Are you currently (or have you been) in a Clinical Trial?
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Emac- this last test I had was a tempest blood test.
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emac- So, for a PI3KCA mutation, Piqray is a good drug for bone-only disease (Patients with bone-only lesions (n = 22) achieved a median PFS of 16.6 vs 5.6 mos for patients without bone-only lesions, tho the drug is hard due to the blood sugar issue and also rash. The AKT kinase is elevated in PI3KCA cancers, and Capivasertib (AKT inhibitor) has been submitted to FDA for approval (PFS was about 10 months, altho it didn't matter if the cancers had high AKT or not).
Among chemo options, give a thought to Enhertu, as some MOs are pushing to move it ahead of Xeloda, given that the PFS is relatively high (10 mos for those who had prior CDK4,6i+endocrine therapy).
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Cure - isn't there a next gen for Piqray in the testing stages now? I feel like I read that somewhere.
Going to IV chemo from CDK 4/6 seems a bit extreme though from a quality of life standpoint!
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Sondra- Well I only know RLY-2608 PI3KCA-alpha) and Capivasertib (Akt), both still in trials…and taselisib, apparently a super toxic drug. These options kinda suck…
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There are several kinase inhibitors in trials for instance RLY 5836, LOXO 783, TOS 358 all in phase I, also STX 478 and Inavolisib. Learning of my PI3KCA mutation in late 2022, I inquired at UW-Madison about their options but stuck with PIQRAY (plus Jardiance & Januvia) until earlier this month. It was stopped so I could join a KEYTRUDA/fulvestrant study.
I’m told the last spot of 47 was held for me. I’ll have a liver biopsy then get the 1st infusion. FoundationOne showed a qualifying level of PDL1. Otherwise, a triple negative diagnosis is required to receive pembrolizumab. A port is planned for subsequent treatments which are every 3 weeks. The poor veins in my “lymphedema free” arm finally get some relief!
Since IV access will already be there, it’s possible Enhertu could become my 4th line of metastatic therapy at some point. I had a good 4 year run on Verzenio and had hoped alpelisib would be helpful. It kept my tumor marker numbers stable however hepatic MRIs with Eovist contrast kept showing advancing disease. So, on to the next thing…
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Vinrph,
Is it a new result (the PDL1) or were the levels high from the get-go?
If you go to the start of this thread, KattySmith (despite ER-positive) got 9 months (as I recall) from a trial of Keytruda plus a next-gen version of the NSAID Celebrex. I haven't heard of any update to that trial, but I don't think it required high PDL1. In mice, adding an anti-inflammatory like Celebrex increased response to Keytruda from 30% to 70%, and so there are a couple of trials now ongoing.
Foundation One testing in my case showed a spliceosome mutation, SF3B1, which is like a CDK12 mutation in that it increases the expression of neoantigens in the cancer, and should help to make it more responsive to immunotherapy. However, I think it may still be that more would be needed, particularly to remove immunosuppressive cells from the tumor. Nevertheless, having this mutation would enable me to try Keytruda, even without high PDL1, so I'm definitely considering it and very interested to hear how it goes for you.. Good Luck!!!
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Thank you @cure-ious. I am keeping my eyes on all of these options. I have my quarterly CT scan on Tuesday and will see the PA for my oncologist on Thursday next week. Crossing my fingers everything is still stable.
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cure-ious, I am on the RLY-2608 trial that you mentioned. I am just about to finish cycle 1. The SEs have been minimal so far. I won’t truly know how it’s working till scans in late July, but my AST and ALT rapidly dropped into the normal range and alkaline phos. has dropped over 100 points. Tumor markers down too. So who knows. But I’m hopeful.
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@believe60 That is awesome to hear! And after only 1 cycle. I can’t wait to hear more good news from you in the coming months. 🤞🏻
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Believe60- Wow, great news, boy I hope the SEs continue to be minimal!!! A link to your trial is below, it is phase one but they must expect success because it is planned for 235 participants. It is interesting that they are also testing people who were unable to take Piqray. Are you also getting Fulvestrant?
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Believe60: Some details from ASCO2023 about the trial are listed below- this sounds promising. They are testing a large range of doses; what dose are you getting?! They say most common SEs are nausea, increase in blood creatinine, fatigue and headache, but low-grade and manageable- are you getting any of those?
RLY-2608 trial at ASCO 2023: Of 16 patients with breast cancer and measurable disease, 56% (n = 9) experienced radiographic tumor reduction, and 81% (n = 13) achieved stable disease (SD) or partial response (PR). CT DNA analysis showed that nine patients were already cleared of PIK3CA-mutant ctDNA by the start of cycle 2.
RLY-2608 was found to have a differentiated and favorable toxicity profile, with most toxicities being low grade and manageable. RLY-2608, unlike Piqray. selectively hits the mutant form of the PI3KCA kinase much more strongly than the normal one, and is likely why they see fewer side effects. As of March 2023, dose escalation was ongoing in both arms. No dose-limiting toxicities were observed, and the maximum tolerated dose (MTD) had not been reached.
