Are you currently (or have you been) in a Clinical Trial?
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Saulius, You are certainly right about how slow they are- I didn't see any updates on these trials out there for a year- is the problem the tumor microenvironment is too tough? For DF they aren't saying how durable the responses are, yet the phase 2 is fairly large trial, so they should be accumulating some numbers by now- also they are notable as the only Her2 antibody to be offered in combination with checkpoint inhibitors or chemo, but is that because they only get a decent PFS when the antibody is used in combination?
Meanwhile, newer antibodies are coming along all the time, some bind both natural killer and T cells and facilitate interaction with tumors:
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Hello all,
Well, good grief…
Good news: TTX-MC138 might have a slot open for me. I need a ferrin and transferrin saturation test before we'll know, and they want to do Caris and Tempus panel on me as well. This is all WONDERFUL news, except…
I was consulting with another facility and gave a verbal agreement to a different trial—NUV 1511, a drug-drug conjugate. I did call the facility as soon as I got word of TTX and told them to put a hold on the slot and I'm looking at another trial. But this would be the second time I've done that to this poor doctor, and I feel horrible. I certainly don't want to burn a bridge there either, and…
the last I read about TTX, they were not yet at therapeutic doses. BUT this is the 3rd (and I believe final cohort of their Phase 1 trial) so the dose is now 3.2mg as opposed to .4mg and .8mg. That's a big jump, so perhaps it will be therapeutic now…and I feel like my liver is only going to get worse, and if I want to try this trial, I better do it now. Their Phase 2 won't open until Summer 2025, and I don't want to miss my opportunity.
So my choices are:
- NUV-1511: a drug-drug conjugate. She said they've had a patient on it for 5 months. It is keeping people stable but not regressing. The side effects are blood-related (I don't remember what she said, cytopenia or something) but they are managing it. They have slots available and can get me in in three weeks or so.
- TTX-MC138: the one I really want, but not sure it's at a therapeutic dose yet. But I don't want to lose an opportunity to be in the Phase 2 trial.
I'm probably going to go with TTX, but Dr. Cheedella is going to murder me in my sleep. :/
CBL
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CBL: I’d go for the TTX; I think it’s very reasonable to hope that the 3rd-cohort-dose is therapeutic.
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Thank you, @luce. I think I'd be crazy to pass it up, but I feel terrible about going back on my verbal agreement. I probably should get over it, because she probably is by now, haha.
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Okay, here's the latest:
I qualify for TTX if my ferritin and transferrin levels are not too high. I looked up the symptoms and I don't have any, so I think I'll be okay. We will discuss a start date on Tuesday when I sign the end of treatment paperwork for Bria-IMT.
My RECIST score for progression last time was 25%, this time it was like 39% or something horrible I already blocked out. So overall from baseline the two they were measuring grew like 3 cm, and the other 43 lesions had 'mild growth.' Well as far as I'm concerned, mild growth of 43 little ones is still a hell of a lot!
I hope the TTX lives up to the hype. My math sucks, but I think there is a 400% increase from .8 to 3.24? That's cohort 2 vs. cohort 3, so if it's not therapeutic, it's at least better than I could've had. We shall see. I'll get all the deets on TTX (if I pass the tests) on Tuesday I believe.
As far as canceling the verbal agreement, my nurse said not to worry about it. It's the nature of the beast, and if the tables were turned, he'd understand and it happens all the time. So letting that go. (but still not canceling until I know if I'm guaranteed a spot in TTX)
That's it for this report. I'll update on Tuesday.
CBL
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CBL, Any info on whether anyone has had a durable response on TTX?
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The last thing I read is that there has been no response yet, but that was because they were not at therapeutic doses yet.
"Despite the fact that responses have not been observed yet, and some investors might be disappointed, H.C. Wainwright notes that the initial cohorts are likely below therapeutic dose levels. It is also highlighted that the study is still in the early stages of dose escalation with only three patients enrolled in each cohort."
So with the 400% increase in dose, I think I have a shot at it being therapeutic and hopefully fingers crossed it will work!
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Cure-ious,
I'm off Enhertu effective yesterday, so need to make some big decisions. I've learned of another study at Univ Wisconsin Madison that my oncologist did not mention: NCT06157892. The drug is Disitamab Vedotin alone or with other anti-cancer drugs. It's related to Her2. I've now sent a message to my oncologist with questions. What do you know about this study or drug?
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So this drug is from Seagen, developing next-gen ADCs, with a different and potentially better Her2 targeting antibody that works well in Her2-low cancers.
Study results thus far say this drug works well in cancers that progressed on Enhertu. And I also think some of these Her2 antibodies being developed for a new kind of immunotherapy, where the antibody binds Her2 and PDL1 or Her2 and targets on immune cells, are showing some progress, so if you took this now there could be easier things available for next step. They say this works on cancers with liver mets, we need more of these!
