Are you currently (or have you been) in a Clinical Trial?
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It would be helpful if the mods could bring in a guest breast oncologist from time to time, so we could ask a few questions, after the first couple of lines of endocrine therapy, the best steps forward and sequence of events can be far less obvious
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Thank you everybody to keep this thread so packed in info!
@cblaurenceauthor I think OS it is very important as weel as PFS, because as Cure-ious said a therapy can work also after it is discontinued. Also certain therapies may turn cancer more aggressive after they stop working, other weakened it. And again, some therapies may make working better or not working at all the lines of treatments that are use afterwards, by enancing or eliminating some tumor caracteristics.
So keep track of it (if for example a drug keep people PFS 8 months but after that they immidiately decline and have a very short OS) is import. All though the study may not understand all the causes involved in the process, but it is sure an important number number to keep in account!
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Excellent point about PFS and OS. My cancer exploded after Trodelvy stopped working—like in a month my liver was 60% tumor. Fortunately, the Halaven seems to be working somewhat to keep it under control. I don't think I'll have much of a choice but to go on the vaccine and hope it keeps going.
Thanks for the info and I'll keep everyone posted!
CBL
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Amel, I feel the same way about Orserdu, e.g., it may not work for long if monotherapy is insufficient to hold back the cancer, but at least it is quickly clearing out the reservoir of ESR1m cells, and these might not return if we don't select for them with AIs, so overall its making forward progress.
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SPECULATION AHEAD:
Okay, so get this sh*t…
I just received the results from my Signatera test: it went from 129 to 3.5. That's a like 96% drop. The last drop was from 1529 to 129. This is all on Halaven. So my tumor markers went down 50 (25%), then Signatera goes down 96%, but my scans supposedly show slight progression. However, my last set of scans were misread, so I'm guessing this round has also been misread. Jesus.
I have an appointment with my regular oncologist in 90 minutes. The Signatera report was published yesterday so she probably hasn't even looked at it yet, but I'm guessing she'll either reorder scans, a re-read of the scans, or a repeat test of something. With any luck, I'll stay on Halaven and skip the trial for now.
If it turns out a change of treatment is not necessary, I'll be grateful, don't get me wrong… but WTF? I sure the hell don't need to be on this kind of emotional rollercoaster AGAIN and freaking out my family and friends, and wasting my time and trial people's time, etc. etc. Get it together, radiologists!
It's possible my liver is so covered in cancer, it's hard to decipher, but @#$TT$RW!!!
Anyway, I'll post what she says as soon as I know. Ugh. Stupid cancer.
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what is the signatera measuring? Meaning which value went down?
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This was for circulating tumor dna - similar to tumor markers, but more precise.
At least that's my understanding.
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Okay, so she wasn't as impressed with the Signatera results…not the news I was hoping for, but at least all my worry and stress wasn't for nothing. :)
Considering the mixed response indicated on the MRI, she still considers it progression and a change in treatment is necessary.
She doesn't consider a vaccine to be immunotherapy (which I was concerned with since I don't have the PD-L1 or anything else to say I'd be a good candidate).
She will run weekly labs until I start the trial in case my cancer explodes like it did last time we can back out of the trial and start Gemzar right away.
Sorry for the freakout. Will let you know what the trial coordinator says about my questions.
CBL
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CBL, Sounds like Halaven did a lot, and maybe its better to leave a bit early & give time for the vaccine to work? Good luck!
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Updates stats on RLY-2608+Fulvestrant for PI3KCA mutants
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Cure-ious very intrresting what you wtote about Elacestrant and clearing esr1.
I wish there were more studies about all this, the right meds sequencing, the effect on meds on cancer cells genetic...i think is so important.
CBL good luck. Let us know about the vaccine!
