Are you currently (or have you been) in a Clinical Trial?
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So, following progression on Fulvestrant plus CDK4,6i, the various clinical trials have seen that further Fulvestrant activity is noticeably weak and limits the effectiveness of additional combination therapy. Activity of Fulvestrant as monotherapy drops from 3-4 months to around 1-2 months, and adding anything else doesn't help much. So the focus has been to move to combos with the newer SERDs.
One combination that has gotten some traction is CDK7 inhibition. CDK7 inhibitors boost p53, a potent tumor suppressor, and work much better in cancers that still have normal p53 (ie work much less well in cancers with mutant p53)- about 70% of MBC apparently still has normal p53 after endocrine therapy. Links below discuss the activity and SEs of CDK7i, and announce that a new clinical trial will open up in the second half of this year to combine a CDK7i (Samuraciclib) with ARV-471, the ER-degrading PROTAC. Samuraciclib causes a lot of diarrhea and nausea, so they are trying to get better inhibitors. Future studies may be restricted to those with cancers that do not have TP53 mutations, because they respond better…
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And what to do if the cancer does have a p53 (TP53) mutation? First, not all mutations are the same, and some for example will disrupt the ability of p53 to control expression of certain host cell genes, but do not affect its ability to block the growth of tumor cells. Other mutations prevent p53 from its normal function of inhibiting cancer cell growth. Recent studies have examined how p53 blocks cancer cell growth, and conclude it is at least in large part due to blocking the activity of a protein called Yap1.
For those cancers, one could in principle take a statin, because statins are strong blockers of Yap1. There is one commercial Yap1 inhibitor in trials, but it has strong SEs and can cause liver damage. In the meantime, statins are a good (and safer) alternative.
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Syros also has a CDK7 inhibitor that has been in phase one for quite awhile. When combined with fulvestrant, 5/12 heavily-pretreated patients were stable for at least six months, and 3 of the 12 had tumors shrink. Three remained on treatment more than six months, and interesting one had a TP53 mutation! Presumably this drug would work better in combination with a new-generation SERD.
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The link below is to a clinical trial for ER-positive MBC, called MORPHEUS-Breast Cancer, which tests the new SERD Giredestrant in combination with other therapies, one arm of which includes the CDK7 inhibitor Samuraciclib.
The trial is for progression after 1st or 2nd line endocrine therapy, which had to include a CDK4,6i. Measurable disease (ie not bone-only). In addition to the US, there are multiple sites available in Australia, Israel, South Korea, and Spain.
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Interesting study published June 8 in Cell: It is well-known that one mechanism for resistance to CDK4,6i is increased activity of the CDK2 kinase. Now, researchers find that CDK2 inhibitors initially inhibit cancer cell growth, but the cells can recover from that quickly, like within hours. The reason is interesting, and is due to increased CDK4,6 kinase activity. So these kinases toggle off of each other, like a see-saw. The study, published with Pfizer, explains why Pfizer is now doing trials that combine CDK2i with a new inhibitor that is highly selective for CDK4 (over CDK6)- indeed, the thought is that Ibrance lacks the OS benefit the other CDK4,6i because it is the least effective at inhibiting CDK4….They speculation is that this may be a good combo for those who did not respond to CDK4,6i, or for treating those who have become resistant to CDK4,6i.
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Here is a link to a Pfizer Phase 2 trial testing both CDK4 and CDK2 inhibitors, it seems like its for both early and advanced cancers and might include bone-only cancers. Some sites in the US, as well as Argentina, Brazil, Merida (Mexico), Bulgaria, Prague, and South Africa, but only 122 patients.
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Here is some interesting information about those who progressed on Ibrance-Faslodex, coming from an analysis of mutations before treatment and upon progression in the PALOMA-3 trial. Testing various genes known or suspected to induce progression: They tested exons of RB1, CDK4, CDK6, CDKN1A, CDKN2B, NF1, exons 5-8 of TP53, as well as known mutation hotspots in the PIK3CA, ESR1, ERBB2, FGFR1, FGFR2, FGFR3, AKT1, KRAS, NRAS and HRAS genes. Using this panel, they identified new mutations in 31% of patients that arose after treatment started. Conclusions:
- Most mutations are those giving resistance to Faslodex, rather than resistance to CDK4,6i. This is consistent with other studies showing that Faslodex monotherapy is significantly less effective post-CDK4,6i (drops to 1.7 mos from around 3-4 months), and that limits how well it works in combos. So, few Rb mutations or CCNE mutations.
