2020
2021 - Exemestane, Everolimus (Afinitor) start Feb, 18 radiation treatments April/May
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BlueGirl, Since you have not yet been on Faslodex, that trial is great as would be some kind of faslodex combination if you can't get into the trial- the thing to keep in mind is after progression on Faslodex or a SERD you still might get a long run on the ARV-471, esp in combination, since their numbers indicate a really good PFS for those who already progressed on I-F...
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Nkb, Indeed Syros came out with very good CDK7 inhibitor results today, the thing is they are behind the UK-Carrick CDK7 inhibitor because they had to ditch their first CDK7 drug because it was IV whereas Carrick had the oral form, now both companies have CDK7i in pill form- the Syros trial was a phase 1 with all-solid tumors, and the results they are discussing are in pancreatic and colon cancer- because the FDA fast-tracked this for breast cancer last month the numbers must look good for breast as well, which is awesome! We might get another totally different type of CDKinhibitor to add in to the mix for endocrine resistance. It was first studied for TNBC
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BevJen,
Enhertu is the big headline out of ESMO 2021, as it now is moving into secondline for HER2-positive cancers with a much longer PFS, something like 24 months! Amazing, clearly its a great drug.
Enhertu is used for lung cancers that have HER2 mutations, it should also work for MBC. ERBB2 mutations often arise upon progression from I-F, and if you inhibit the HER2 then the cancer becomes sensitive to endocrine therapy again.
I wonder if the HER2/ERBB2-mutant cancers are not also included in the ongoing trial for HER2-low, because the mutation would give rise to increased HER2 kinase activity, should be same result as what happens in cancers with modestly-amplified HER2 gene. It depends on whether the assays they use for the clinical trial are looking at the level of expression of the HER2 gene- versus if they look at overall HER2 kinase activity in the cancer- you could send them an email to ask about that, but you are right, pharma have not yet reached out specifically to HER2 mutant MBC, probably because the numbers are not so high
https://clinicaltrials.gov/ct2/show/NCT04494425
BTW, the famous Jackson Labs have started screens to figure out which pathways most strongly needed for growth of ERBB2-mutant MBC and the effects of different specific gene variants:
https://www.prnewswire.com/news-releases/heligenic...
https://www.genomeweb.com/cancer/heligenics-jackso...
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Oh, wait- I do think that trial just looks at gene amplification.
Here is a phase 1 trial combining a HER2-directed ADC with an ATM kinase inhibitor for MBC and other cancers with ERBB2 mutation and for HER2-positive tumors
https://clinicaltrials.gov/ct2/show/NCT04704661
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BGRS- Am I correct- You have never been on chemo or faslodex?
you seem to be a great clinical trial candidate for the AZD9883 SERENA-1Study. It requires a 6 month washout from faslodex and 4 for tamoxifen. Now would be the right time for this trial. The drug has gone to phase 3 randomized on other trials so it has potential.
How close are you to Nashville? Please consider SCRI and ask specifically for Dr Hamilton. I believe there are many trials here that you would qualify for including the ones you listed. My experience is very good. The trials pay for hotel and some pay for travel.
Dee
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BevJen- Here is the relevant trial, it is phase two testing Enhertu for HER2 activating mutations in any kind of solid tumor, including breast. You can have had prior anti-HER2 drugs, but have to have progressed from secondline treatment, no prior chemo required. This trial also has international locations..
https://clinicaltrials.gov/ct2/show/NCT04639219
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BGRS - I was on the AZD9833 (Serena) trial. It gave me 8months before progression. I was pleased with the trial since I had been on Faslodex previously. I did the arm with Everolimus. Everolimus was hard for me especially while I had covid, so I stopped it after 5 months. They allowed me to remain on the trial and take the oral SERD alone. The oral SERD was easy. ~Kar
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Thank you for the replies on my questions. Looking at the DR notes who is running the trial, he is recommending I stay on current Exemestane/Everolimus unless there is progression. I guess the CT end of week should provide that. Why is it that staying on current untill progression is the recommended course of action, when there might be something better. Faslodex, not new, but the trail test an oral version, which is thought to work better as well as easier to administer. Chemo..... I did a 2 ingredient cocktail in 2016, which did not shrink the tumor by much, so I am not eager to try it again, especially since it has become MBC since then.
