Are you currently (or have you been) in a Clinical Trial?
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As discussed above, Enhertu ADC (approved for Her2-positive and in trials for Her2-low cancers) comes with a risk for lung problems, because there is a rare situation where some people have Her2 expression on normal lung cells. This can cause respiratory problems and the patient has to get off of the drug. However, this issue is rare, and doctors know to watch out for it. Having lung mets may make one more concerned about trying the drug, but the two issues (ie, Her2 expression levels on normal lung cells vs lung mets) are obviously completely different.
For example, here is a 46yo MBC patient with lung mets who is currently doing well on Enhertu:
https://www.wbtv.com/2020/09/04/newly-approved-dru...
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Susan,
Regarding the Her3 ADC, there is a paper showing that it synergizes with checkpoint inhibitors. It did not indicate whether high PD1 expression was required for the effect (but presumably if one had high PD1 they woiuld already respond to the immunotherapy without the ADC.. They say in the Finn/UCLA paper that the tumors that tend to respond well to Ibrance have low PD1 but high Her3, which is consistent with this paper saying the Her3 tumors don't normally do well with immunotherapy on their own)
Abstract
Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3-targeting (HER3-targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor-resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.
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Dee- you are a fearless pathfinder! I admire your efforts and I’m praying that you are lead right into a successful treatment plan. Hugs.
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Dee I loved your post.
I, of course didn't love that you feel frustrated and let down and worried and anxious...but you are entitled to feel everything you are feeling. I am glad you posted that you did all the leg work. I have been private messaging with someone on here that goes to my cancer center but does not have my MO and she feels hers doesn't go "outside the box enough and look for new things for her"...I told her most MO's don't...we bring them ideas and things and then they look. Gosh Cureious helped me SOOO much that at one point I brought my MO a folder of what looked like a short novel...I was actually embarrassed bringing it...but we have to. They are busy as well with patients and their stuff I don't mind bringing stuff and having to do the leg work as long as they cooperate..but I will admit it can be frustrating and tiresome just like you feel Dee.
Vent away lady we are all here to listen and cyber ((((HUG)))) you!
PS: you really are awesome and know so much you are a value to this community and I especially value all the insight you have given me
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Dee,
I wonder if you should look for another MO. Although I also do my own research, I rely on her to weigh in on what I have found. She is already familiar with all of the trials. She has also gone to bat for me to get on drugs like Keytruda for off-label use. She has also convinced a pharmaceutical that I am not HER2+ even though my FISH said I was (IHC said equivocal).
I spoke to her about the U3-1402 trial but she said the SEs have been really bad.
BSandra, I believe Enhertu, Trodelvy and U301402 have different antibody targets, HER2, TROP2 and HER3, respectively. However, they all deliver a TOP1 inhibitor so I think you can only be on one of them. Although I am not TN, I'm on Trodelvy and it is keeping me stable. I am HER3+ and HER2 low (IHC=2, FISH=2.17). Daiichi Sankyo also has a third ADC in development. Don't know the details. Not sure why they all deliver the same payload. Would be great if there were ADCs with different payloads so we could get on more than one of them.
Hugs, Susan
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Susan, Great points, what are they thinking, of course they should have different payloads- our docs dole out lots of regular chemos, but we are only allowed to get one ADC?! I had read they design the ADC chemo using old chemos that are too toxic to use nowadays, so we won't have already seen the drug and become resistant to it, but why not just design ADCs that would be alternatives to specific conventional chemos?
Important to know that the Her3 ADC is showing bad side effects.
Dee, I wonder if your MO, or a new MO if you decide to change, cannot call and get compassionate use for Lasofoxifene or anything else you want, on the basis that you have this immunodeficiency and cannot get these in a trial? It definitely seems wrong that you are taking some drug in a clinical trial because you cannot have the one you would prefer to try owing to this condition. The answer could be no but they should be trying hard to get good options for you, this exclusion seems so unfair..
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In lung cancer Phase I trial for U3-1402, 42% had SEs >= 3.One person died of lung complications, not ILD.
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Here is an interesting review of the CAR-T design and whether it should be from single patient cells or try to use donor cells Perhaps it will be better to use CAR-NK (Natural Killer) cells. Other option would be stem cells as source, then differentiate them to the CAR vehicle as needed.
https://www.nature.com/articles/d41586-020-02675-w
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Dee, I HATE to hear this and feel your pain, anger, fear and frustration coming through. I am thinking of you. {{HUGS}}
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Cure-ious,
Thanks for posting that article about CAR T therapy -- very interesting.
