Are you currently (or have you been) in a Clinical Trial?
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"When treatment was initiated after the formation of detectable metastases, therapy involving MN-anti-miR10b elicited durable regressions with no evidence of systemic toxicity5,8. Importantly, after four to six weekly treatments with MN-anti-miR10b in combination with low dose chemotherapy, we observed complete regression of detectable metastatic lesions. At that point, even though therapy was discontinued, metastases did not recur"
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A friend in pharma asked if I was excited about the new CDK inhibitor Roche acquired, and commented that he thought they were likely to push it through trials quickly. I hadn't heard about it, here are the details:
- In Sept Roche paid $850 mil to buy multiple CDKi drugs from Regor, a pharma based in China
- The top drug, RGT-419B, inhbits CDK4 more strongly than FDA approved CDKis and has some activity against CDK2, without hitting CDK6. Phase one trials indicate it works on CDK4.6i-resistant MBCs and has monotherapy activity. Roche’s Genentech subsidiary will now take over global clinical development.
- Roche is also planning to combine it with their PI3KCA alpha-specific drug, inavolisib, currently also in trials.
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Cure-ious-That's exciting news. I wonder why Regor wanted to sell it?
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no idea, but $850 mil in cash, plus more if they hit certain benchmarks in near future, sounds like a lot for a company founded in 2018….they also have an Ozempic-type drug, so it may have been getting expensive to bring multiple drugs to market fast enough
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Thanks Cure-ious and everyone for sharing useful information.
I did some research on clinical trials, when it comes to CDKs, if these meds are still effective for patients who previously progressed on a CDK like palbociclib. one trial’s exclusion criteria say that "participants with known RB1 mutations or deletions, which the investigator believes would cause resistance to CDK4/6 inhibitors, are excluded". also the trial excludes those on strong CYP3A4 inhibitors or inducers. I thought this might be helpful for those considering giving CDK inhibitors a second chance, even though many oncologists are not into trying another CDK after prior progression. the selection criteria seem pretty strict, but it’s good to know options exist for those who might still benefit from revisiting CDK therapy.
My Guardant liquid biopsy reported ESR1 dropped to 0.3%, but the liver tissue (biopsy) showed it at 45%, which is why my MO insists that once ESR1 is detected, it won't go away. My MO also mentioned that since the cancer has progressed on two lines of hormonal therapy (the second being a SERD), hormonal therapy may not be effective anymore. Interestingly, the Caris report shows that ER is still high, PR dropped to 0, and AR is quite high, are there any meds for AR+?
other mutations are reported as well which I think drive the cancer, such as NF1. Caris suggested a NCI ComboMATCH trial binimetinib + fulvestrant. I’m a bit concerned about why they chose fulvestrant instead of newer SERDs or SERMs, my best guess is due to the extensive data and well-established SE management protocols, so making it more predictable when paired with a newer targeted therapy.
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enobosarm is for AR+ tumors but I have no reason to believe it is effective in esr1 mutations.
you could try it; it’s available for sale under the name Ostarine .1 -
Wow, Snow-Drop, I didn't appreciate how the ctDNAs sampled by Guardant are so clearly completely different from tumors in the liver, and presumably others that would be esconced in the brain or other tissues as well. So, ESR1m does NOT go away, and therefore one would always want to be treating those cells, a fact that is conveniently ignored by most clinical trials, who only offer Fulvestrant as the ET backbone in any combo. And even worse for combos that further include a CDK4,6i, since those would only work if Fulvestrant works.
As Luce mentions, you could try enobosarm, which does inhibit ESR1m, assuming that the trial would not allow you to remain on Elascestrant?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889594/
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my experience with enobosarm, if anyone cares: after letrozole, it kept me apparently-stable for five months (but did not reduce my tumor markers or % of my mutations—four est1 and one PI3k—on guardant liquid biopsy report). I then switched to high-dose estradiol, which reduced all those markers by a lot. Switched back to enobosarm because of side effects but tumor markers rose, as did my PI3k mutation, which went up 12-fold. Esr1 m % remained the same (low) after estradiol had apparently somehow reduced them. No idea what’s actually going on in my organs; I elect to not get imaging. So what I learned is this: Enobosarm might somewhat control esr1 m if their expression has been reduced by other means (estradiol or elacestrant) . It is not effective on PI3k m once those cells become resistant to it. At least in my case. So I think it could be a good add-on to a PI3k inhibitor, being that the options we have for antiestrogen therapy with those are currently limited.
