Abemaciclib Verzenio for Stage IV
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Ailurophile, thanks for posting. I am very interested in these cocktails and believe they have some promise in some formulation/combination of drugs or another.
Cure-ious - I had a PI3K alteration from the get go. Despite that and many amplifications, I lasted for 15 months on hormone therapy, with Ibrance added 7 months in. I believe I would have made it longer if I took Ibrance from the beginning. And perhaps longer if I took a cocktail like this or another formulation. I tried Afinitor and it didn't reverse the cancer but did slow down the growth. I did develop an ESRI alteration after hormone therapy but most of the other alterations/amplifications remained the same between 2014 mets diagnosis via supraclacivical lymph node biopsy and 2018 liver biopsy and many treatments along the way. I had understood that although the PI3K pathway was typically activated to overcome hormone therapy, it was not necessarily that the alteration did not exist before then. It was just inactive until it wasn't.
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Hi JFL!
Exactly, this would have been the perfect trial for you to start out on!
Sequencing studies show that the mutation that activates the PI3K kinase is not found in most primary cancers, but is eventually acquired in 40% of the cases. But having the mutation does not necessarily mean PI3K, or PI3K alone, is driving the cancer- you could have other potent pro-growth oncogenes that are pushing the cells to grow (myc, beta-catenin, there are plenty including the FGFR amplification), and obviously in your case ER was one of those, until it mutated to ESR1. I don't know of any mechanism where you would have the PI3K mutation but "something else" needs to happen in order for the PI3K kinase to be active
BTW, CDK7 inhibitors work on ESR1 cancers (altho I think you already know that!).
I saw a trial with Erdafitinib in combo with I/F, is that what you are going to try?
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I had the PI3K from the get-go too, and this month marks two years on I/L. Happy for a relatively uneventful two years and my onc said I should be positive and aim for three years. Hope springs eternal. I am looking into Y90 and readying myself for a battle because it's not done for breast cancer mets in Canada.
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cure-ious, I just was on Tamaxifen for almost 5 years(after four rounds of chemo and double mastectomy) and that was a fail unfortunately. The new cancers on chest and liver grew when I was on it. I need to learn a lot in here from you guys. It seems that all of you have tons of useful information! Thank you all for sharing what you know. It makes it easier to go through this unknown path.
So from what my understanding is, the mystery pill is going to block 2 other newly discovered proteins inside the cell. Sorry I can't explain much more because I am not good at biology.
Piggy 99 Thanks for those links, very helpful
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cure-ious
I went through papers and found this:LY3023414 inhibits two proteins, PI3K and mTOR. These proteins may be involved in the growth and survival of many kinds of cancers
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Thank you for posting the precise molecule name.
Holy hell, its a PI3K/mTor DUAL inhibitor. Seems like a powerful combo.
http://www.lillyoncologypipeline.com/molecule/pi-3-k-m-tor-dual-inhibitor/overview
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EGCG is a dual inhibitor also. no idea if it could be powerful enough, or at what concentrations, but maybe worth trying until we can get our hands on that drug?
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this forum is getting interesting again. combinations is the future of verzenio, and i am glad people are starting to get into these trials. i, too, have had a pi3k mutation from the start, by the way, despite always declining the indicated anti estrogen therapy. i am currently trying to inhibit some of the pathways these newer drugs do "naturally"/cheaply/quickly/accessibly/with less side effects (yeah, right, but one can hope), with supplements and/or repurposed drugs. needless to say, the headspinning mountain of research is making me batty.
autophagy is another pathway that gets upregulated in verzenio resistance, so that's probably something to keep an eye on once one blocks mTOR or pi3k.
according to my onc, mTOR inhibitors' insulin spikes settle down after a month, and it does not cause diabetis. not so for everolimus, i believe.
i have read about oen woman doing extremely well on everolimus for years as everyone around her became resistant or died. she is on a strict medical ketogenic diet. i don't think metformin has been as helpful as keto in that class of drugs. i hate keto, for the record, but it may be wise to consider when on pi3k inhibitors.
sadly, verzenio may be quitting on me: i found out on friday that all three tumor markers i get monthly (ca 15; ca 27.29, cea) are up. so i am feverishly trying to revive verzenio by blocking its pathways of resistance. no one knows if that is possible with everolimus, say. or, rather, someone probably knows, but there is this nasty culture of keeping research mum.
