ESR1 mutation treatment options and new SERD/SERM research

[Deleted User]

this is an interesting explanation taken from

https://patientpower.info/er-news-ahead-of-san-antonio-breast-cancer-symposium/

SERDs.

So this pill version of the next generation of fulvestrant. And how this drug works is instead of blocking estrogen binding to the estrogen receptor on cancer cells, we can think of estrogen as food for those cancer cells to grow. Instead of just trying to block the estrogen from binding, we know that there's this mutation called ESR1, where those estrogen receptors are like a light switch. They just get turned on and they're always signaling even if estrogen isn't around. And so, what the SERDs do is they're degraders. They actually bind that little estrogen receptor and chew it up and spit it out. So, it's a really exciting new class of medicines that I think is going to help a lot of people. And I've heard through the grapevine, we're going to be hearing some things about that class at San Antonio.

Dee

Grannax2

Dee that is great news. It sure helped me for about nine months. It' failed recently, as you know. The liver BX and liquid BX are at Tempus now. Hoping that I have developed a new mutation that will have an actionable TX for me. 💞

cure-ious

Dee, That is a very exciting notice- they indicate we will have FDA-approved SERDs by Dec? Maybe I am mis-reading that? I didn't think we had any SERD available in the clinic, despite being in trials and constantly discussed as the next best thing for more than a decade?! And its exciting to think that San Antonio may finally have something for ER-positive cancers beyond the CDK4,6 inhibitors, hope this stuff is coming along for all of us!! Usually they post abstracts a month ahead of the meeting, which would be now, but their website is hopeless, cannot figure out if or when the abstracts go online..

[Deleted User]

I think that SanAntonio is just going to review the new SERD drugs in trial from my understanding. They are a pill and not a shot🙌🏻 I think they sound very promising. And the new Class of ERa drugs which I can’t remember the acronym.

When I asked Dr Hamilton about lasofoxifene which is supposedly fast tracked she stated it is still in phase 3 and is a long ways away. 🥴

Dee

moth

fyi, San Antonio abstracts drop Nov 17 (except those embargoed for press release; they will drop on the day the press release does).

Chemokaze

Hello - Hoping for the SERD pill for sure. I just did a little math, and figured I’ve had 56 Faslodex shots total. I’m grateful of course.....but ....

I haven’t been on the boards in a while, more of a reader than a poster...but truly think of and appreciate everyone in this community.

I just had a good PET scan a few weeks ago...I have not updated my profile, but I have been on Ibrance 100s for about a year now. I had too much diarrhea with Verzenio and chose to give ibrance a try....I was getting Zometa every month for 2 yes, but frequency decreased now to every 3 months. Yay!....Take care

[Deleted User]

chemokase

The good part is you have great response to your Tx. The bad part is all those shots! Thanks for connecting here.

Dee

cure-ious

Here is an interesting abstract from SABCS, page 367, quite a few big names on this abstract!:

https://www.sabcs.org/Portals/SABCS2016/2020%20SAB...

ESR1 mutation as a potential predictor of abemaciclib benefit following prior cdk4/6 inhibitor (cdk4/6i) progression in hormone receptor-positive (hr+) metastatic breast cancer

They report subgroup analysis identifying "two patients with ESR1 mutations (in the absence of concurrent driver alterations in RB1, FGFR, CCNE2, and ERBB2) who demonstrated progression on palbociclib but sensitivity to abemaciclib. In one patient, cfDNA obtained prior to palbociclib and fulvestrant exposure failed to reveal any ESR1 alteration. Following progression on palbociclib, and prior to sequential exposure to abemaciclib, an ESR1 Y537N alteration was identified. The patient went on to receive 16 months of abemaciclib monotherapy. In a second patient, an ESR1 D538G alteration was identified following progression on palbociclib and fulvestrant. The patient had several intervening regimens, and subsequently went on to receive abemaciclib and fulvestrant for 16 months."

Conclusions: HR+ breast cancer cells expressing mutant ESR1 isoforms were resistant to estrogen deprivation but retained sensitivity to abemaciclib in vitro. Furthermore, patients harboring ESR1 mutations via targeted sequencing of cfDNA, in the absence of other known mediators of CDK4/6iresistance, were shown to derive clinical benefit from abemaciclib following prior progression on palbociclib. These results suggest that patients with HR+ MBC, ESR1 mutation, and clinical resistance to anti-estrogen treatment and palbociclib may be candidates for abemaciclib treatment.

