Are you currently (or have you been) in a Clinical Trial?
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@cure-ious I act on assumption that I am not the only one who needs my MO attention. Like with the CARIS test: first one from liver biopsy was done per their order. This is how I know I have RB1 mutation. But it is not necessarily that my GI has the same one as Guardant360 doesn’t show any mutations. So I asked for genetic testing on GI biopsy and my MO agreed it would be beneficial. But she thought it would require a letter to insurance to have them approve second genetic reporting. I was waiting and waiting and at some point I called CARIS and asked them if this can be done. And they were very nice. Not only they called me back, but 20 minutes later after the first conversation they called again to let me know that insurance will cover second testing as long as it is from a different site. I passed this info to my MO and team and they requested my slides from my GI and send them over.
I think the worst case scenario- they won’t answer me. But who knows!Here is some interesting info:
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I wrote to them too and hopefully they will start testing in NJ at the end of this year.
Thank you for the articles. Will go over them now.Appreciate the work you do
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Also as discussed above Pfizer is touting their KAT6 inhibitor for endocrine-resistant cancers:https://www.nature.com/articles/s41591-024-03060-0
Abstract
Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2−) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2− mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration:
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Cure-ious-what would we do without you? I am so grateful for your willingness to share your knowledge. I have no scientific background but you are able to explain things so well. Thank you.
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Here is the KAT6 trial. Requires not more than 3 lines ET nor more than 1 line chemo:
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Thank you for all of your info. Cure-ious. I really appreciate it!! I haven’t posted lately but I keep up on this and a few other threads. After coming off the ARV-471/affinitor trial due to severe grade 3 pneumonitis my lungs felt so much better and I started Truqap in the end of February. I haven’t had a good response to any treatment yet progressing on or having a mixed response first on Ibrance and then Enhertu. I had one stable scan on the trial but then pneumonitis. My trial doc at UCLA suggested truqap should work because I was responding to affinitor before the pneumonitis. I started February 26 and my tumor markers dropped quickly and by 80%. I had my first scan in May and it was my best scan in 2 years since diagnosis. Mediastinal and hilar lymph nodes resolved completely, lung nodules resolved, liver mets smaller and less FDG, and most bones except my sacrum resolved. I was elated. But my markers are starting to climb a little again 2 times in a row. It’s been about 6 months and the PFS is 7.4. So I’m looking for trials again to just have options but the pneumonitis disqualifies me from several. The KAT 6 trial doesn’t mention pneumonitis as an exclusion so I’m going to look into Cedar Sinai. I am a little leery only because if I am progressing and I’m currently on Faslodex I wonder if it’s not going to work for me with the other agents or if it’s pik3 drug that could be failing. I don’t want to move onto xeloda and potentially eliminate myself from a trial with a second chemo… I am also debating circling back and trying Verzenio with tamoxifen with it which my onc at UCLA said I could try since I haven’t used either drug before and they’ve been tested. But I sure hope I’m still stable truqap has been great for me. But I want to have my options in place for the future. So thank you for all of the info. and your extensive knowledge. :)
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Ah, you guys thanking me is so sweet, but you do realize I'm posting this stuff for myself as well? I go back and read stuff I posted, not even that long ago, and have no recollection of ever even reading about it!
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MommaCJ, Thanks for updating- I think quite a few people here have had this problem with pneumonitis, and some trials can be hard to get into for that reason, so I think it would help us to have an idea of what drugs are in phase 3 and might end up getting FDA approved so we can plan out what to try…
I noticed that KAT6 was one of a couple drugs Pfizer had at the top of their PR release at ASCO 2024, and that trial looks promising. KAT6 is an epigenetic drug, it erases some of the modifications on histones and can make both the tumor and the microenvironment quite different, so its possible it really changes up the response you might get this time. Please post whatever information you get about this trial as you talk to the team involved there.
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Regarding PI3KCA inhibitors, there are three mutant-selective drugs in trials: two drugs, RLY-2608 and STX-478 (the latter has a trial at Cedars-Sinai in LA), inhibit the mutant forms of PI3KCA and may act in a similar manner and have fewer side effects than the FDA-approved Piqray and Truqap, and LOXO-783, which is different and only inhibits the H1047R mutation. For the LOXO drug, the big global phase one trial was just scuttled by the pharma, stating only that they have better drugs in development that would "serve the patient better".
RLY-2608 has been going on longer than the STX-478 drug and looks to be quite good for those cancers with PI3KCA mutations.
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Another epigenetic drug (similar to KAT6) called entinostat had a big effect on TNBC when combined with two immunotherapy drugs (PDL1 and CTLA-4 type)- whereas TNBC typically might get a 15-20% response to immunotherapy, that jumped to 40% when adding in entinostat… ER-positive tumors boosted up to 10% response.