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My oncologist thought this might not be approved until next spring but the FDA approved it 2 days ago. Looks very promising! The median progression free survival in Phase 3 was over 15 months compared to 7.3 with iBrance and Faslodex alone. It targets endocrine resistant ER+ tumors with PIK3CA mutations. I just started Xeloda but I’m going to ask about this.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive2 -
MommaCJ, Inavolisib does look promising, and the great thing about being FDA-approved is that it now could be combined with Elascestrant for those resistant to Fulvestrant. As you say PFS is 15 months, ORR is 58% (tumor shrinkage!), but note that these numbers are for first or secondline therapy where it was combined with Ibrance and Faslodex, these patients had not seen prior CDK4,6i. Inavolisib is a similar drug to Piqray with side effects of high sugar and rashes, but they conclude "Inavolisib is generally well tolerated and has milder side effects than other drugs that target the PIK3CA mutation. Side effects that are managed early in treatment tend to go away more quickly…" There is another trial ongoing to see how well it does for those who are already resistant to endocrine therapy.
Other drugs in this category include RLY-2608 and STX-478 (still in trials), which are more selective and target only the mutant forms of PI3KCA (ie, much lower effects on normal cells), so they come with far fewer side effects. Progression from these mutant-specific PI3KCA drugs can arise as a result of AKT activation or loss of P-TEN, and so in cases like that one might then be able to take Capivasertib (or perhaps Inavolisib), and therefore benefit from having had both lines of therapy.
https://www.fiercepharma.com/pharma/roche-burnishes-breast-cancer-portfolio-fda-approval-itovebi-threat-novartis-and-az
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For cancers resistant to CDK4,6i, including those with p53 mutations, ASXL1 mutation, Cyclin E amplification or other mutations that lead to high levels of CDK2-the hoped-for-fix is to inhibit both CDK2 and CDK4, because studies have shown that these two kinases act as a kind of toggle switch-ie, you push down one and the other one pops up.
There is an interesting phase 1/2a clinical trial (NCT06188520) to test a strong CDK2 inhibitor, AZD8421 (IC50=9nM, so it binds tightly to CDK2), in combination with Camizestrant (an oral SERD) and Ribociclib. The study is offered at just a few sites in the US (TX, TN, MO, RI) as well a several sites in the UK, Spain, Korea and Australia, and will be recruiting through spring 2025. There are no restrictions on previous lines of therapy. Because it is phase one/first-in-human, they will be looking to define a tolerable level of drug, which has been tricky for other companies working in this area, so fingers crossed that this drug works out, because we really need it!
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Wow!!! A new paper in Nature reveals that two medications will synergize to robustly kill TNBC…
Here, from the abstract:
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution…..
In short, they show that TNBCs with mutations in PTEN,PI3KCA or AKT1 have highly active AKT1 kinase that is driving their growth. They find that shutting down the AKT1 pathway using the drug ipatasertib, in combination with re-setting the DNA methylation status of the cell (by using an EZH2 inhibitor drug called tazemetostat) causes the cells to revert to a more normal state where they are much more easily and effectively killed by the drugs. Only the combination of these two drugs does this, ie both steps have to happen. the two drugs they are using are or have been already in various clinical trials, and so now surely clinical trials will follow to try the combination in humans.
Bottom Line: AKT plus EZH2 inhibitors kill TNBCs
70% of TNBCs have PTEN/AKT1/PI3KCA mutations and 80% have high levels of EZH2, so this could be widely applicable.
Because endocrine-resistant ER-positive MBC also over-expresses EZH2, it will be interesting to learn whether PI3KCA mutant ER+ MBC responds similarly to the combination of AKT1 and EZH2 inhibitors
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For leptomeningeal cancers, a new proton craniospacial radiation technique was shown to double overall survival. The article also mentions that volumetric modulated arc therapy craniospinal radiation (VMAT CSI) is more widely available and may act similarly. The treatment should begin after diagnosis and does not require suspending systemic therapy.
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Luce, thanks for letting me know about this drug, I wouldn’t have known otherwise… and thank you for sharing your experience with enobosarm.
Cure-ious, I really appreciate you sharing the latest research. It’s fascinating to learn about fixing resistance to CDK4/6 and how targeting both CDK2 and CDK4 works. kudos to science!
from my own experience, I’ve come to believe that leaving cancer active hoping an estrogen degrader will take care of it can open opportunities for more mutations, I am not a big fan of hormonal- mono therapy. good to know there’s still hope for CDK resistance. at this point, I’m ready to try whatever comes before starting xeloda. I decided to go ahead with local therapy for the 2 liver tumors that progressed on Elacestrant, either Y90 or microwave, whichever I qualify for. I’m hopeful that after this, I can start a new CDK treatment.