I've been looking at several clinical trials at NIH that deal with T cell therapy -- for the nonscientists among is, is that different? One trial is looking at genetically engineered autologous T-cells, one is looking at cells engineered using the Sleeping Beauty Transposon/transposease System (whatever the heck that is), and yet a third is looking at tumor-infiltrating lymphocytes (which I think but am not sure is something totally different -- this may be the Judy Perkins trial???). They all look very interesting, all have a lot of requirements, all have significant hospitalizations at NIH, but they all sound like they could become something.
Any comment from you, our science guru?
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I have a strong aversion to anything to do with immunology, so many cells with so different names and mysterious functions- hopefully somebody with real understanding can come along and chime in...
In the CAR-T procedure, they are engineering cells to express a T cell receptor that will attack some specific tumor antigen (some protein fragment that is on the surface only of only the cancer cells). Those cells are grown up and injected into you and go attack the tumor. One challenge is what T cell receptor do you use, what proteins are on your cancer cells? We don't have a marker on the cell surface of all ER-positive cancers (the estrogen receptor works in the nucleus). They analyze your cells for that, which would probably be prohibitively expensive outside of a trial. But now we know there is at least one universal cancer antigen that is on all cancer cell surfaces, and there will be a clinical trial on that starting next year. The more cancer-specific antigens they find, the better.
Another problem is if the cancer is shielded by other immune cells so the T cells can't really get at it- They are trying cytokines and NSAIDs and other drugs to get access to the tumor, so immunotherapy and CAR-T can work. Other problems are if the cells are too short-lived, or too long-lived, there are a lot of issues, but they also can give the most transformative results
So, what trials are you looking at? They could all be doing CAR-T of some sort. Judy was in the Steve Rosenberg trial. To do a CAR-T procedure costs about 100K+, so there aren't so many of these trials around and they are picky about who they take, no idea what the criteria are..
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Dee, you have worked so hard, worked for your very life, and it is so wrong that you have doors slammed in your face. This is not right. You need a champion on the inside.
Here is a quote from our JFL on the Piqray thread, discussing drug approvals. She is interested in Enhertu, but the principles apply to other drugs, too: “ ...there are laws requiring insurance companies to approve off label uses of cancer medications if certain conditions are met - primarily, one doesn't qualify to take the drug in a trial and at least 3 reputable, peer-reviewed medical journals have published safety/efficacy data on the off-label use for which one is seeking insurance approval. I was able to get Ibrance/Faslodex/Aromasin approved under this law back in 2015, in advance of when Ibrance was FDA approved for use with Faslodex. Given that Enhertu is approved for HER2+ already, certain safety/efficacy data for use in HER2 low has been published in multiple reputable, peer reviewed medical journals, and I don't qualify for Enhertu in the DESTINY-04 HER2 low trial because I have exceeded the permitted number of chemo used, I do have a shot at getting it now.“
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Cure-ious,
Thanks for the further explanation of CAR T. I think that the trials that I've flagged at NIH are variations on that. But I'm not applying just yet because each of the trials requires that the participants meet RECIST criteria, and I am having my lone liver tumor that could meet that ablated in October. Most of my disease right now appears to be in my bones, and unfortunately, many trials won't use that for qualification.
Anyway, the three trials that I have flagged are the following, for any inquiring minds who want to know:
NCT01174121 -- this is a TIL study that I think either is the one that Judy Perkins was on or is related -- it involves taking white blood cells from tumors, growing them, and then giving the cells back to the patient. This one requires 4 weeks in the hospital (not exactly appealing in Covid times)
NCT03412877 -- this is a Stephen Rosenberg study, or it's so labeled -- this one involves genetically engineered autologous T cells, trying to isolate mutations and then cause the white blood cells to attack the tumor cells. Involves 1 week in the hospital to get chemo, then receiving the changed cells, and then a stay in the hospital for 1-2 weeks.
NCT04102436 --also a Stephen Rosenberg study -- this also involves modifying white blood cells to recognize changes in their tumor -- it uses something called the Sleeping Beauty System and also involves targeting mutations, from what I can figure out. Again, it's a wonderful 4-5 week time in the hospital. Also involves chemo. Also requires oral meds, plus filgrastim (everyone's favorite).
I think they all sound really interesting. It's whether one wants to spend that amount of time in the hospital, plus go through all of the testing before and after the hospitalization. As I said, I live near enough to the hospital to do this, but not if I can't see anyone from my family for 4+ weeks. I guess it's a tradeoff for me.