This was not a trial, but rather a correlation that they found in a couple of patients: In short, if you develop resistance to I/F because the cancer acquired an ESR1 mutation, you might want to try Fulvestrant and Abemaciclib, or even Abemaciclib as monotherapy...

[Deleted User]

Thanks cureous

It's hard to go by just a couple patients anecdotal cases but it sure gets researchers excited and possible clinical trials started!!

My first line Tx as you know doesn’t fit that story. My MDACC doc saw I progressed while trying all 3 AI’s so she presumed a resistance component before we did the sequencing and found ESR1 Y537N. So I asked for verzenio because of the brain barrier cross, and it was everyday and had good results in trials. She chose Faslodex because of my AI resistance. I progressed at 3 months with partial response of some necrosis in one tumor.

I know the researchers are trying to get the most out of the cdk 4/6 and trying to overcome the resistance, I hope the research on new serds will prove effective alternatives to faslodex andmake a better combo with the cdk 4/6

Dee

cure-ious

Oh, Dee, I'm sorry I didn't realize you'd already tried doing this- At this point, shouldn't they already KNOW who can take Verzenio after Ibrance, and exactly how effective or not it would be? You would think they already have more data just from subgroup analyses of trials that are now long over!

Well, these guys really need to step it up...

theresa45

Dee – I also have an ESR1 Y537N which I developed after a long run on letrozole. Ibrance/Faslodex did not work, but I have an RB1 loss mutation. The RB1 loss is why I never tried abemaciclib. I was briefly on the G1 Therapeutics oral SERD monotherapy trial which did not work for me. Since then I've been on chemos and am currently stable on Enhertu (DESTINY Breast04 trial for HER2 low). You wrote that you had a good run on everolimus/faslodex. Was that after or before you progressed on verzenio/faslodex? I'm wondering if once you progress on faslodex it is not likely that combining faslodex with another treatment (alpelisib, everolimus) will work… Any idea?

Thanks and best wishes on your trial! Theresa

BevJen

Theresa,

I don't have the answer to your question, but I had a long run on letrozole (2006-2019) so when I started Ibrance in 2019, my MO changed me over to Faslodex. I have the Pik3CA mutation, and so when we have discussed alpelisib/piqray, my doc always says -- of course, since you've been on faslodex, we don't really know if that combo will work for you. So I suspect there is some question about combining faslodex with other treatments. I would guess that if you are on a combo treatment, they are never totally sure which drug failed? Just my amateur guess.

[Deleted User]

Theresa, Glad you are stable! I don’t see why you could not try Envirolimus/Faslodex if your situation changes.

From what I have read,the ESR1 Mutation means AIs just don't work very well. Most Tx then turn to Faslodex instead. the ESR1 mutation does not prevent Faslodex from working but the thinking is it reduces the efficacy. So they are looking for better alternatives.

Since metastatic I started with verzenio/Faslodex combo and only got 3 months. Envirolimus/Faslodex was my 4th TX. First 3 months was only a small lung met- liver was stable. After 6 months I got more small diffuse liver mets. I then changed to the cdk 2/4/6 trial.

Wish we had more anti-hormone treatments to stop the estrogen. I am 100% ER+ but could not qualify for any of those trials at this time for various reasons

Dee

theresa45

BevJen – Wow! That IS a very long run on letrozole! I was on letrozole for 18 months as first-line for Stage IV which I thought was good. I took tamoxifen for 6 years until my Stage 4 was diagnosed. My oncologist says the same thing about Alpelisib/Faslodex (ie, that it might not work after progression on Ibrance/Faslodex), but she is not ruling it out as an option. She suggested possibly combining alpelisib (or everolimus) with exemestane since I haven't been on that AI. However, with the ESR1 mutation that seems even less likely to work. I think that your amateur guess is spot on.