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Snow, Will you have a biopsy to see if the cancer has new actionable mutations, like Pi3KCA etc? And are there clinical trials available? Will be interesting to learn what they are doing with liver treatments nowadays
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I'm in a total panic mode! I felt like there were something bad happening with my liver, and it actually was. After 2 years and half of liver mets that wern't actually causing any problems, I'm now in bed with a fever, with nausea, diarrhea, pain to my side abdomen, enlareged liver, general discomfort, and I feel like I need to fall asleep from one moment to the next.
My liver number went very up:
ALT: 152 (up to 49), AST: 373 (up to 34), bilirubina totale: 0,7 (0,3-1,2), bilirubina diretta: 0,3 (up to 0,3), fosfatasi alcalina: 294 (33-98), gamma gt: 395 (up to 38).
Everything happened in less than a week, as much as the first 4 days I though I had just a flu. But is getting worst by the day.
Unfortunately my next oncologist appointment is the 4 of November, to discuss a TAC i will have the 31 of October, and they don't want to posticipate it. They just told me to dismiss my current theraphy. I don't even have a liver biopsy in sight and i never did one since my MBC diagnosis.
I really wanted to do the VELA trail at progression, but I'm so afraid they are not going to accept me. I never of though to have this kind of progression. It is not at my hospital, so I will just eat an aspirin and go the meeting, i will not tell them my discomfort. But the liver value?? They are there!!
My alternative anyways is paclitaxel, and i dont hink it is going to be as effective as a cdk2i with a cdk4/6i combination. (There is also a cdk2i with chemo, but as I read cure-ious wrote cdk2 and cdk4 do like a swing, and than i read even more about online, I don't want to burn me a chance of having an effective therapy and use it without a cdk4 combined).
Anybody ever tried to enter a clinical trial in my situation?
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Hi Amel!
Wow, I don't have any specific insights here, but it seems like you need to get to Urgent Care or even emergency room, they will take you in quickly as a metastatic cancer patient, get you out of pain and look a lot more carefully at what is going on right now with the liver, see if its blocked or something (more than just having tumors there).
And it might be a good idea to change up what the cancer is seeing, try an ADC like Enhertu or Trodelvy? And by then maybe there are stronger endocrine therapy options that include a CDK2/4 inhibitor, or go in a different direction with the BriaCell IMT therapy, which is like a cancer cell line vaccine that triggers some immune responses to the more common MBC antigens. BriaCell doesn't seem to shrink ER-positive tumors much, but it does seem really good at keeping them stable after you shrink them with an ADC. Here is a link that Luce posted:
It is in phase 3 trials but the company says they will provide it to patients who can justify needing it, so the MO just has to contact them. So if the ADCs shrink the tumors and the BriaCell helps maintain that state, then you could get back to the endocrine therapies?
Hopefully you are already getting the help you need and feeling better!!!
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I mentioned this to Amel in the liver mets thread, but this was my exact situation. The liver mets exploded, I went on Trodelvy to beat them back (which it did beautifully) then I was able to get on the BriaCell IMT trial.
I have my second dose tomorrow, and I'm still waiting on tumor markers from yesterday's draw, but the liver numbers are relatively steady.
Scans are November 15th, with no cause for alarm yet. If I do progress at the scans, I can move to the arm with the vaccine+other drug (can't remember name) instead of the vaccine only arm I'm in now. OR I can look for a new trial. OR I can try the TTX-MC138 trial which is super exciting, but still in the earliest doses. OR I'm looking at an Aurora A inhibitor too.
I'll keep everyone posted!
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Thank you @cure-ious and @cblaurenceauthor for your reply, i will definitely ask for the Bria cell!
They just called me back from the trial VELA and they told me I'm excluded in any case, due to high liver value. I was almost relieved after i read your post, and after be almost shure i will have to take this 300 km to go and 300 to come back in this conditions for nothing, because i was almost sure they wouldn't accepted me.
So an oncologist from the same hospital of the clinical trail that i always ask a second opinion told me i need to do a standard chemo, because the only approved med is trastuzumab deruxtecan and my score of her2 on my primary breast cancer was 0, but it was in 2018. I don't think i have time to wait for a biopsy and the results. Also 5 months ago on a liquid biopsy everything was negative, so he say they still probably negative. And there is no many therapies approved for mutations here, will be another clinical trial that i will not be eligible to do. So i will may be start a chemo, ORDER with all of my forces a liver biopsy and if when the results are ready if I can i will start something else better. And hopefully the chemo will kick those mets down. Tomorrow morning if i'm still in this conditio i will go to the urgent care anyways. And call if they can give me a private liquid biopsy for her2, so expassive, but they put me in this conditions.
@cblaurenceauthor finger crossed, you also have so many options there, you are luky!!
Now i stop filling up this thread with the wrong topics and move to the liver mets! Sorry about this. I will write for only clinical trial related things, i just had so much hope in the VELA trail...!