In an analysis of 27 patients with breast cancer treated in both arms, 19 patients (n = 70%) were still receiving treatment at the data cutoff, these are early days.
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cure-ious thank you so much for that link. I have had SEs. Some nausea but that seems to be resolving, fatigue, and decreased appetite. The weird one I had recently was low potassium. They gave me an IV of potassium and I felt much better fatigue-wise. I do get fulvestrant shots on this trial. I am taking the 1,000 mg dose of the trial drug twice a day. I think that it about the highest yet. Possibly there are people trying 1,200. The funny thing is, since these doses started down at 50, 100, or 200, the largest dose pill they make is 100 mg. So it’s 10 pills in the morning and ten at night! That’s fun.
and rk2020, I sure hope I have good news in the months to come!Hoping for the very best for everyone here.
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My PD-L1 level was determined in December 2022 via FoundationOne’s analysis of the liver biopsy. No tumor genomic profiling was done previously. I had a Guardant360 assay run last month in order to look for an ESR1 mutation but none was found. It’s a comfort that NCT03393845 is a phase II trial with an already set dosage for a well known agent, KEYTRUDA.
I checked the beginning of this thread and saw the original poster, KattySmith was in a study that used Opdivo, a different immune checkpoint inhibitor. She may have succumbed to this awful disease, having not been heard from since late 2021.
I’m in awe of anyone participating in a dose finding study. So, believe60, you go girl!
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Husband…I am hoping Xeloda is gonna do great for your wife. She really is blessed her cancer has not seen a lot of chemos…mine… well thats a whole other story.
I am now considering…. stopping treatment after the enhertu… I will scan in July but as my MO says "I am really in tune with my body and know when I have progression". and its true. So when I went to FL for the trial…after the 2nd treatment my bilirubin dropped and my liver pain subsided…I thought wow this is working!!! Then 2 weeks later bilirubin back up and liver pain back…progression… I was right. I thought at that point… "I think what happens now is, my cancer see's a new treatment and initially responds…but then smartens up and stops"… this explains why Travera and such would show my cancer is sensitive to certain treatments..bc it is … INITIALLY…but then after it sees it again..it stops. I believe this is happening right now with Enhertu. Had 2nd treatment… my liver pain subsided for 5 days!!!… my bilirubin went from 1.7 to 0.6…. now yesterday.,…. liver pain back…. bilirubin wont be checked until July 3.
Im just sick of this. I need to accept the fact that NOTHING is going to work…really there is only Abraxane and Vinorelbine left anyway and I am NOT doing abraxane it showed ZERO response on Travera…. Im pretty much … DONE…. So I believe by scans July 17th results the 19th… thats it for me. I will live out my time and be done.
This disease sucks….and one of the things I am realizing I hate most about it…. is the HOPE…the hope that "I just havent found the RIGHT treatment yet" and then being let down. I mean some people are on 1 treatment for 5 years or more…I never even got more than 3 months… I cannot honestly expect my cancer to respond to treatments when its seen 10 treatment lines… sickening… this is not me being "negative" this is my TRUTH…. Rant over…
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Nicole, my heart goes out to you and every woman in your situation. It's just so sad.
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@nicolerod Damn girl something has to go right for you after all the wrongs. I had read about reintroducing drugs and finding some success. I see you tried this with Eribulin, but I want to say I believe is was a hormonal therapy. Maybe Curious could help with input. Prayers and love being sent out to you everyday.
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Nicole, Was the NCI able to grow up some TILs? I didn't hear about how that went…
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Irishlove I did go back to Eribulin when I flipped to TNBC didn't work
Cue won't know about cells until after scans in late
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Cure-ious or Anyone,
Hoping you can clarify something for me. I had Strata genomic test in Aug 2022 and it showed ESR1 p.Y537S mutation 30% and CCND1 amplification (associated with estrogen resistance). My reading tells me p.Y537S has greater resistance to estrogen deprivation. After this genomic finding my next treatment was Everolimus and Fulvestrant for 3 months and I had progression. My MO does not think I will benefit much from the oral SERDs Elacestrant or the newer Camizestrant because I did not respond to the Fulvestrant. Estrogen resistance seems to be the concern. I'm now on Xeloda (just completed 6 mo) and have early indications of progression (rising bilirubin). My cancer center (UW Madison,WI) has a study open on Camizestrant pared with different drug options NCT03616587, so this might be a possibility for me for next treatment. But my MO is more leaning towards Enhertu because of the possible estrogen resistance. Questions: Can you explain estrogen resistance a bit? How is it different from Estrogen Neg? Can a tumor regain estrogen sensitivity? With estrogen resistance, is the ESR1 mutation, which is a qualifier for Elacestrant, now a mute point? Hope you see this. Thank you.
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Hi WeninWI:
My understanding is that whereas Faslodex works on some ESR1 mutations, it does not work on the Y537S mutation, and this would be one of the primary reasons that a newer-generation SERD would be indicated.