Dee – It's encouraging to know that you got some benefit from Faslodex/Everolimus even after you progressed on Ibrance/Faslodex. My cancer is also still highly ER+ (95%), so I keep praying that one of the new oral SERDs or lasofoxifene will be effective with ESR1 mutations. I was excited when lasofoxifene was fast-tracked and read that "The study showed that lasofoxifene can disrupt the active conformation of the ER-alpha Y537S ligand-binding domain." That was in May 2019! The early oral SERD trials were monotherapies, which seemed less likely to work, especially when most of the participants had developed resistance to hormone-treatment. I'm glad that recent trials are now combining oral SERDs with CDK4/6 inhibitors and/or everolimus. I hope that the CDK 2/4/6 trial will be very effective for you!

ShetlandPony

I asked my onc how we could know whether Ibrance or letrozole had failed me, and she said, “Both". What?? I next tried Faslodex + Afinitor but it did not work. We later learned that the cancer was apparently using the ERBB2 Path to get around those previous drugs. So we block that ERBB2 path with neratinib, and we use faslodex so the cancer cannot revert to the ER route. So, even though faslodex failed with afinitor, The longer I go, the more I have to think it is working with neratinib. Does this make sense?

What I am trying to get to is that whether ESR1 or something else is preventing a SERD from working, maybe a different med along with the SERD will be successful.

theresa45

ShetlandPony - Thanks for sharing your experience. What you're saying absolutely does makes sense. I will probably try either everolimus or alpelisib with Faslodex at some time in the future. Blocking mutliple pathways seems to be the logic behind all these combos. The hard part is finding the right combo... I hope that Faslodex + neratinib will continue to work for you for a long time!!!

ShetlandPony

Thank you, Theresa. I’m coming up on ten months now.

[Deleted User]

Shetland

That makes sense about Erbb2 letting the cancer grow and now blocking it with neratinib. I wonder if ERBB4copy number gain only on the RNA could really be enough reason to try neratinib for me. My home MO and I think we may go after the Neuroendocrine next.

Theresa/ I asked my trial doctor about when lasofoxifene will be released and she said “a long time" since it is just now going to phase 3

Dee

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theresa45

ShetlandPony - 10 months is great! I hope that it will continue to work for a long time!

Dee - That's disappointing that lasofoxifene is a long way from becoming available outside of trials. Thanks for the info!

[Deleted User]

I'm doing some research for my next trial to see what is out there for "anti-estrogen" for ESR1 mutations. SABCS papers-

AZD9833 continues to show an encouraging efficacy and dose-dependent safety profile as a monotherapy or in combination with palbociclib. A Phase 2 study comparing the efficacy and safety of three doses of AZD9833 versus fulvestrant (NCT04214288), and a Phase 2 pre-surgical 'window of opportunity' study (EUDRA-CT; 2019-003706-2) are ongoing. page 203

Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity inpatients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270). page 151

Rintodestrant demonstrated robust ER target engagement on FES-PET, as well as substantial decreases in ER H-score, cfDNA VAF, and Epi+CD45- CTCs. These data, along with promising clinical benefit in pts with heavily pretreated ER+/HER2- ABC, regardless of ESR1 or PIK3CA mutation status, warrant additional investigation of rintodestrant (NCT03455270). pg 273

H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα). A phase I-II study was conducted to explore the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics, and efficacy of this agent in advanced ER+ and Her2- breast cancer pts (NCT03250676). pg 488

H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients including those with a constitutively active clonal ESR1 Y537S mutation.pg 245

The phase I-II trial (NCT03250676) enrolled 130 heavily pretreated pts with ER+, HER2- metastatic breast cancer, including 12 pts harboring high allele frequency clonal ESR1 Y537S circulating tumor DNA (ctDNA). pg 652

EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial cancer Recruitment for the EMBER study is ongoing (NCT04188548). pg 674

A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D- 0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting.(NCT03471663) pg 709

OP-1250 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN) that completely inactivates Estrogen Receptor (ER), blocks ER-driven transcriptional activity, inhibits ER-driven breast cancer cell growth, and induces degradation of ER. To examine ctDNA pre- and post-therapy for mutESR1 and PIK3CA variants, and other relevant markers. To evaluate whether ESR1 in circulating tumor DNA (ctDNA) can be correlated with response and/or activity of OP-1250 NCT04505826 pg 801