- 37/195 patients had pre-existing PI3KCA mutations, and these were almost all still there after Fulvestrant-Ibrance. Another 16/195 patients acquired new PI3KCA mutations ( this corresponds to 8.2%), one person got two PI3KCA mutations. Almost all the new Pi3KCA mutations were E542K. A similar number of patients got PI3KCA mutations in the control arm (Fulvestrant monotherapy), so this mutation is due to Fulvestrant resistance, not resistance to the CDK4,6i.
- 25% of patients had ESR1 mutations. Unlike PI3KCA mutations, the course of the ESR1 mutations was very dynamic during treatment, as some patients who had pre-existing PI3KCA mutations lost those during treatment (some specific ESR1 mutants can be eliminated by Faslodex). Some of these patients got new ESR1 mutations, and other patients developed ESR1 mutations where none were detected before treatment. The strongest ESR1 mutation, Y537S, which cannot be inhibited by Fulvestrant, was the most common of newly acquired ESR1 mutations. Overall, 49/195 patients had ESR1 mutations, whether pre-existing or new, and most of the newly acquired mutations ( 25/195 patients) were ESR1 Y537S. The ESR1 mutations also developed (or persisted) in the control arm (Fulvestrant monotherapy), meaning the mutation is due to resistance to Faslodex, not to the CDK4,6i.
- A variety of other mutations were found to be newly acquired during treatment, and these were also found in the Faslodex alone arm, including: Her2, KRAS, FGFR2 (1-3%). They report some APOBEC mutations were picked up, these had not previously been known to cause I-F resistance.
- So, at the end of treatment, the study picked up 37/195 patients with PI3KCA mutations, and 49/195 patients with ESR1 mutations. PI3KCA mutations are treated with drugs like everolimus, Piqray, and soon to be approved Capivasertib; whereas ESR1 mutations are treated with the new-generation SERDs- note that these drugs eliminate the ESR1 mutation after the first cycle or so, and after that most of the cancer cells are growing with the normal estrogen receptor.
- Patients who had TP53 (p53) mutations before treatment had the same mutations after treatment- Faslodex did not cause a loss of these mutations, and neither did the mutation frequency go up during treatment or cause progression.
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Interesting articles Cure-ious.
sounds like the new SERDs only need one month to get rid of ESR1 mutations
that the resistance to palbo/fulvestrant was due to the Fulvestrant.
that the CDK2/4 combo has promise. (with AI or SERD?)
wonder if when you get rid of the ESR1 mutation you can go back to a AI (other than the one you took before you became metastatic) or are all AIs off the table now.
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cure-ious, the info you post on studies/trials is unreal! Keep up the excellent work please!!
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thanks for the encouragement, NkB and MSWife!! Nkb, those are great questions, and I have no idea how this will work going forward… We need the SERD to also work against the normal estrogen receptor, and this is the problem with a drug like elascestrant, which works fine on ESR1 but not so great on regular ER- the only SERD I'm aware of that seems to clearly be better than Faslodex (which is stronger than AIs) is Camizestrant, which is still just in clinical trials. I guess on progression one could move back to Faslodex combo, and knowing MOs, they would want them paired with something different. Would they do SERD plus a CDK2 and CDK4 inhibitor? And will they want to go from one SERD to another, assuming multiple get approved? Its very unclear…
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There is an article (maybe you posted it) that says that studies of Camizestrant taken along with all sorts of other drugs (many CDK4/6i and other drugs) have been in trials since 2018- so that is encouraging.
Cheers!
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Well, NkB, you were the one pointing out that bone-only mets have access to far fewer trials, so I hope these can hurry along so we all get access to new options…
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Yep- they've got to get approved before bone only will get them. I am interested in them teasing out the efficacy of enhertu and other drugs for bone only people.
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@cure-ious
I am another one who greatly appreciates your knowledge and the time you take to share it with us. I read everything you post multiple times, as I find comfort in knowing as much as possible about this beast we are all fighting. My MO only gives me the short and superficial version unless I drill down, so I go to every appointment with index cards full of questions. I'm beginning to think that you know more than she does.
@nkb
I took have bone only mets and worry about the available options once Kisqali and Fulvestrant fail. I had a rough adjustment to Kisqali but have been doing well on it for a year and would hate to give it up. Wonder if they would let me keep it and just switch out Fulvestrant. It seems to me that there's a "map" of standard treatments that we are moved along without much effort at "fine-tuning" to see if an individual might benefit more from a deviation in the route.
Sorry for such a long post, but this discussion struck a chord with me.