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ESMO update: A phase Ib/II study in patients with metastatic breast cancer (mBC, n=26) and other solid tumours (n=7) demonstrated that a combination of selective inhibitors of CDK4 (PF-07220060) and CDK2 (PF-07104091) was generally well-tolerated with promising antitumour activity. For patients with mBC, median progression-free survival was 8.3 months and the clinical benefit response rate was 50.0%. Of the patients with mBC and measurable disease (n=18), 5 had partial responses (all with known ESR1 mutations) and 5 had stable disease. Commenting on the results, Siu says, “This is a clinically relevant strategy as all patients with mBC in the study had previously received CDK4/6 inhibitors. Resistance to these agents occurs and such patients will require new treatments. It is also noteworthy that patients with ESR1 mutations appear to be particularly responsive to the combination used in this study and may serve as a selective biomarker for future evaluations.”
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Background. We present dose escalation multicenter data of PF-07220060 (PF-60, CDK4-selective inhibitor) plus PF-07104091 (PF-91, CDK2-selective inhibitor) in patients (pts) with HR+ HER2- metastatic breast cancer (mBC) and advanced solid tumors (NCT05262400).
Methods PF-60/PF-91 (100/225, 200/75, 200/150, 300/75, 300/150 mg) was given orally twice daily (BID) in 28-day cycles. BC pts could start fulvestrant at Cycle 3. Primary objective: safety and tolerability; secondary objectives: pharmacokinetics and anti-tumor activity. Efficacy data reported for mBC pts.
Results
At data cutoff 9 of Oct 23, 33 pts median age 56y, median 3 prior lines of systemic therapy (range 1–14) were enrolled. 26 (78.8%) had mBC (all prior CDK4/6i, 80.8% fulvestrant, 50.0% chemotherapy); 7 pts had other solid tumors. Treatment-emergent adverse events (AEs) occurred in 32 pts (97.0%; 21 [63.6%] grade [G] ≥ 3). Most common were nausea (66.7%; 3.0% G3), neutropenia (66.7%; 33.3% ≥ G3) and diarrhea (63.6%; 3.0% G3).One pt discontinued due to treatment related AEs. Dose-limiting toxicity occurred in 2/6 pts at 200/150 mg [1 G3 nausea; 1 G2-3 hematological AEs], and 3/8 pts at 300/150 mg [1 G4 thrombocytopenia; 1 G3 fatigue; 1 G2-3 fatigue and gastrointestinal AEs]. Steady state exposures were comparable to monotherapy. Early (cycle 1 day 15) decreases in circulating tumor DNA were seen. Based on safety, 2 recommended doses for expansion (BID: 100 mg PF-60/225 mg PF-91; 300 mg PF-60/75 mg PF-91) were chosen in combination with endocrine therapy. Of 18 mBC pts with measurable disease, 5 (27.8%, all with known ESR1 mutations) had RECIST v1.1 partial responses (PR) with duration of response up to 12.1 months (mo), 5 pts (27.8%) had stable disease. For mBC pts (n=26) median progression free survival (mPFS) was 8.3 months, disease control rate was 69.2%; 6 pts are ongoing at data cutoff.
Conclusions
PF-60/PF-91 combination was generally well tolerated with promising antitumor activity in heavily pretreated post-CDK4/6i mBC pts, including 5 PRs in mBC pts with ESR1 mutations and mPFS 8.3 months. Dose expansions are enrolling CDK4/6i-treated and naïve mBC pts.
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Has anyone been involved in any clinical trials targeting B7-H4? Any success? Trying to decide what my next steps should be. Progressed on Trodelvy and Enhertu.
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Thank you cure-ious for posting the presentation from the NCT05262400 trial at ESMO (for the CDK2 and CDK4 combo). That was the trial I was in from late February 2023 until April of this year - so I was one of the heavily pretreated patients who had a good response. I'm now on Enhertu - and to my surprise and my home oncologist I'm having a good response too. So one upside of having done the trial was that in the meantime Enhertu became funded here in Canada for people with low HER2+.
Good luck to the others looking at trials, I'm sorry to have no advice other than to keeping trying and to commiserate that finding and participating in trials is a lot of effort.
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Hi NewGardner!!! So great to hear from you, you rock!!! Girl are you serious that you are now 15 years metastatic?! Damn!!!! You also should be proud to have contributed to that CDK2-4 trial, they have since discovered that if you hit CDK2, then CDK4 takes over, and vice versa, so you gotta hit both. But that CDK2 drug has been really hard to take, esp as combo, and has taken a long time to even get this far, so hopefully they are pushing it hard across the finish line now…
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MLane,
For AZD8205, 9/44 got tumor shrinkage, however it does have the same chemo payload (Topo I inhibitor) as Trodelvy and Enhertu, and there is some speculation that you get diminishing returns by hitting the cancer with the same chemo and just a different targeting antibody, so you might ask the trial people about that?