This was the end of phase one, the trial is no longer recruiting but the pharma says they hope to have a phase 2 trial up by the end of the year…
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Thank you Cure, I will definitely post what I find out. I had a partial response to iBrance. I wish it was a different CDK4 drug but it's Pfizer so naturally they would use iBrance. I find the triplet study very interesting. I am ER+ about 60% and Her 2-. My Caris report said, which my oncologist found very interesting, that my PD-L1 biomarker was positive 100%. It is very rare with ER+ mbc so she thinks I could possibly be a good candidate for immunotherapy if there was a trial or I could somehow try it. I'll have to look into that trial too. Thank you!!
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MommaCJ, Definitely rare to have such a high PDL1!! I wonder if you have also high tumor mutation burden (TMB)? that might be another (ie separate) indicator for immunotherapy response. And would that mean you might respond to the trial that is using CAR-T against MUC1, interesting to consider…
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Circling back to PI3KCA mutations…
The makers of the PI3KCA inhibitor RLY-2608 are planning a phase two trial to open up by the end of the year that will offer the drug in combination with fulvestrant and the new Pfizer CDK4 inhibitor, atirmociclib.
Atirmociclib is more selective for inhibiting CDK4 (and not CDK6), which should cause less neutropenia, and is also about 20x stronger than Ibrance and 4x stronger than Verzenio.
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Three recent reports in the latest Cell show that anti-PDL1 and anti-LAG3 immunotherapies synergize (ie, act much better than either alone) when combined to treat melanomas.
And interesting, there is a report from earlier this year that a woman with heavily-treated metastatic TNBC (in skin and lymph nodes) in a phase 1/2 trial (NCT02460224) who received this combination of PDL1 and LAG3 immunotherapy had a durable response of 50 months that as of last Feb was still ongoing. In this case, the cancer had 3 putative targets for the LAG3 immunotherapy.
"In this report, we present the case of a patient with TNBC who experienced a complete tumor regression when treated with a combination of PD-1 and LAG-3 blocking antibodies. In particular this case belongs to a phase I/II, open label, multicenter study investigating the safety and efficacy of the humanized immunoglobulin 4 (IgG4) anti-LAG3 mAb ieramilimab (LAG525) ± the humanized IgG4 anti-PD-1 mAb spartalizumab (PDR001) in patients with advanced solid malignancies."
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Immunotherapy breakthroughs will come in other cancers before they find success for ER+ MBC, so its worth keeping an eye on advances: Two recent papers in Science report that combining JAK inhibitors with PDL1 checkpoint inhibitors worked significantly better than either alone, opposite of what theory predicted. The idea is PDL1 is activating the T cell and JAKi is keeping the T cells from exhaustion and working on the myeloid tumor microenvironment:
Study #1: In lung cancer, adding the JAKi to the mix partially or completely shrank the tumors of 14 of the 21 participants (67%). And it kept their tumors at bay for a median of more than 2 years. In other clinical trials, by contrast, tumors have been found to shrink in less than half of people with metastatic non-small cell lung cancer who get pembrolizumab as an initial treatment. And among those whose tumors do shrink, the treatment typically stops tumor growth for only a few months.
Study #2: Dr. Teijaro and researchers at the University of Minnesota were testing the JAK inhibitor ruxolitinib (Jakafi) and the immune checkpoint inhibitor nivolumab (Opdivo) in a clinical trial of 19 people with Hodgkin lymphoma. All participants had previously received an immune checkpoint inhibitor that hadn’t worked for them or had worked only marginally. When immune checkpoint inhibitors fail for people with Hodgkin lymphoma, there are few treatment options left, Dr. Teijaro pointed out. “Their [cancer is] resistant to most [drugs] by that time. This is a really tough patient population to treat,” he said.
But when nivolumab was reintroduced with the JAK inhibitor, tumors shrank in 10 people (53%), including six patients whose tumors disappeared completely. Two years after the start of the trial, 46% of participants had no sign of their cancer growing back (disease progression). In contrast, 2-year progression-free survival was 23% in a small clinical trial of people with lymphoma who received nivolumab and another drug after nivolumab alone stopped working.
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Below is a link to a good review article that details the genetic changes in endocrine-resistant cells. Most common are ESR1 (a constitutively active form of estrogen receptor that no longer needs estrogen to drive cell growth) and PI3KCA mutations. In addition, there are several different mutations that can drive CDK2 levels very high and in this case sensitivity to CDK4,6 could be restored in the presence of CDK2 inhibitors, and some of these mutations might not be on the front page in Guardant but on the second page as part of a list of mutant "Variants of Uncertain Clinical Significance" so it is worth having a look at some of the more prevalent of those mutations. Another process that can contribute to resistance is an increase in the tumor mutation burden (TMB), which is listed at the bottom of the first page of Guardant reports.
https://www.sciencedirect.com/science/article/pii/S1535610820301495
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Hi curious and others!