Thank you
Eleanora
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Eleanora- I think there is a "cookbook" that MOs follow- the order may not be important, but, can vary. There are many new treatments that require a certain mutation. In the past people had to keep in mind how many chemos they tried or other details so that they still qualified for trials. what Cure-ious and I were discussing is that trials may say they take bone only, but, in reality you don't qualify if you are bone only. Most studies use the RECIST as a way to measure the response of a tumor to treatment using CT. There is some new data Recist 1.1 says you can use bone lesions with soft tissue components (?) using MRI or PET- they are doing it at MD Anderson and maybe other sites.
I think that the cancer world is finally getting the clue that doing studies without bone only patients leaves us with no information on how it will work once it gets approved. Also we don't get early access to some very promising drugs. Some institutions look back later to tease out how their bone only patients are doing with approved drugs once they are using them.
UCSF told me that if I had a 2 CM hole in one bone I might qualify for a trial.
Hopefully you will get a good long run on your Kisquali - many drugs in the pipeline. I still think a trio of drugs is going to be the ticket- but, who knows. You have many options right now so enjoy your good response while you can.
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Nkb
Thanks for the further explanation. I have been told that my age (70+) alone would disqualify me from a trial, even though I am in perfect health other than having MBC. I am trying to learn about the newest treatments so that I can discuss them with my MO. She does seem to follow a "cookbook" but has been receptive to some persuasion in the past.
I look forward to following your discussions.
Thanks
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Hi I hope everyone is feeling ok today. I've been watching this thread and following everyone's story. I went though standard treatment in 2016 as stage 2. In 2021 I found out the cancer has spread to my lung and spine. I was on Ibrance for 8 months. It does control the lung mets but never worked to my bone. I then joined a PIK3 clinical trial RY-2608 which last 8 months then spread to my liver. Next to Xeloda 3 months liver keeps progressing. Now my MO wants me to start Enhertu. My husband's pushing me to follow nicolerod's footprint by joining Rosenberg's NIH trial. My MO has arranged a liver biopsy next Monday. I have 10 small lesions but only 1 is bigger than 2cm. If I do the Monday biopsy I may be no longer qualify for the NIH trial. Anyone can give me some suggestions? I'm thinking
- postpone the liver biopsy, wait for NIH's response. ( Cons: I don't know how long it will take and I'm not having any treatment now.)
- Is it better to save ENHERTU for later? use after the NIH trial fails?
I'm praying for nicolerod. God please give her peace and courage to recover from demolition.
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@nikkiqh. I am currently on that trial for RLY 2608. I’m about 7 weeks into it. My first scans are next week as I finish the second cycle. My Mets were already in my liver (and bones) before I started it. My liver Mets had actually grown a lot at my last CT and that was the end of ibrance/fulvestrant. Do you mind me asking what your dosage was? I am on 1,000 mg twice a day. Having some SEs.
I have been following this thread, and I am praying for everyone on here. Nicole, I really hope and pray you can have time with your family all together. You deserve for good things to come your way.0 -
@nikkiqh - I am also pursuing the NIH trial. I am still trying to learn all the details, and everyone is a little different, but for myself, I've been thinking about it as something to do in parallel. I just started Trodelvy, and if I can proceed with the trial, I talked to my doctor about taking a treatment break to do the initial NIH surgery. The NIH needs some time to process that surgery, so for me, it makes sense to go back on Trodelvy while I wait (assuming Trodelvy is working). As for the biopsy, can you pick one of the smaller lesions to biopsy, so that you can save the larger one for the NIH surgery? Or are all the other lesions way too small to biopsy?
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@believe60. I had it at 800mg for 7months until my scan showed liver mets. Then they had me on 1200mg for one month see if it could become effective again. It didn't work. I'll say this pill never worked on my bones(always have mixed scan result) but it did remove a bad guy on my lung. And the SE is minimal. I really hope and pray good things happen to your next scan.
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@jsniffs. I just realized we are the same age! I was too diagnosed at 36. I'm off treatment for 2 weeks now waiting for a liver biopsy to confirm the hormonal receptor status. My liver lesions are small, and I don't want to do two liver biopsies in such a short time. When I was on XELODA (7+ 7 schedule) , the first two months I felt great. But my bilirubin was a bit high around 2.4 so my MO had me rest for 18 days. When I resumed all my SE disappeared. Pain came back. I immediately knew it stopped working. It was really strange. That's why I want to save Enhertu later without interfering with this NIH trial.