Is it likely they would only discuss/know about trials in their clinic?
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hi all,
Finally got the results from CT scan. My liver tumours are shrinking, bone mets are stable & tumour markers are falling. I'm on a Canadian trial funded by Stand up to Cancer using tomivosertib & Abraxane. The trial is actually for Paclitaxel but I had 4 anaphylatic reactions to it, so finally put me on Abraxane. MO has dose reduced me & changed to one week on, one week off because of severe SOB, so hopefully it will still work for me.
cheers, dee
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Dee, that's wonderful news!! So, the SEs are mostly from Abraxane? Do you have issues with the tomivosertib? And how long have you been in the trial?
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Dee - So glad to hear your good news and that they have gotten the dosage and schedule under control! Excellent!
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GG26- whoopee! Great news after all your reactions
BGRS- no trial wants to mess with a systemic drug that is working to shrink tumors or give stable disease. Stay on a drug until it stops working because it should buy you more time. Most trials want you to be “refractory” or resistant to current treatment. SCRI in Nashville will not assess you for trials outside their clinic. They have patients who fly in and some who drive 6-9 hours to get treatment.
The other Dee
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thanks all!
Cure-ious, yes, the SE's appear to be mainly from Abraxane as we stopped the trial drug for 3 weeks and none of the SE's went away which is why the dose reduction & change in schedule. I did have problems with the tomivosertib after about a month, getting a rash, very dry mouth and headaches so a dose reduction was done from I00mg 2x per day to 1x. I am just beginning week 21, fingers crossed for many more weeks. Next scan November 2, awaiting yesterdays TM's number.
cheers, dee
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Cure-ious,
Sorry to reply so late to your suggestion to ask Hope about getting on a PARP inhibitor. I had a VATS procedure to close up the pleural space that kept filling up with fluid. Recovery a lot harder than I expected but the procedure was successful!
In my Caris report, it does mention that a PARP inhibitor may work since I have a high LOH. I asked Hope about it and she said PARP inhibitors were unlikely to work for me.
I'm excited about the news about two new CDK 7 inhibitors. Enhertu is also a possibility for me though I've already been on Trodelvy and HER2 equivocal. ARV-471 looks promising but the closest site is at UCLA. Waiting for more trials of Enobosarm. UCSF is supposed to start an Enobosarm trial this Fall but it will likely not be open to heavily-treated patients.
For now, I started on old-school Gem/Carbo at a low dosage since I'm still weak from the lung procedure. Hoping it will buy me time while waiting for more trials.
Hugs, Susan
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Susan
Glad to here you are recovering. Hopefully you will feel like repeating your profile picture soon! 😉
Gem/carb is a good combo. When will you scan again?
Dee
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Susan, finding better biomarkers for PARPi is a hot research topic right now, and they know that pathways are involved other than the ones we already know about, ie BRCA mutation or DNA repair defect, so the hunt is on for a better test. But of course until then, MOs have no reason to use them off-label.
Enhertu is potentially great news for those who are HER2-low or presumably also HER2-mutant, the chart below is from a trial for HER2-positive cancers that tracks PFS, look how much better it did (dark blue line) compared to the standard Kadcycla HER2 treatment (gray line)...
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Thanks Dee!
I had scans at the end of August so probably won't have them until the end of November.
Hoping ARV-471 will continue to work for you for a long time.
Hugs, Susan
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Cure-ious- did the Enhertu study break out results for Her2 low from Her2 + ?