Wow, some amazing information here! Thank you Curious and all!! I will have to do some studying for sure!!
KAT6 trial is still going well. Tumor markers went all the way to normal but then I had to take a break for a week because of low white blood cell count and they jumped quite a lot and I could feel the Mets again. Crazy after only one week off. My liver scans continue to improve. I haven't seen the bone scans but radiologist reports while they are extensive, they seem stable. I go back in a week so hopefully tumor markers have dropped back down. When I stay on top of eating red meat and keep my white cell count up, my energy is better than any treatment I have been on for sure! (Liver and onions are my friends!). Main SEs are very drippy eyes and taste is off. But I do still nap daily.
I understand the new arm of 3 weeks on and one week off is not going well.
Curious, yes I was on I/F for 5 wonderful years with some help from radiation. Esr1 very low of 2% and no PI3KCA mutations. AI never really worked for me.
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Hi @cure-ious and All
I guess we have the same problem with RB1 and your ASXL1 mutations that cause resistance to CDK4/6 and drive CDK2 up. So far I was unable to find any publications on the drugs that can target CDK2 and restore sensitivity to CDK4/6i. If you have any info please share
Thank you
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Laguna,
Yes ASLX1 mutation is just one of several ways that CDK4,6i resistance can develop, and these usually lead to unrestrained CDK2 activity. Studies indicate to reverse resistance we want to: 1) get CDK2 down; and 2) hit CDK4, but not really CDK6 (less neutropenia). There are two CDK2 inhibitors but still in clinical trials, Pfizer has PF107104091, which has been in development for a long time and several people on this site were on early trials where the dose was way too high and SEs were too hard, not sure where it stands now, and BLU-222, which I think is looking good but is still in phase 1. From MD Anderson site: “Robust preclinical research has shown that there are certain tumor types that have the potential for increased levels of certain biomarkers, such as cyclin E and CDK2 activity and/or loss of the Rb tumor suppressor,”. These dang trials take too long!
https://www.tempus.com/publications/loss-of-asxl1-tumor-suppressor-promotes-resistance-to-cdk4-6-inhibitors-in-er-breast-cancer/?srsltid=AfmBOoqmCLajJxZtNvnEOEICVnQctn9J60kkVezCvJuvnQcx2ZOdDFrg
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Perky, You definitely put KAT6 on my list, its exciting that the epigenetic inhibitors are showing promise! They see activity of the drug even as monotherapy, and with fulvestrant response was 30% with PFS of 11 months (5 months to ongoing responses…)- looks really good
Also, altho we all track TMs like the stock market, they can jump up literally months before scans show anything, one article that said on average it can be six months or more before scans show anything.
I have a general question for trials- if you have progression, you want to get on a drug fast. But trials make you wait 2-4 weeks, after they sign you up and evaluate you- so what do you do in the meantime with the waiting?! I see lots of trials with things worth trying, but the way the system is organized, it seems better to just go with whatever your doctor can rustle up in short order?!
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This BLU-222 is still ongoing, but for some reason the 11 patients on combo BLU+Ribo+Ful were not followed up. Still no optimal dosage. But it requires multiple lines of treatment (5-6) and HER2 negative. I don’t know if the consider those who had surgery, chemo and AI 16 years ago as pre-treated or it only applies to the recent treatments? And also do they differentiate between HER2 negative and low? I am low.
There was a partial hold on trial due to photosensitivity, but it was lifted in 2023 so hopefully they will proceed this year. I think they are enrolling patients now
https://www.targetedonc.com/view/fda-lifts-partial-hold-on-phase-1-2-vela-trial-of-blu-222-for-solid-tumors
https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.1056
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Hi Laguna, Yeah, they only count metastatic treatments; and I agree, given how critical it is to get CDK2 inhibitors out, its not clear why we aren't hearing more about them and how the trial is progressing.
Here is a poster; they haven't treated a ton of people so far, but give details for one responder with a 30% tumor shrinkage undergoing treatment
"A 77–year–old female with Stage IV HR+/HER2− breast cancer (metastases to bone and liver) with PIK3CA and ESR1 mutations, who had been treated with 6 prior lines of therapy in the metastatic setting (CDK4/6i palbociclib +letrozole, exemestane + everolimus, alpelisib + fulvestrant, capecitabine,gemcitabine, and TDxd). Prior to coming on study, the patient had progression on TDxd with a new liver metastasis"..