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Bev- Agreed, it should be easier to find some effective checkpoint immunotherapy combo trials and wait awhile longer for the CAR-T procedures to be worked out
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A new paper in Nature took a systematic approach to identify all the genes that are needed in a cancer cell to hide effectively from the immune system. Interestingly, they found that genes involved in the autophagy network (a pathway used to dispose of large molecular complexes and damaged organelles) are involved in protecting the tumor, and that an autophagy inhibitor that blocks the VPS34 kinase can overcome this effect.
https://sci-hub.scihubtw.tw/https
/www.nature.com/articles/s41586-020-2746-2#citeasPrevious studies have already discovered a synergy between autophagy inhibitors and immunotherapy (link below), so all we need now is for some clinical trials to get going for ER-positive MBC..
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Dee,
A few days ago you were asking for advice on NGS testing and what people knew, etc.
Well, today my MO responded to me and said that when I have my microwave ablation of the lesion in my liver (now scheduled for Oct. 19th) she would like it if the IR could try and get a biopsy of the tumor before ablating it. I've had Foundation One tissue testing in May 2019. A couple of months ago, I had Foundation One and Biocept liquid biopsy testing done. My MO would like another biopsy and genomic testing now, if they can get enough tissue to do that -- and this time, she wants to try with Tempus to see if we can get any more definitive information about what's driving my cancer.
This prompted me to do a little bit of research on Tempus, with which I'm not so familiar. That led me to a good article talking about all of the NGS possibilities, including a handy dandy chart explaining some of the difference among them.
https://www.hematologyandoncology.net/files/2019/0...
I thought the article (especially the chart comparing NGS procedures, etc.) to be quite informative (even if written more for a clinician than a patient). Passing it along.
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Bev....Tempus is who my MO uses too. They seem to be very good. Thats what I will do as well...in addition to also getting a biopsy when she goes in for my Y90.
Cureious I did a lot of research with regards to triggering Autophagy....some good videos on that...but the verdict is still out, on whether its actually gonna be GOOD or BAD...b/c they can eat their debris to stay alive...or sometimes they die from autophagy....ya just don't know which will happen...thats the SHORT of it...lol and literally just SHORTENED it...not worded the way it should be ...but yea...you get the gist of it I'm sure...lol
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Thank you very much for that article, Bev!
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Thanks for all the support and info here! I really appreciate y'all. I had a visit from my brother yesterday (had not seen him since Christmas) and feel refreshed and in a better place mentally.
I got a call late on Friday from SCRI that I will sign consent on Wednesday for the CDK 2/4/6 trial and get my bloodwork and scans right afterward. 🙌🏻
biopsy and first dose the following weekThere was some concern about tumor availability (Resist criteria) for the biopsy, because they need to be able to observe a different tumor for measuring and my biggest tumors are the locally treated ones that are all shrinking. I told them I have one untreated 1.5 cm tumor in the liver that should work for the biopsy as well as new tiny growth in the liver and a second untreated tumor in the lung that should be measurable for the trial. They were going off old scan reports, so I sent them the latest ones. Don't know how that happened.
Even in the confusion, I have a peace starting this trial and hope it will give me stable disease.🙏🏻 So far no confirmed partial response has been reported, but several patients have stable disease. It is scary though because one person had organ failure so that is on the list of potential SE😳
I recently switched to a new home MO who is getting involved, thankfully. He looked over the trials and said that he is willing to give breast cancer drugs one more try. If I continue to progress, he wants my next line to be a platinum-based combo for the Neuroendocrine features.Then he will help me pursue the off label PRRT at either MSK or Moffitt. I have already made those contacts and he will help me negotiate the waters when necessary. Meanwhile he is great about watching my care. My MDACC doctor is going on maternity leave so I was assigned a random new doctor that I can choose to see after my trial scans in early December.
I don't believe I would meet the criteria for “right to try" or expanded access yet for lasofoxifene or other hormone trials because I still have drugs that I can try for standard of care (Halevan, gemzar, etc) and I could push for a PARPi that could be tried off label because of my MRE11a. That is one reason we want the extra biopsy samples for a new genomic testing and why my MO wants to switch gears to the Neuroendocrine route to see if that is what is driving the cancer. FYI-Afinitor has allowed growth but it has worked the longest fo me and it is also used for Neuroendocrine.
The good news is the Pfizer cdk 2/4/6 trial will let me stay on IVIG. I am 8 weeks out and feeling a little vulnerable. One more blood test to check levels then I will get the infusion if needed.
Onward to the next line! NCT03519178
I believe this article is generally about my trial
https://www.pfizer.com/news/hot-topics/attacking_cancer_cells_that_develop_resistance
FYIAnyone have a skin lunch biopsy in the butt? Just wondering what that is like
Dee🦋
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Interesting article, Dee. And it has your - and my -- favorite phrase in it: whack-a-mole!!! Glad you are feeling more positive. Onward and upward!