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@nikkiqh - Oh wow, that's interesting that we are the same age. Sorry you are dealing with progression. The uncertainty of figuring out the next treatment is always a pain. I've had a couple of liver biopsies, and I have found them to be quite easy (very little in terms of recovery). The biggest issue would be if the lesions are big enough to find/biopsy. I totally understand trying to "save" things both in terms of drugs and tumors. I never thought I'd be telling a surgeon, "don't take that tumor out, I might need it." :)
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@jsniffs. I'm planning to fly to MD for the NIH Trial screening test next week. I hope not to have too much progression by then.
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@nikkiqh thank you for sharing your experience on RLY 2608. My first line was the ibrance/fulvestrant and it seemed to be working well on my bones but liver Mets grew. Was only on this for 6 months. Then got into the trial. Please keep us updated on your experience with the NIH trial. Wishing the very best for you.
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Wow, best of luck getting into the NIH trial!!! Clearly, it takes quite a bit of time for them to grow up the TILs, and its best to start as early as you can qualify..
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So, regarding the PI3KCA drugs, there is an additional drug by the same company that is testing RLY-2608, called RLY-5836 (link below), which is also for mutant PI3KCA and doesn't inhibit the normal PI3KCA. I just want to note here that the write up of the RLY-5836 trial sounds like they will take bone-only MBC, and so I sent them an email and they confirmed that they do. So, if you have bone-only MBC with a PI3KCA mutation, you could qualify for this trial. It is phase 1, so goal is determining the optimal dose, but is large for phase one (designed for 220 participants), AND is being tested alone, with Fulvestrant, or with Fulvestrant plus one of any of the three CDK4,6i. Clearly, they are not expecting killer side effects if phase one is already testing the drug with fulvestrant AND in a 3-way combo with Fulvestrant and CDK4,6i!! The Trial started in March of this year and runs through 2026. Sites are in Memorial Sloan Kettering/NYC, MGH/Boston, Sarah Cannon, FLA, TN, and IN, (so no west coast) but she said they pay for travel, lodging and food for the participant and one other person to go with them, not clear if that means you would sign up at the site and then just be treated at home in terms of bloodwork and scans, or what the exact deal is. I don't know if bone mets patients are accepted into the earlier RLY-2608 trial, but I kinda think not. RLY-5836 is similar to RLY-2608, in that it hits mutation-only PI3KC, however it is a different chemical formulation.
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Also there is an update for the PI3KCA mutation-specific RLY-2608 drug trial, being tested alone and with Fulvestrant:
RLY-2608 has been generally well tolerated in the 42 patients treated as of the cut-off date:
- The overall safety profile consisted of mostly low-grade adverse events (AEs) that were manageable and reversible
- Across all doses, there were no dose-limiting toxicities, no treatment discontinuation due to AEs, and no Grade 4-5 AEs
A patient with metastatic HR+/HER2- breast cancer, with two PI3Kα mutations (H1047R, E453K), who progressed following 12 lines of prior therapy, including chemotherapy (including Enhertu®), endocrine and HER2-directed therapies, received RLY-2608 400mg BID monotherapy. An unconfirmed partial response (ie tumor shrinkage) by Response Evaluation Criteria in Solid Tumors (RECIST) was recorded at 8 weeks. Subsequent to the data cut-off, this partial response was confirmed, and the patient remains on treatment with no AEs reported as of April 4, 2023.
Among the 16 breast cancer patients with measurable disease:
- Nine experienced radiographic tumor reductions (3 helical, 4 kinase, and 3 other)
- 12 exhibited a best overall response of stable disease and 1 partial response (4 helical, 7 kinase, and 4 other)
- 11 remain on treatment as of the cut-off date
Median duration of treatment for all breast cancer patients was approximately 4 months:
- 70 percent (19/27) remain on treatment as of the cut-off date
- 600mg BID dose: approximately 4-month median follow-up
- Six of seven 600mg BID patients remain on treatment
- To date, a maximum tolerated dose has not been reached and dose exploration is ongoing to determine the recommended dose(s) for the dose expansion cohorts (part 2), initiating in the second half of 2023
- Six of seven 600mg BID patients remain on treatment
nikkiqh and believe60 are/were on this trial, contributing to these data!!! True pioneers, we are following you guys, esp as you clearly know how to pick a good trial…
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Wow, the RLY-5836 looks like an interesting study. One of the exclusions is to have taken a PiK3 inhibitor and I have done two days already on the Piqray so that may disqualify me. I have been given a two week "trial package" on the Piqray while insurance/Novartis is still battling it out. It's been approved at $4K/mo now so I am looking at copay cards. If I can't get it approved at a reasonable copay I am going to ask my MO about a clinical trial.
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jsniffs and nikkiqh,
Please keep us informed of your efforts to get into the NIH TILs Trial and outcomes.
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