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Nope, it was just data for HER2, don't know if that trial even included any HER2-low cancers
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thanks, cure-ious. I think there are six different studies going on right now.
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A recent paper in Cell identified the enzyme NMNAT-2 as massively overexpressed in ovarian cancers, and showed that it works with PARP16 to control protein translation- those cancers were effectively killed by inhibiting PARP16, in this case using drugs that are not yet in clinical trials.
https://sci-hub.se/https
/doi.org/10.1016/j.cell.2021.07.005While not discussed explicitly in this paper, NMNAT-2 levels can be high in breast and other cancers, and in fact the best of the current PARP inhibitors, Talazoparib, has been reported to work so well because it, unlike the others, can inhibit both PARP1 and PARP16.
So in the future we may not only get new biomarkers to predict who could benefit from a PARPi, but also new inhibitors that have been specifically designed to hit PARP16. And note that this has nothing to do with BRCA mutations or DNA repair defects, it is a separate pathway that is very sensitive to PARP16 inhibitors.
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Scientists at UCSF report in the latest CELL the discovery of a new function for the estrogen receptor in cancer. It is well established that ER acts in the nucleus to bind specific sites in DNA that control expression of certain genes, and that drugs like AIs and tamoxifen block this activity of the ER. The new data shows that ER also binds to the mRNAs made from some of these genes and also affects their translation into protein in the cytoplasm. The existing ER inhibitor drugs do not block this newly discovered activity of the ER, and the authors argue this effect of ER may help other pathways to control cancer cell growth to direct endocrine resistance.
https://www.sciencedaily.com/releases/2021/09/2109...
Of course ER degraders like Faslodex and SERDs would effectively block ALL of the activities of the ER. Nevertheless, the discovery opens up approaches to screen for drugs that block the protein translation activity of the ER, and indeed they speculate that protein translation inhibitors like the Tomivosertib that Dee is taking in her clinical trial may be acting on this step...
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A paper in Nature Comm looks at ER-positive cancers that acquire expression of HER2, and because of that become resistant to endocrine therapy. What happens in these cells is that when they are exposed to endocrine therapy, they lose expression of two mismatch DNA repair genes, MLH1 and PMS2 (also called MutL), which activates HER2 and that then gives rise to endocrine resistance. Treating these cells with HER2 inhibitors restores sensitivity to anti-estrogen therapy. The authors propose screening expression of these genes (using assays already in use for colorectal cancers) to better predict who should be treated with anti-HER2 drugs along with endocrine therapy. The data also help define the signaling changes that create HER2-low cancers.
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I have the AKT mutation and am considering the TAPISTRY trial so I can access Ipatasertib. I’m wondering if anyone has any experience they would be willing to share with the trial or with Ipatasertib itself.
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Just wondering if there has been any information about Covid Vaccine affecting tumor markers (CA15-3 for me). My markers have risen dramatically with nothing showing on the PET scan, started around the time of first vaccination in February. I don't know enough science to understand why there should be or not be a connection but the thought popped into my head as I try to figure out what can cause markers to rise dramatically other than cancer. Could just be coincidence.
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Lisa, Apparently Ipatasertib faltered in some other trials, like for TNBC and in combination with chemo for HR-positive MBC,and the trial you are considering is the last one standing- however Capivasertib, is getting good press as leading among the AKT inhibitors- here is a phase 3 trial where it is combined with faslodex and CDK4,6i that just started this spring, however they are excluding anyone with prior CDK4,6i so nowadays that would mean they are looking for firstline
https://clinicaltrials.gov/ct2/show/NCT04862663#co...
There is also a phase 3 where Capivasertib is being combined with Faslodex (no CDK4,6i) and in this trial you cannot have had prior faslodex or prior AKT or mTOR inhibitor (like everolimus)
https://clinicaltrials.gov/ct2/show/NCT04305496
OTOH, maybe Ipatasertib will show benefit in the combination trial you are considering...
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