Among heavily pre-treated pts, SAR439859 demonstrated antitumor activity, similar to historical single-agent fulvestrant activity in less heavily pre-treated pts with advanced/mBC (2L+ setting; no prior targeted agents) (indirect comparison). In both subsets of pts with fewer prior advanced lines of therapy, SAR439859 showed trends of greater clinical activity versus historical fulvestrant activity. SAR439859 had a favorable safety profile with limited TRAEs. No safety signals of cardiac or ocular toxicities were observed. Ongoing parts of the study are investigating SAR439859 in combination with targeted therapies. Based on the monotherapy results, a randomized phase 2 study is investigating SAR439859 compared with physician's choice in a 2L+ setting (AMEERA-3; NCT04059484). pg 300 & pg 513

Development of a potent mutant-ESR1 targeted agent, ERX-245, for treating metastatic therapy-resistant breast cancer. From our virtual and functional screen, we identified an ERX-11 analogue, ERX-245 as the most potent hit to target MT-ERα. Docking studies modeled a better fit of ERX-245 into the ligand binding domain of both the Y537S and D538G MT-ERα. Pg 328

In a patient-derived xenograft model, which bears ESR1 Y537S mutation and is hormone-independent, AC682 significantly inhibited tumor growth whereas fulvestrant only showed weak efficacy. In conclusion, oral chimeric ER degrader AC682 demonstrated robust ER degradation and anti-tumor efficacy in preclinical models, supporting its continued investigation in the clinic. pg 341

a significant benefit was seen in pre-clinical models with lasofoxifene either as monotherapy or in combination with a CDK4/6i over fulvestrant (with or without a CDK4/6i) in breast cancer cells expressing ESR1 mutations. The multicenter phase 2 (ELAINE 1) study is currently enrolling patients evaluating the activity of lasofoxifene monotherapy compared to fulvestrant. pg 641

Hope this info helps someone else.

Dee

theresa45

Dee - Thanks for sharing your wonderful summary of new anti-estrogen treatments discussed at SABCS!! I also have the ESR1 Y537S mutation and found your list very useful! I'm sorry that your CDK 2/4/6 trial was not effective. I saw that you are about to enroll in the Phase 1/2 ARV-471 trial. Just last week, my oncologist mentioned that trial to me as a possible next option. It is currently open and recruiting at Stanford. I hope that you will have a great response! Best! Theresa

werone

Hi Theresa,

ARV-471 trial opening up in bay area ?

belll

Dear Dee, Thank you SO much for sharing your research on clinical trials for those with the ESR1 mutation!!!

belll

cure-ious

Hi Dee and Theresa,

I was just reading a paper that looked at the acquisition of ESR1 mutations with time for patients on Ibrance-Letrozole therapy. They found some, of course, showing that Ibrance does not prevent this mutation from popping up. It is not often found before treatment, but arises from the pressure exerted by endocrine therapy on the tumor to mutate. I thought it was interesting they mentioned that "the increase in mutant allele frequencies frequently co-occurred with an increase in the tumor marker CA 27.29. These results suggest that ESR1 mutations may be predictive of development of resistance during palbociclib and AI therapy."

Specifically raising the possibility that an increase in CA27.29 might be somehow be selectively picking up some ESR1 cells. In your cases, did you have increased CA27.29 at the time when the ESR1 mutation was detected? And/or, how did you learn you have the ESR1 mutation? And then it appears these can go away on therapy with Faslodex or especially a SERD, and I wonder if you ever saw the ESR1 levels go down? And then also if the ESR1 levels went down was there a corresponding decrease of CA27.29?

cure-ious

Theresa, Also I read that ARV-471 is scheduled to open up a trial for secondline/thirdline therapy where it could be combined with physician choice, did your MO say anything about that? This supposedly happens this summer. What would determine you deciding to join the existing trial with Ibrance (other than it is right there at Stanford and apparently they have openings?) versus waiting for the other trial and picking what drug to combine it with? I would think they would want at least Verzenio to be an option if they are aiming to be the choice for secondline as most people would have already taken Ibrance, given that it was the first to be approved- thanks

[Deleted User]

Cureious you find such interesting articles! My CA27-29 was normal 36.3 in Aug of 2019. CA 15-3 was slightly elevated then at. 31.5. My 1st molecular panel was Dec 2019 while I was on Xeloda. It found the ESR1 but my MO suspected it / that’s why I started with verzenio and Faslodex. No one checked CA 27-29 until 2 weeks ago and it was 41.