There is good pre-clinical data for SGN-B7H4V (see below), which has a chemo payload is different from Trodelvy and Enhertu, maybe this could also be a good choice
https://www.researchgate.net/publication/374464094_SGN-B7H4V_an_investigational_vedotin_ADC_directed_to_the_immune_checkpoint_ligand_B7-H4_shows_promising_activity_in_preclinical_models
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MLane- Don't know if its an option for you, but eIF4A is looking like a good target too
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So here is something different: Research by the Stand Up 2 Cancer team for PI3KCA, including Lewis Cantley who discovered the PI3KCA protein, realized that PI3KCA drugs were creating some DNA damage similar to what is seen in BRCA mutant cancers. They reasoned that these drugs should synergize with PARP inhibitors, which are normally only used to treat BRCA mutant cancers, and found that they did. That has lead to some trials, esp focusing on ovarian cancer patients who got resistance to PARPi (ie to allow them to go back to PARPi drugs), but also to some MBC studies. Most importantly the results conclude that these drugs kill cancer cells, even for cancers that lack PI3KCA or BRCA mutations!
Now a Phase 1 trial is looking at this question using Capivaserib (TruQAP) rather than Alpelisib (Piqray) and have reported promising results:
Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers, with or without DNA damage response and PI3K-AKT pathway alterations.
so this might end up giving us a new line (PARPi+PI3KCAi) that wasn't even on the list before…
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This seems promising! I think, lol. Not sure what I’m reading. I’m still waiting to see which arm I’m in. Will update next week.
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CBL- The link you posted there is for BriaCell-IMT, which is in phase 3 trials now. It works best for Her2-positive cancers: Results reported at the 2024 ASCO Annual Meeting.
•Median overall survival of 15.6 months in Phase 2 Bria-IMT™ study patients treated in combination with immune checkpoint inhibitor
•OS of 15.6 months compares favorably with 6.7-9.3 months reported for similar patients in the literature
•Ongoing Phase 3 study investigating Bria-IMT™ in similar metastatic breast cancer population
•No drug related discontinuations to dateThe overall response rates in the hormone-receptor–positive, HER2-positive, and triple-negative breast cancer subgroups were 10%, 50%, and 0%, respectively, so mostly this benefits the Her2-positive cancers
The exciting part is that now that they are in phase 3, they are making this treatment available to everybody who qualifies (mostly by not having other good options, etc), so you could get it from your own MO.
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For ER-positive MBC, the efficacy of paclitaxel was doubled (at least) by the addition of pelareorep.
Final BRACELET-1 efficacy data were collected and analyzed two years after the last patient was enrolled as specified by the protocol. Results of the final BRACELET-1 analysis show that the median OS was not reached in the pelareorep + paclitaxel arm, as more than half of the patients in that arm remained alive at study end. In contrast, median OS for the paclitaxel monotherapy arm was 18.2 months, and the hazard ratio was 0.48 for pelareorep + paclitaxel vs. the paclitaxel monotherapy. Had study follow-up continued beyond two years, and patients survived only until the next planned visit (in four months), the median OS for patients in the pelareorep + paclitaxel arm would be 32.1 months. In accordance with these results, the two-year survival rate for patients in the pelareorep + paclitaxel arm was 64% compared to 33% for paclitaxel monotherapy patients. Additionally, the final median progression-free survival (PFS) for BRACELET-1 was 12.1 months in the pelareorep + paclitaxel arm vs. 6.4 months in the paclitaxel monotherapy arm, representing a 5.7-month benefit with a hazard ratio of 0.39.
Confirmed overall response rate (ORR) was 37.5% for pelareorep + paclitaxel and 13.3% for paclitaxel. As previously reported, ORRs at week 16 (the trial's primary endpoint) in the pelareorep + paclitaxel and paclitaxel monotherapy cohorts were 31% and 20%, respectively.