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many thanks (as always) to piggy99 and cure_ious for breaking down the science for the rest of us!
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more thoughts: for those of us on monotherapy, please do NOT pause verzenio if you get overwhelmed by side effects, but lower the dose instead. in monotherapy, the verzenio-induced senescence is a false senescence, meaning the cancer cells return rapidly to cyling (and possibly rebounding) once the drug is withdrawn. this fact was first presented in san antonio in 2015. there is some synergy that happens when anti-estrogen therapy is added (beyond the estrogen blocking itself) that causes a true senescence, meaning the senescent cells stay in senescence, so pauses are probably safe/r.
but i've seen too much advice along the lines of, oh, just take a break, palbo has it every three weeks. verzenio is NOT palbo. i think it is probably safer to stay on it by lowering the dose if at all possible.
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more thoughts: adding immunotherapy (if you can access it) after the first 3-4 months of preloading and while verzenio is still having a cytotoxic effect (evidenced by dropping rather than stable tumor markers, in those of us whose tumor markers are reliable) may well be an effective combo, although the JPCE trial is being mum. (My oncologist asked them last week and got no reply.) once tumor markers become stable, which may indicate that the cytotoxic phase is over, the chances of immunotherapy succeeding probably lessen.
my thinking on supplements with anticancer effects that happen to be antioxidants is currently this: probably okay after the cytotoxic phase. verzenio's cell-killing happens via ROS (still trying to find out it its other mechanisms rely on ROS also, but if so, almost-certainly to a much lesser effect), so antioxidants may interfere with that. later, maybe not a problem and some of those supplements may even help. just my thoughts, not medical advice. and i would love to hear others chime in.
i'll probably still avoid the master-antioxidant, glutathione, and its building blocks whenever possible (they are hard to avoid), but other substances that may fit into my cancer puzzle---the aforementioned green tea extract, say--and that also happen to be antioxidants, i'll probably integrate within the next few weeks in my (probably doomed) quest to reverse the onset of verzenio resistance.
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Luce, the idea of pausing treatments has always left me uneasy as well. Some of us just need round the clock treatment (or at least, I feel I do). I do not like that MOs are so lax about it, including mine. Sorry to hear about your potential progression and hope that it all turns out to be nothing. I know you are not interested in doing hormone therapy or chemo. Have you done any genetic paneling? You may be able to find another targeted therapy based on your results. Do you have any next treatments in mind in addition to the complementary options? I hope your use of repurposed drugs and other alternatives has an impact and gets the Verzenio back on track.
Cure-ious, I will be taking erdafitinib alone in the NCI MATCH TRIAL. I would prefer to take it with something else but the trial you mentioned is not open to those who are "heavily pretreated" like me, unfortunately. I didn't find any other trials with erdafitinib at this point. My MO had looked into starting me in another MATCH trial arm a year and a half ago for another pan-FGFR inhibitor but my biopsy was botched and I was unable to get the required Caris / F1 test. I don't know what that drug was called and whether the arm was simply closed to further participants or canceled. Refresh my memory - what are the CD7 inhibitors? I have seen you post about them before but can't recall the details of this class of drug at the moment.
Lucia, good luck getting Y90. Is it used for other cancers in Canada such as colon and liver?
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JFL, thanks, I'll keep everyone posted. Liver cancer yes, colon I'm not sure.
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Ailuro- In retrospect, it is probably a good thing you were on tamoxifen since it works completely differently from aromatase inhibitors (like letroole/Femara) and so it means you should get the full benefit of the Ibrance-Femara combo. Plus your doc is going above and beyond by putting you on the newest drug in the mTORC1/PI3K pathway. Tamoxifen competes with estrogen for binding to the estrogen receptor, whereas letrozole/femara block the enzyme aromatase, which is used to make what little bit of residual estrogen your body can make when the ovaries are shut off.
Please let us know about your experience with this new combo!! Most of us will go onto an mTORC1/Pi3K inhibitor at some point, and there is just one FDA approved drug, hopefully another one coming this summer, and everything else is available only in a trial. Also if you can ask them if there have seen others having had great success so far on that combo...
