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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