Endocrine resistance comes about as the cancer mutates and becomes less dependent on signaling (ie growing) via the estrogen receptor. Other pathways tend to take over and the cancer can become more aggressive as a result, and behave more like other cancers that grow on PI3K or Myc or Ras or whatever. The goal of combination treatments are to try to push down whatever the alternate pathway seems to be, and force the cancer to go back to estrogen receptor signaling. The SERD in the combination is then expected to kick in.
I'll go check on this and the interim results of your nearby trial (which I think would be my first choice too) and come back to ya..
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So, WeninWI, the cancer testing from last year already showed a couple of reasons why it might not respond well to endocrine (hormone) therapy: ESR1 Y537S mutation, and Her2-low. The high cyclin D is a way the cancer becomes resistant to CDK4,6 inhibitors. New testing might find more things.
You can't deal with everything in one shot, but the whole point of SERDs at the moment is they can and do get rid of the ESR1 mutations, and they do so pretty quickly, like after the first or first couple cycles. The mutation recedes and the normal estrogen receptor becomes the most prominent again. So, if you can ever become sensitive to anti-estrogens again, you would want this mutation to go away by trying a SERD.
But what combination would you pick to try in your trial? Probably not the CDK4,6i, because you already were exposed to that and the CycD amplification is going to make it less sensitive. Your local trial (SERENA-1) offers the SERD Camizestrant together with the various CDK4,6i, or with everolimus, which you also tried previously. Beyond these, however, the trial also allows it to be paired with the AKT inhibitor, Capivasertib, which did fairly well in phase 3 and is expected to get FDA approval in fourth quarter of this year (Oct-Dec).
This post is already getting long, so more details about Capivasertib and Camizestrant will be in a later post.
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ESR1 mutations develop as a way to resist AIs, they aren't often found in primary tumors nor in tumors progressing after Faslodex. The most common are Y537S and D538G. The Y537S mutation helps the cancer escape from endocrine therapy, whereas D538G makes the cancer more metastatic. Y537S is the most resistant to Faslodex (you would need about a 50x higher level of Faslodex to inhibit Y537S!, no wonder one gets progression).
High levels of HER2, or more commonly PI3KCA/AKT/PTEN, can also push cancer to resist endocrine therapy. Capi is an AKT1 inhibitor, which means it also inhibits the PI3KCA pathway, so by combining Camizestrant with Capivasertib, you would push estrogen receptor back to its normal non-mutant form and also block the cells from turning on the PI3KCA pathway as a means to escape. One way the cancer might eventually progress from a combination Cami-Capi treatment could be to increase the HER2 expression even higher, for example. This would make the cancer even more sensitive to Enhertu, and that might be a rationale for scheduling the SERD Cami-Capi combo before Enhertu.
An interim report on the SERENA-1 trial that you are considering showed that 50% of tumors expressing ESR1-mut had a partial response or stable disease at 6 months (24 weeks) on therapy, including 5/10 patients harboring Y537S
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Lastly: Capivasertib makes tumor cells more dependent on estrogen receptor activity, which is why there is a strong rationale to combine AKT inhibitors with endocrine therapy. It also works well on ESR1 mutant cancers, and even if it didn't, the cancer isn't going to remain ESR1 mutant for very long after starting the Camizestrant SERD.
So,see what your MO thinks and ask the trial folks if they think you are a good candidate! These guys have all the experience, we can just work up rationales on paper, as it were. On paper, I think this should be a good trial. And, if not, how about getting some immunotherapy or TILs, and keep an eye out on the Her2, the higher it gets the better Enhertu works. Enhertu will drive down the Her2, just like SERDs chase away the ESR1 mutation, so its not like you can take lots of Her2 therapies, so as resistance proceeds check to see if Her2 has changed…
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PS Sorry to be so long, folks! Capivasertib causes grade 3-4 diarrhea in like almost 80% of those taking it, so beware of that! For that reason, it is given 4 days on, 3 days off, and supposedly with Immodium, etc, is tolerable. Once approved, we will hear whether that is true or not
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Cure-ious - Thanks so much for sharing all that detailed info. It’s incredibly helpful!
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Dear Cureious - what a beautiful mind you are! If all oncologists would be like you, most probably we would already have a cure. Hugs,
Saulius
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cure-ious,
Thank you so much…..lots of info to absorb and try to understand! My next scans are in a few weeks. So will see if I'm off Xeloda and on to something new. I'm at 4 years since Stage 4 diagnosis, and when I saw my MO last week I repeated back her original prognosis of "4-5 years"…..and her only response this time was "Yes".
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Saulius, I'm a professor emeritus (ie retired) who ran a lab focusing on molecular signaling pathways, how they work and are (mis)regulated in cancer. We also worked out the main part of how HIV gene expression gets turned on in active T cells, cloned the host proteins involved etc. This diagnosis freaked me out until I was finally able to return to reading the scientific literature, which surprised me by giving me real hope, something which the MOs and meds were completely unable to do… Knowledge is power, as they say, but also a little knowledge can be a dangerous thing, so tread carefully and keep your mind open, realize that you may be on completely the wrong track, but know that you can work your way back…
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