Disitamab vedotin in Breast cancer
In preclinical studies, disitamab vedotin, composed of a fully humanized anti‐HER2 antibody linked to the microtubule inhibitor monomethyl auristatin E (MMAE) via a protease‐cleavable vedotin linker, has shown a higher affinity to immobilized HER2 than trastuzumab.Following internalization, MMAE is released through proteolytic cleavage of the valine‐citrulline (vc) MMAE drug linker. Additionally, MMAE can also exert a bystander effect on adjacent tumor cells regardless of their HER2 status, leading to increased HER2 selectivity. In preclinical breast cancer studies, disitamab vedotin has shown potent antitumor activity, including HER2-low. [7]
SABCS 2024
During the ‘Novel HER2 Therapeutics‘ Poster Spotlight Session of the 47th San Antonio Breast Cancer Symposium (SABCS), held December 10 – 13, 2024, the first study results from a phase 3 clinical trial (NCT03500380) of disitamab vedotin in treating patients with HER2-positive advanced breast cancer with liver metastasis, were presented. [7][8]This first prospective randomized phase 3 study demonstrated significant efficacy in patients with HER2-positive advanced breast cancer with liver metastasis. The study results were presented by Professor Jiayu Wang from the Cancer Hospital, Chinese Academy of Medical Sciences.
Approximately 45% of patients with HER2-positive advanced breast cancer have liver metastasis, which is a significant adverse predictor of overall survival (OS). Patients with HER2-positive advanced breast cancer with liver metastasis have a poor prognosis with a 5-year survival rate of only 8% to 12%, for whom no satisfactory therapies are currently available.
A RemeGen-sponsored, randomized, open-label, multicenter phase 3 study comparing the efficacy and safety of disitamab vedotin versus treatment with the tyrosine kinase inhibitor lapatinib + capecitabine in patients with HER2-positive advanced breast cancer with liver metastasis. A total of 104 patients were enrolled, of whom 53 received disitamab vedotin and 50 received lapatinib plus capecitabine. All patients had previously been treated with trastuzumab and taxanes.
As of data cutoff date (December 31, 2023), according to the assessment by the Independent Review Committee (IRC), DV significantly improved progression-free survival (PFS) versus lapatinib + capecitabine (median: 9.9 months vs. 4.9 months; hazard ratio [HR]: 0.56 [95% CI: 0.35-0.90]), which is consistent with the investigator-assessed PFS (HR: 0.62 [95% CI: 0.39-0.98]).
The overall survival (OS) data, though immature, indicated a benefit trend in favor of DV. The safety profile was consistent with past disitamab vedotin use experience, with no new safety signals detected.
“This is the first confirmatory phase III study that demonstrated promising efficacy of an HER2-targeting ADC in patients with HER2-positive advanced breast cancer with liver metastasis,” noted Professor Jiayu Wang.
“Disitamab vedotin demonstrated clinically meaningful benefit compared with lapatinib + capecitabine and a manageable safety profile, potentially offering a promising new treatment option for patients with HER2-positive advanced breast cancer with liver metastasis previously treated with trastuzumab and taxanes,” Wang added.
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Here is a report from a year ago in OncLive:
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Dear CBL, could you ask the NUV trial investigators if you could go for this trial after TTX?
Dear Cureious, I am always baffled by so many choices - it is difficult to select a drug for a patient already, and the market is exploding with new mabs/adcs, so what is going to happen with poor doctors who have to make decisions in the future? Or drugs will be selected by some AI algorithms?:/ I don't think there will be one drug to cure it all - there still will be 3-5 drug combos for many years to come…
Saulius
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Hi Saulius,
I didn't have that question on my list to ask, but it is now! It would be a good thing to know. TTX is an mRNA-10b (think that's right) inhibitor and as far as I know, the only one, so it very well might keep me off of other trials. We shall see.
CBL
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@bsandra I am happy and daunted at the same time just trying to look at the Phase III clinical trials. I'm not a scientist by any stretch of the imagination, but I know something about research and I keep thinking I'll be able to master the language to understand these things, but I am so so glad to have folks like @cure-ious . I wish there was some way to collate and translate these trials and make them understandable for non-scientists, namely metastatic breast cancer patients.
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Saulius, Are there other Her2 antibodies you are tracking? While it was obvious these would be a big priority for Her2 immunotherapies and vaccines, I hadn't realized they might also be used for Her2-low cancers, and provide treatments for the "post-Enhertu" space.
Although genomic testing has completely changed the treatment landscape, many of the clinical trials listed on Guardant and other reports are missing newer and more promising treatments (IMHO), and some of the mutations listed as variants of unknown significance are in fact know cancer-causing mutations for which treatments may be coming along. I assume AI is going to make a big difference in this area and that the next-gen test reports may be a lot more informative. Another change I've noticed is many more clinical trials being offered globally.
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My MO told me the DF1001 study with Zanidatamab/Evorpacept combo NCT05027139 (at Univ Wisconsin Madison) is for women who have NOT had Enhertu. That's not exactly how I read the criteria as written on ClinicTrials.gov……."Patient must have progressed after one line of systemic chemotherapy". I've progressed after two lines of systemic chemo (Afinitor and Enhertu), so maybe that's what she means? Not sure how to raise more questions without sounding challenging.