I was supposed to be in the ibrance arm of ARV 471 but since I had 2 separate rounds of Faslodex I was disqualified. Interesting about physicians choice combo. I will have to ask about that.

Dee

cure-ious

So Dee, does that mean disqualified from the whole trial, or just from the combo with Ibrance? I sent an email to the ARV-471 people asking if they will allow prior Faslodex in that trial, but no response so far..It seems to me they are getting some good responses with monotherapy, even with an ESR1 mutation, tho I would want to combine it with something if I were taking it. Anyway, clearly you have ESR1 mutant but CA 27.29 is not that high..

[Deleted User]

cure-ious

I’m on the ARV 471 trial - single agent. I was told I would get Ibrance combo but there are some restrictions to previous hormonal therapy limited to 1 (I think) in the metastatic setting. So because I had Faslodex twice ( 2 different times) plus sandostatin( for the Neuroendocrine part) I was disqualified to take the combo therapy. Trials are tricky, you think that they have all the info then the sponsor can change it up at the last minute. Happened to me twice now.

Dr Hamilton said they have seen good response for single agent- even some tumor regression. I am hoping for that. She did want the ibrance combo ( even though I failed on verzenio/Faslodex and CDK 2/4/6) to hopefully have a “good backbone” for the serd to work better in her words.

I’m glad I don’t have to deal with Ibrance ( the cdk 2/4/6 was hard on my GI) this trial will probably be my last Hormonal based attempt to control the cancer since I don’t qualify for others due to number of lines or IVIG.

Honestly, I look at this trial a test for my weird cancer. 100% ER positive but the original cancer stained 90% Neuroendocrine. So if it doesn’t work,I plan to switch gears. My home MO was excited about VLS-101 ( he actually looked it up before my visit this morning and new that Merck bought the company for about $2.5 Billion to get this drug) we talked about the payload and he said it could be promising. Love him for being prepared and willing to talk science with me.

Dee

cure-ious

Hopefully MikainSB will chime in, but she has had success for 15 months on monotherapy with this drug for ESR1 (its a SERCA)..

About H3B-6545
Estrogen receptor alpha (ERα) plays an important oncogenic role in the genesis and progression of luminal breast cancers and historically has been a target of endocrine therapies. However, recently, hotspot mutations in ERα have been detected in nearly 30% of endocrine-therapy resistant metastases. Functional studies have shown that these ERα mutations can confer ligand-independent activation of the ERα pathway and can promote partial resistance to existing classes of ER-directed therapies. H3B-6545, a first-in-class small molecule selective estrogen receptor covalent antagonist (SERCA) demonstrates activity in tumor models that harbor wild-type or mutant ERα. H3B-6545 activity against ERα mutants resistant to standard therapy provides an opportunity to target a currently unmet medical need both as a single agent and in combination with other breast cancer therapies.

mikainsb

Hi My People. (My People for the ESR1 and seriously scientific dialogue herein). Thank you for the invite/awareness Cure-ious.

YES! I have been on H3B-6545. It has been HIGHLY successful for me. All scans have shown tumor reduction (liver mets) and stasis (bone mets). My markers though (both CA27.29 and CA15.3) are now about four times what they were when I started the trial drug, 15 months ago, like three thousand or something scary like that. The markers did an initial doubling upon starting the drug, then a deep dive, but have recently accelerated upward again, despite good scans. I found H3B-6545 by far the most tolerable drug I have ever been on. I do have drug induced bradycardia, but it didn't bother me at all. Please let me know if you want more information about my experience on H3B-6545. I am so grateful for the fabulous 15 months I scored on it.

I am only 44. Basically my cancer could not be controlled until I had an oophy (ovaries removed). Even then, my blood work often showed higher than expected levels of estrodial. So while I did Ibrance/Faslodex, and held for 2 years, estrogen is really my problem, so probably related to ESR1.

I am either going to go to Havalin (chemo) or Lasofoxifene.

@AlabamaDee, seriously printing out what you wrote up so I can better follow up on it.

@Cure-ious, thank you for letting me know about this thread!