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Luce,
As you know, immunotherapies synergize with all sorts of treatments that blast apart cancer cells and introduce some of the cancer to the bloodstream where the immune system can prime off of it, including chemo or radiation. Verzenio and Ibrance synergize with immunotherapy by increasing tumor infiltrating lymphocytes to attack the tumor, but there are other compounds that can do this as well. Two drugs you can consider are the CDK7, CDK12 inhibitors and Alisertib (Aurora A kinase), the latter of which is said to be increased as a mechanism by which the cancer can escape mTORC1/PI3K inhibitors, and may be a resistance mechanism for other drugs as well. The question is how do we know what might be driving the cancer after progression? I guess sequencing for new changes?
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Cure_ious: it seems verzenio may enhance immunotherapy for a number of reasons. had i read the paper below while i was trying to decide whether or not to add keytruda, i probably would have gone for it. it explains the synergy that previously had been too vague to me to jump. i only just found it two months ago, though:
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JFL, It seems like trials either require that one already be heavily pre-treated (usually for phase 1), and then switch to exclude anyone who has seen much in the way of treatment (for phase 2), so it is hard to keep track. It would help if these trials progressed more quickly, but I guess if the drug is any good, then the trial will take a long time before enough people have progressed. At least you have a great option in Erdafitinib, and managing the side effects are probably/hopefully relatively worked out from people who have taken the drug for other cancers?
Circling back to CDK7 and CDK12. The main group at the moment working to bring them to clinic in the US is Syros in Boston (another group has a drug and is testing in the UK).
CDK7 shows great activity against ER-positive and triple-negative breast cancer (also ovarian and prostate). CDK7 works well on cancers that have become resistant to Ibrance, and also on cancers with the ESR mutation. I think the drug being tested now in trial is injected, but there is a pill version that is working its way to clinical trial.
Here is the current trial (SY-1365 is the CDK7 inhibitor, is tested with fulvestrant), which is offered as a secondline treatment. It requires progression on Ibrance-Femara.
https://clinicaltrials.gov/ct2/show/NCT03134638
This trial will be completed next year, so updated results should be released this year. Hopefully the phase 2/3 versions of this drug are more inclusive (ie do not exclude prior chemo), and use the pill form of the drug...
Another company also has a trial going on in the UK that also tests a CDK7 inhibitor (pill form).
CDK12 is a great target for an inhibitor, but the drug is not into clinic yet. Some of the drugs inhibit both CDK7 and CDK12, and its possible that the CDK7 inhibitor tried here also blocks CDK12, they are closely related kinases. A suprising finding was published in Cell last year, showing that if a cancer has a CDK12 mutation (about 5% of breast, ovarian and prostate cancers have CDK12 mutations), then it makes the cancer sensitive to immunotherapy. They went back to prostate trials and identified four prostate cancer patients who had tried responded well to immunotherapy- and amazingly, three of those four also had the CDK12 mutation). For this reason, a clinical trial opened last fall for any type of cancer that has a CDK12 mutation, because the thought is now that those cancers will respond to immunotherapy.
But for the 95% of us who don't have a CDK12 mutation, the hope is that a CDK12 inhibitor will not only block the growth of the cancer, but also make the cancer respond to immunotherapy.
CDK12 is also critical for BRCA expression, so people taking a CDK12 inhibitor should also become senstive to PARP inhibitor; therefore CDK12-immunotherapy and CDK12-PARP inhibitor combos may be tested. But all of that is assuming the CDK12 inhibitor does not have bad side effects, so it will be tested alone first, and therefore obviously all of this will take some time. Still, its just good to know that more promising drugs are coming along..
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i have no idea what i am going to do next. nothing, maybe. i am tired: tired of the research, and tired of the side effects of the drugs that are being offered to me, and that only have a small chance i'll respond to them, and only a short response window if i do. still trying to "fix" some of the mechanisms of resistance, but fully aware that i am unlikely to succeed, especially without actual hands-on help from, say, an integrative oncologist who is on top of all this research. i don't know of any.
i could get a liquid or a tissue biopsy. my choice. i am more inclined toward liquid because of seeding from biopsies. if tissue, i'll insist on prescription NSAIDs before/during/after.
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CDK 2 is also implicated in resistance. and my onc says PARP inhibitors are being looked at as possible combo. oh, i saw you just said that!
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Luce,
Here is what Syros released last year, so hopefully there will be an update at the next AACR meeting at the end of March.
https://ir.syros.com/press-releases/detail/31/syro...
how about that Keytruda-EP4 inhibitor trial?