And according to my MO, the other clincial trial with disitamab vedotin (NCT06157892) has a waiting list of 2-4 months. So I asked her to add my name to list. This means I will have to start one of the chemos she recommends (Doxil, Taxol, Erubilin) or go on Hospice.
Wendy
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@weninwi We don't have the same type, I'm ER+ PR-, HER2 (0), but Erubilin beat it back about 75% and slowed it down. I didn't have any side effects, and it was very easy. It only lasted 5 months, but it gave me time to find a clinical trial. Hope you find something that works for you soon.
CBL
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cbl,
Thank you for your comments. Sounds reassuring. When you say no side effects, did that include NOT losing your hair, eye brows, and eye lashes?
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@weninwi No, actually my hair started to grow back on Erubilin. Trodelvy had me bald as a cue ball and was rough for me—I couldn't write, was depressed, and super fatigued—, but Erubilin was great. One week on Erubilin, I was writing again, had energy, hair growing…It's still wispy and thin and growing super slow, but I think that's from my last trial. And most importantly, it kicked the crap out of the cancer!
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wanted to check if anyone tried Elacestrant/Abemaciclib or other hormonal therapy after being on ADC (enhertu) & abraxane/ taxol
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werone- My MO said insurance (Medicare) was unlikely to cover both Elascestrant and Abema as both are pricey drugs, so I am also curious to know if others have found that it was covered no problem- some many drug combos are out there now that docs are unlikely to always know exactly what will or won't get thru
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Thanks @cure-ious . i was wondering if these combos work for people who have already used 2-3 line for ADC+Chemos.
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Well if the cancer is now endocrine-resistant, one could try CDK2 inhibitors paired with the newer CDK4 inhibitors and some oral SERD….
including the new Pfizer CDK4 inhibitor PF-07220060 which is even stronger than Abema and can work on cancers resistant to the first-gen CDK4,6 inhibitors- it is now in phase 3
CDK2 inhibitors coming along:
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Cure-ious,
The Inclusion Criteria for NCT06157892 Disitamab Vedotin Alone of With Other Anticancer Drugs reads:
Cohort A (HER2-Low Breast Cancer) Inclusion Criteria
- Prior therapies requirements
- No more than 3 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mBC.
- Have progression on or after, or intolerant to, T-DXd, sacituzumab govitecan, or other topoisomerase I inhibitor therapies, if available as local standard of care therapy
I don't really know which of my past treatments would be classified as cytotoxic chemotherapy regimens including ADCs? Have I had more than 3 already?
If I start one of the drugs my MO has now offered: Doxil, Taxol, Erubilin, I assume these would be classified as Cytotoxic Chemotherapy, right?
0 - Prior therapies requirements
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thanks for the insights @cure-ious
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WeninWI, yep those three are all chemo- as are ADCs are like Enhertu, Trodelvy, etc. Drugs targeting ER, CDKs, PI3KCA, etc, are targeted therapy so they wouldn't count…
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Hello! I have progressed after 8 years on letrozole/IBrance. I was recently offered a spot in a trial at Dana Farber for the new Pfizer CDK4 inhibitor PF-07220060- 50% of participants would be on Faslodex + PF-07220060, and 50% would only be on the new drug (no Faslodex). This seemed a little chancy. My Guardant blood test in 2021 was negative, but in 2024 came back with very low % (under 1) of ESR1 and Pik3CA mutations.
The oncologist is recommendeding Faslodex + Verzenio as an alternative 2nd line treatment, which is where I am headed, I guess. But not elacestrant. Does that make sense?
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Polemomium, Wow, you got an amazing run on firstline! I agree w/your assessment, and if ESR1 and PI3KCA levels jump in future as cancer gets more resistant (as often happens), you will have better options for oral SERDs, PI3KCA drugs, and the new CDK4 or CDK2/4 inhibitors
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weninWI, with such high ER numbers, and the CCND amplification, it seems a trial with CDK2i would be good?
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Pole- Also, regarding Faslodex, it depends which mutations as it can handle some of the ESR1 mutations, tho definitely not Y537S for example- also if the ESR1 is low and/or subclonal, maybe he is concerned that Elascestrant might not work on well on those mets that have the wild-type ESR? I think the approval originally said it was for mutations greater than 1%, but insurance nowadays seems to be OK with any value. there will be many chances to get either Faslodex and Orserdu in future endocrine therapy combinations, so he might be thinking of a longer term strategy, I'd ask him…
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Polemonium: I think it does make sense to not use a SERD yet because using a SERD now may exclude you from future trials that use a SERD. And your percentage being so low, although no one seems to really know how the % impacts treatment response, at least not last time I checked a few months ago. (As for whether to go with the trial or your oncologist’s recommendation, I’d go with switching endocrine therapy to fulvestrant and MAYBE switching to verzenio, but might try staying on ibrance for now. That way, you could try verzenio and a SERD in future. There are trials backing up my recommendations:
PADA 1 for the switch to fulvestrant
Ember 3 for combining SERD with verzenio. Works across mutations, including Pi3k.
As for which specific ESR1 mutations are considered more fulvestrant-resistant than others, I have a screenshot from SABCS that might help. Mind you, the data is from 2018.
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