"The fact that the median overall survival was not reached because more than half the patients were still alive at the end of the study is a remarkable achievement for us," said Wayne Pisano, Interim CEO and Chair of Oncolytics' Board of Directors. "It shows just how promising pelareorep treatment can be for extending the lives of breast cancer patients. This is further exemplified by the near doubling of the 2-year survival rate for patients who received pelareorep combination therapy."
- Things were worse when they added a checkpoint inhibitor
- Some patients in this trial were in earlier-stages, like 2nd line
- They are preparing for a phase 3 trial
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Look like pelareorep have a good response, I wonder if it work well on his own...I couldn't find any studies of it on his own for breast cancer.
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So, one unfortunate aspect of liver mets is they are notably less responsive to immunotherapy (IO). A new paper in Nature Immunology from the experts at Penn suggest that one key to better cancer treatments overall, including response to IO, is dealing with inflammation in the liver, which activates STAT3 and leads to release of compounds that block dendritic cells and T cell activity.
This suggests a need to add anti-STAT3 and anti-inflammatory compounds to treatments where liver is involved. The king of anti-inflammatory may be the new Ozempic-type drugs, but also Celebrex/NSAIDs, and the MSM powder is anti-Stat3 and anti-inflammatory…
https://www.pennmedicine.org/news/news-releases/2024/april/could-the-liver-hold-the-key-to-better-cancer-treatments
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And I'm reminded that Katty Smith, who started this thread, got 7 months in a trial that combined taking a Celebrex-derivative with Keytruda, as you can read from the very first entries here…
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Interesting stuff! I still haven't heard which arm I'm in for the vaccine trial, but I can try NSAIDs to reduce inflammation. I also have fatty liver and liver mets, so it's a mess. Fortunately, my numbers are still good, except for Alk phos and another one not common one I don't remember, like GTT or something.
Thanks for posting, @cure-ious !
I hope to have an arm by tomorrow.
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Okay, so I found out today I'm in the Bria IMT vaccine only arm. The other arms were vaccine plus a Keytruda-like drug or physician's choice (Gemzar). I think it's the best one for me since I don't think the other drug would do much for me (HR+, no PD-L1, etc.) and the Gemzar would just burn a treatment and keep me off a different trial for longer.
There are three other trials I want at that facility: an Aurora A inhibitor, a CDK2i, or TTX-MC138. The last one had great animal results (like cured it in 65% of stage 4) but I think that happens a lot and they can't transfer it to humans. It's not open yet, but I'll try it if I can.
So far my liver is holding up but by the time I get dosed, I'll be off treatment for 35 days. I'm a little worried since the vaccine takes longer to work if it's going to work at all and I'm not scheduled to be scanned for 8 weeks (or symptoms/bad bloodwork) so I'd rather fail faster and jump to the Aurora or TTX trial.
I'll keep the thread posted!
CBL
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CBL, I thought this link was very helpful in considering Bria-IMT and when to take it, here they are suggesting it as something that can be tried even after ADCs like Enhertu. and I think earlier studies showed responses were not really any better when Keytruda was added, so maybe don't worry about that one.The cell line has multiple neoantigens and works in all MBC subtypes.
"These are the kinds of trials we need to do in the post-ADC world…. If this regimen does work, [these data] could lead to the approval of Bria-IMT plus a checkpoint inhibitor as a standard of care post progression on an ADC,” Brufsky said.Chumsri further contextualized the significance of this regimen in the context of cancer vaccine development. “If you look at the history of cancer vaccine development, there has not been any other additional cancer vaccine approved since sipuleucel-T [Provenge] in prostate cancer 14 years ago. Therefore, this cell-based vaccine could provide us with an entirely novel treatment paradigm.”
Please update often here, would love to hear about it all, side effects etc, and best of luck!!!
https://www.onclive.com/view/bria-abc-trial-explores-novel-post-adc-strategy-for-metastatic-breast-cancer
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Wow, CBL, the TTX-MC138 trial is interesting, I did not know about it. Inclusion criteria are pretty simple, the mechanism of action is different from known classes of drugs… really very interesting!
Saulius
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