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Dee really happy for you and glad your brothers visit lifted your spirits!
I am on a platinum based- Eribulin/Halavan...I have to tell you (with regards to side effects) so far so good! But I am heading into cycle 3 and thats when things can happen but I am believing all will be GOOD! AMEN!
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Dear SusaninSF, absolutely, Enhertu, Trodelvy and U3-1402 have different targets but please note that these drugs are so powerful (like Enhertu and U3-104 that have bystander effects) that margins between what they target ,,on paper" start to disappear. Most of the cancers that are HER2- by IHC, are still HER2 positive (1+ or 2+), and all of them (Luminals and HER2 enriched, also normal-like) might be TROP-2, HER3+, PD-1 "negative" on paper but actually still positive when you look at %. So application matrix starts to depend on genomic/expression profile, not on older HR/HER2 evaluation. Let's say someone with HER2(1+), ER+ and PD-1 in theory might be treated with Enhertu+ER-blocker+Atezolizumab (which was never tried and toxicities might be too big, I agree). I think such approaches and combinations, especially for a good RECIST MBC population would start to produce first, at least radiological, pCRs... Therefore I think Enhertu is for almost everyone who is at least a bit HER2+, not just for HER2+people, same with Trodelvy and others... I am positive for MBC future, I just hope future is tomorrow and not in 25 years...
Dear Curious, I think one company, like Daiichi Sankyo, who found a ,,good platfom" with a water soluble deruxtecan, is not able to invest that heavily trying to add other payloads to one antibody. Anyway, they would not be able to do it easily, i.e. to add anything else... To add deruxtecan they had to develop a special linker. That one would be different for another payload, which would take thousands of hours of development, if possible to get that linker, then stability, and then clinical benefit at all...
Saulius
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Saulius, You make a good point, drug companies will not spend to make a better/safer version of something already available in the clinic, what was I thinking?!
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Not sure if anyone is looking for an immunotherapy trial right now, but if you are, you might look into the NIMBUS trial, which is NCT03789110. It was recommended to me by a doc from UT Southwestern to whom I wrote actually asking about another trial. It's being offered right now at Dana Farber, UT Southwestern, and U Pittsburgh -- I think that's it. It's a combo immunotherapy trial of nivolumab and ipilimumab -- both have been tested before, but not in this combo, I don't think, and also not for metastatic BC that is "hyper mutated" and HER2 negative. Both drugs are given intravenously, one every 2 weeks and one every 6.
There are a whole lot of restrictions (as with all of these trials) and from what the principal investigator at Pitt just told me, you have to have a tumor that is at least 1 cm (also a common thing, from what I understand).
Just thought I'd put it out there.
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https://emeatribune.uk/trojan-horse-treatment-makes-cancer-self-destruct-without-use-of-drugs/
Thoughts.... (besides it will take 50 years to get approved)....
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Nicole,
It will take 50 years to get through.
I think someone else posted an article on this, or something similar. It sucks to see these things that sound great but that haven't even come to the clinical trials stage.
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I get frustrated when people post on the breaking news thread about things that are years away from any possible practical application.
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hey all
I sign trial papers and get my CT scan tomorrow. I have been having horrible general headaches and shooting neck ache only on the right side. I had the neck ache part back in January but it subsided. The general headache has been going since June (2 clear brain MRIs).
I am wondering if it has anything to do with my port which is on the right side. Got the port last December. I also have neck arthritis, breast scar tissue worse on right, Lymphadema in right arm.
Why do these things have to flare when I have big events? 🥴
Also- I was thinking about asking for the Caris CDX ngs for my biopsy since it includes RNA and so much science is expanding there too. Anyone here have that one?
going to check which one insurance will cover.Dee
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Dee,
Good luck to you on this trial.
You are wise to check on insurance coverage on the Caris test. I just wrote to Tempus, which my MO wants to use on my upcoming liver biopsy, to see about coverage under Medicare. They directed me to fill out their financial form online just in case Medicare doesn't cover, which would limit my out of pocket to $100.
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BevJen, That looks like a great trial, Nivo-Ipi is a powerful combination, the trial is just for people with high tumor mutations 9 or greater per megabase DNA, and therefore more likely to respond to immunotherapy.
The rest of us have to find trials that include something to increase an inflammatory microenvironment and exposure of the cancer to the immune system, such as the trial Kattysmith describes at the top of this thread, which gave her a nine month respite and I think weareonthecusp also did have a positive response to that trial, both of them treating ER-positive cancers (don't know their tumor mutation burden). Should be other good immunotherapy trials that have started up since then but not sure how to find them (easily)
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