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Cure_ious: sounds interesting, thanks, but the press release is dated april 2017. i'll see if i can find any updates on that, though. generally, i am probably not good trial material. i was way too sick to qualify before verzenio kicked in. should it truly be quitting on me now, i'll be up s***'* creek again in no time: in monotherapy, cancer looks to rebound rapidly after cessation of verzenio treatment. so meds must already be far enough along in trials to potentially be available via compassionate care.
regarding immunotherapy (in general) : a fecal implant from a responder might be wise. they are actually looking into that at the NIH now. there was a long paper in lancet last month about the microbiome. it used thousands of words to say,'it's obviously crucially important but we don't have any idea yet what to do with that realization.' i have been on probiotics for years now, and was eating fermented foods long before i had cancer (and even more after), but we still have little idea of our currents manipulations and strains help much. the current approach (bifidobacteria!), primitive as it is, will probably be still part of the future picture but it's all so much more complex.
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Agreed, it has to be something from what is available now, or Alpelisib which is coming? Hopefully you don't have to change!
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i probably have mentioned this before, but while looking at how to elicit a durable response, or encourage verzenio's immunotherapy activity or compatibility, let's keep NKs in mind. NKs have recently (and somewhat surprisingly, according to the author of the paper) been found to be the cells that kill senescent cells (those cells that were put into senescence by verzenio). it's not necessarily their numbers but how active they are. so if anyone has any ideas, please let me know.
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OK, but Luce, how about just one more trial (for tonite!)?
Because you did not yet go trying anti-estrogens, I bet they would take you in this trial.
And they have a site right there in Portland!
This is Morpheus, testing the best of the best immunotherapy (Atezo) in combination with various other inhibitors
https://clinicaltrials.gov/ct2/show/study/NCT03280...
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I received confirmation that my trial drug, erdafitinib, is with my MO and will be ready for me to start on Friday! Huge relief. I was originally told by my MO that the whole process to enter the trial would take two weeks. That was at the beginning of December. Friday is the absolute earliest I can start the trial medication based on when the trial paperwork was finally approved and I didn't want to wait a day longer than that, given I am not a fan of washout periods for myself.
Cure-ious, my "basket" in the NCI MATCH trial is a Phase 2, single arm.
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Cure_ious: Thanks, but is that link you posted correct? It links to a lymphoma trial last updated in 2012. When I google Morpheus and Atezo, I am not seeing anything in Portland. Could you please repost the link? Thanks!
JKL: Congrats! And much success!
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Hi Luce,
The link I put up there is fine! I'll post it again below. The trial is currently recruiting in Portland, so you could go get all your questions answered in person- the trial started in 2017.
I like this trial, it would be a good one for any of us!.
Atezolizumab (Tecentriq) is the immunotherapy drug they are using. Here are the arms:
1) Atezo plus Enitinostat (HDAC inhibitor)
2) Atezo plus Faslodex
3) Atezo plus Ipatisertib (PI3K inhibitor)
4) Atezo plus Faslodex plus Ipatisertib (yeah, baby, load me up!!)
5) Atezo plus Bevacizumab (VEGF/angiogenesis inhibitor)
Those who progress on the trial are then offered Atezo plus Bevacizumab plus Faslodex (or an AI)
This trial has lots of locations, UCLA, UCSF, Memorial Sloan Kettering, Tacoma, Houston, Ohio, etc..
The site in Portland is at the Providence Cancer Center.
Here is the link again: https://clinicaltrials.gov/ct2/show/study/NCT03280...
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Congrats JFL- Onwards!!
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Also, Luce, for background:
EP4 strongly inhibits cell killing by NK cells and cytotoxic T lymphocytes, which is why adding on an EP4 inhibitor (or a strong COX2 inhibitor like Celebrex) could augment the anti-tumor immune response to immunotherapy.
Also in the above trial, Bevacizumab has been shown to prevent T-cell "exhaustion", which is why some immunotherapies start to work but then shut down, and also opens up the tumor vasculature to allow infiltration by immune cells, so it has anti-tumor activity and also a positive effect on immune cell function.
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cure_ious: thanks for reposting! The original link still stubbornly routes me to a mantle cell lymphoma trial from a decade ago! The new link works.
Thanks also for scientific info on trial.
I’d been looking into Entinostat before. Need to go back and see if that combo might make sense for me.
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