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Exciting report from Luce. Reporting in The Lancet on Truqap (Capivasertib), for PI3KCA mutant cancers:
Between June 2, 2020, and Oct 13, 2021, 901 patients were enrolled, of whom 708 patients were randomly assigned to receive capivasertib–fulvestrant (n=355) or placebo–fulvestrant (n=353). The median age of the patients was 59 years (IQR 51–67) in the capivasertib–fulvestrant group and 58 years (IQR 49–66) in the placebo–fulvestrant group. At data cutoff (Aug 15, 2022), the median duration of follow-up for progression-free survival in censored patients was 13·0 months (IQR 9·1–16·7) for capivasertib–fulvestrant and 12·7 months (IQR 2·0–16·4) for placebo–fulvestrant in the overall population. EORTC QLQ-C30 global health status/quality of life (GHS/QOL) scores were maintained from baseline and were similar between treatment groups throughout the study period (difference in mean change from baseline of −2·5 [95% CI −4·5 to −0·6] with capivasertib–fulvestrant vs −5·6 [−7·9 to −3·4] with placebo–fulvestrant; treatment difference 3·1 [95% CI 0·2 to 6·0]). Median time to deterioration in EORTC QLQ-C30 GHS/QOL was 24·9 months (95% CI 13·8 to not reached) in the capivasertib–fulvestrant group and 12·0 months (10·2 to 15·7) in the placebo–fulvestrant group (hazard ratio [HR] 0·70, 95% CI 0·53 to 0·92). Time to deterioration HRs for all EORTC QLQ-C30 and QLQ-BR23 subscale scores showed little difference between the treatment groups, except for diarrhoea, which was worse in the capivasertib–fulvestrant group than in the placebo–fulvestrant group (HR 2·75, 95% CI 2·01–3·81). In PRO-CTCAE symptom assessment, the proportion of patients reporting loose and watery stools “frequently” or “almost constantly” was 29% higher at cycle 1, day 15 in the capivasertib–fulvestrant group than in the placebo–fulvestrant group, decreasing at subsequent cycles. Other PRO-CTCAE-reported symptoms (rash, mouth or throat sores, itchy skin, and numbness or tingling in hands or feet) were absent or mild in most patients in both groups throughout treatment. According to the PGI-TT, most patients in both groups reported “not at all” or “a little bit” of bother from treatment side-effects.
*And for those with ESR1 mutations, Truqap with Elascestrant should be even more potent.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00373-5/abstract?dgcid=raven_jbs_etoc_email
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That seem a very good result. Will Capivasertib work at all on cancer without PI3KCA, and no other mutations either? It will be available here in autumn, but i think i may not be a good candidate as i have no mutations...
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Hi Amel, Capivasertib is for PI3KCA mutations, which tend to show up in later stages, so it might not be detected up front but only in later Guardant genetic tests or a biopsy…
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Thank you cure-ious I will look into that in my next liver biopsy.
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Hope this is the best discussion board to post this. I found this update on the new oral SERD Camizestrant and comment by Lille D. Shockney RN interesting. Source:
Lillie's comment: "It is always good to see new phase I clinical trials directed toward the development and research of new drugs for patients with metastatic breast cancer. Given that visual effects were the leading treatment-related adverse event at 56%, it will be important to include them in the clinical pathway–specific eye examinations. Additionally, many patients with advanced breast cancer continue to drive and perhaps also continue to work. This may pose a challenge because, if a patient is involved in a car accident, it may be linked to taking this drug. Who, then, is responsible? Is it the patient or the provider who wrote the prescription or, in this instance, enrolled them in this study? Are there ways to reduce this treatment-related adverse event while remaining on the protocol?"
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A new trial is announced that will test the Trodelvy ADC in combination with a new CDK2 inhibitor (for those who are resistant to CDK4,6i):
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My Guardant test lists gene mutations as "Variants of Unknown Significance" on the second page. The top one on my list is SF3B1, a splicing factor. The same mutation was picked up in 2021 on a Foundation One report, which lists nothing actionable. In researching this mutation, it is in 7% of metastatic breast cancers, and more abundant in several other cancers. It gives rise to replication stress in a way that is different from BRCA mutants, but also sensitive to PARP inhibitors. Therefore, other genes in this class may be identified and generate a new set of protein defects that could be eligible for these drugs. Although insurance may not pay for these drugs to be tried, sometimes they do approve if documenting evidence can be provided. Heere is a lay summary of one of the papers:
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for PI3KCA mutant cancers, and update for RLY-2608 was provided this morning-
PFS 9.2 months, ORR 33%. For kinase domain only (H1047 mutants): PFS 10.3 months, ORR 53%
They will open a trial including a new CDK4 inhibitor from Pfizer this year, and start phase 3 in 2025 where the comparison will be Capivasertib (Truqap; PFS 5.5 months)
https://edge.media-server.com/mmc/p/va3nrjyv/
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