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Great Amel! I agree you need help right now, no waiting around for some trial drug, there will be time for that when mets are beaten back & stable…
CBL! I was just wondering how you were doing when I wrote that post!! You got an excellent outcome w/Trodelvy and we will be so excited if the BriaCellIMT is working, that was really an unexpected bonus to pop up on the radar..
I think your other arm might be add-in Keytruda?! And for TTX, did they give any hints of how the trial is going, I agree that one is super-exciting…
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If it's not Keytruda it's something similar…
My tumor markers went up 60 so I have a note into them to see if I should be worried. I'm 99% positive they'll say it could be cell die-off and not to panic. My liver numbers are okay, but they are on the rise, so I'm going to panic anyway until the scans in three weeks. :)
They're not giving me any info on TTX - not purposely being evasive, I'm just not eligible yet since I'm not ready to move trials so it's not on their priority list. My trial nurse did say that sometimes getting in early isn't a good idea because the dosage might not be strong enough. I read somewhere (and of course I can't find it again) that the Phase 2 should be opening in August 2025, so I could do a few different trials before then assuming my liver holds out.
But when I'm ready to jump ship to a different trial (which could be faster than I think!) I will for sure get the info on it.
CBL
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I was half-right: He said don't panic, but it's more likely the treatment hasn't had time to work yet since these markers were drawn after only one round and treatments like this take longer to kick in—unlike chemo which works immediately. (hopefully.)
So I'm not panicking, but I'll be super-ready for the scans in three weeks. :)
CBL
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The following is about a breakthrough on the modification of CAR-T cells to attack solid tumors. While the research was done on ovarian cancer, perhaps this can be extended to breast cancer? I don't have the expertise or experience of cure-ious, so hoping she will provide her opinion.
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What an interesting and convoluted story! I had never heard of XBP-1, but see that it has a big role in metastatic breast cancers. Here is another summary of the research:
So this story dug deep into why ovarian cancers were shutting down infiltrating T cells, and showed that a stress pathway in the cancer was turning on XBP-1 (a Myc-induced transcription factor that drives metastasis and is prevalent in TNBC as well as endocrine-resistant ER-positive MBC). One of many things XBP-1 does is to shut down production of a protein (Transgelin) needed for the T cells to suck up lipids from the environment, and failure to do that was shutting down the T cells. The fix they apply in the paper is to engineer CAR-T cells to produce and secrete a lot of the Transgelin protein into the environment of the tumor, which allowed for the T cells to suck that up and become active again. It seems this should work in breast cancers too.. I guess people must also be researching ways to get rid of the XBP-1 protein. Awesome progress!!!
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CBL- Because the BriaCell vaccine is targeting proteins that are commonly found on the surface of breast cancer cells, including Her2, some cells, possibly including Her2-low cells that may be floating around might get targeted. So even tho you don't yet know whether it is able to fully hold back the cancer, it is probably at least helping and may do that for awhile..
I think the same way about Elascestrant- you don't know when taking it whether it is sufficient, but at least it is whittling down the population of ESR1 mutant cells. So its not like taking a drug to which the cancer is already resistant, which is just wasting time.
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Ooh, that's good to know. As long as it progresses slow enough so I can change trials, I'll consider it a win.
:)
CBL
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Anyone familiar with TOS-358? This could be in my future when/if Truqap fails. Optimal doses have been established and there is little toxicity according to one of my MOs. I haven't looked too far into it yet.
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dulcea- How wonderful- yet another PI3KCA inhibitor! And this one sounds good!!- it is a covalent inhibitor, so will stick on PI3KCA and not come off, as Piqray and Inavolisib do. It is also specific for the alpha-form of PI3KCA, so does not seem to give the glucose hypersensitivity the others do. And 2.2nM IC50 for the wt enzyme, 4.4 for the mutant, so you only need to take one 20mg tablet…
The other PI3KCA drugs in trials have greater specificity for the mutant rather than the wt PI3KCA, and don't bind as tightly, so one needs 2x600mg of RLY-2608 or 1x100mg of STX-478… And they also do not have the side effects of Piqray and Inavolisib.
But none of these drugs gets rid of PI3KCA, so for the long term we need multiple different drugs that can hit this very strong driver of MBC growth, either for sequential treatments or for circling back at later stages..
Did you hear anything about how the trial is going or what side effects they are seeing? Good Luck
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@cure-ious thank you, thank you for that explanation!!
My MO just said that they have just found the optimal dose and that it's pretty tolerable. That's all the information she had at that point. I will take anything that is tolerable! This Truqap is pretty tolerable so I hope it works for a while.
Thanks again.
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