HER2- with ERBB2 mutation
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Thanks. I will post results here. Also posting on the clinical trials thread.
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I was re-reading this thread looking for links to papers for someone, and noticed that I said I would post my results. I have been in the phase II SUMMIT trial using neratinib, herceptin, and faslodex for 7 1/2 months. I had an immediate and dramatic response, and am still NEAD. The ERBB2 mutation is not super common, but it is more common in ILC, and gives those whose tumor harbors such a mutation another possible treatment. I encourage fellow patients to request next generation sequencing when a treatment change is needed, as it may direct you to some good possibilities.
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That’s great news, Shetland Pony, and thanks for sharing your knowledge this is a very informative thread.
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Hi Shetland, I am so pleased to hear that you have had such good results on this combo! I lost track of you and wasn't sure what your current tx was or how you were doing on it, so seeing your post on this thread was a nice surprise. I have been on Piqray for over a year now and my last scans were mixed, CT showing stable but PET showed a new liver met and suspected progression. My mo was ready to change my tx, but after we discussed the scan results we decided to increase my Piqray dose instead. But neratinib with fulvestrant will likely be my next tx if insurance approves it,
I would be very interested in hearing about the se's on your current combo, as well as when the phase II SUMMIT trial will be completed.
I just love hearing you continue to be NEAD on this combo! Hope it lasts for a long, long time.
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So nice to hear from you, jobur! I’m glad you have been doing well, and have a promising next option ready if needed. The short answer about side effects is I have had to learn how to manage the typical neratinib side effect of diarrhea, and the not typical side effect of hypertrichosis (due to EGFR kinase inhibition). The long version is on the Nerlynx thread. Just be ready to either reduce your dose, or use the dose escalation method to start. I am on four pills per day, not the “standard” but insane six pills per day.
I got insurance approval for neratinib, but decided to join the study as my onc was enthusiastic about it. The sponsor, Puma, pays for everything including PET-CT and CT with contrast. (There is a choice of CT or MRI.) They are still recruiting. There are 62 study locations.
Estimated Primary Completion Date : September 30, 2021 Estimated Study Completion Date : March 30, 2022 https://clinicaltrials.gov/ct2/show/NCT01953926
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ShetlandPony, so glad to hear that you're NEAD! Wishing you years, and decades, of the same!
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Shetland, Thank you for the good info and link to the trial. I live in a rural area and was surprised to see there is a study location within a couple hours drive. Thanks too for participating in the trial. You are giving all of us who are looking to this as a future tx the precious gift of good information. So glad it is giving back to you!
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Thank you, Bestbird! Jobur, the trial is a win-win, and it was there just when I needed it.
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I started neratinib about a week ago. Started at 120mg and adding 40 mg per week. So far, so good.
Shetland, hope you are still doing well on your combo. Thanks for the idea of starting low and increasing dose over time.
Anyone else out there who is HER2- with erbb2 mutation?
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Jobur,
I am also HER2- and on my last genomic report (Tempus) I am showing two ERBB2 mutations. It is very much on my MO's radar. I also have multiple other mutations ( I am tumor mutation burden high) and so today, I am starting keytruda, hoping that my cancer will respond on the basis of tumor mutation.
Neratinib is on my list of potential future treatments if this doesn't work. Or the full trial that Shetland Pony is on. I'm curious how you were able to get neratinib outside of a trial? I thought it was only available on trial at this point in time.
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Hi BevJen,
Apparently neratinib is available outside of clinical trials. I didn't have to jump through any special hoops and my part D insurance preapproved it with no problems.
Wishing you good luck with Keytruda. It seems like having more mutations (at least those with new tx possibilities) may be a good thing these days with so many new targeted therapies coming out. Please let me know how Keytruda works out for you and I will post my results with neratinib here too.
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Hi, jobur! (And Bev!) Well, this is exciting, to have two of us on neratinib for mbc. It's just a couple weeks away from a year for me. Still NEAD with normal TMs. On my third try I also started with 120 (three pills per day). My onc had me do two weeks on that dose to make sure I was ok after my rough start, then I went to 160, and there I stay. How are you doing with side effects? Are you taking anything other than loperamide/Immodium? Here is the thread where some of us discuss side effects and dosing. The others are taking it for stage III.
https://community.breastcancer.org/forum/80/topics/870980?page=14#top
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Shetland, its wonderful you are approaching a year already on this treatment. Do you mind sharing which Her2 mutation(s) you have? I have been reading up on Her2 mutations that are thought to be the cause of endocrine therapy resistance for ER+ patients:
"Recently, using isogenic knock-in HER2 mutations in ER + MCF7 cells and xenografts, two activating HER2 mutations located in the kinase domain (L755S and V777L) emerged as resistance to anti-ER therapy progression. These findings are corroborated by other authors, and the same mutations have been identified in metastatic biopsies of eight patients with ER + metastatic breast cancer (MBC), as mutations that were acquired under the selective pressure of ER-directed therapy such as aromatase inhibitors. The same authors demonstrated that the resistance to ER-directed therapy was overcome by combining fulvestrant with the irreversible HER2 kinase inhibitor neratinib. These data suggest that the prevalence of HER2 mutations might increase in metastatic ER+ breast cancer treated with anti-ER therapy, and these mutations are a distinct mechanism of acquired resistance to ER-directed therapy in metastatic breast cancer that could be solved by the treatment with an irreversible HER2 inhibitor. Overall, these data suggest that patients with ER+/HER2 mutations would benefit from HER2-targeted therapies in combination with hormonal therapy. If ongoing clinical trials confirm these results, new approaches could be adopted in order to promote a better response in patients with ER + MBC, and one of these strategies could be to identify HER2-mutant-resistant clones to ER-directed therapy.
L755S and V777L mutations emerge as a distinct mechanism of acquired resistance to anti-ER therapies in ER+ metastatic breast cancer that was overcome by combining fulvestrant with the irreversible inhibitor neratinib. Furthermore, patients with metastatic breast cancer HER2+ with L755S and V777L could benefit of treatment with a new TKI, poziotinib, that is in phase II of clinical trials. Clinical studies suggest that HER2-negative breast cancer patients carrying the HER2 mutations reviewed here can benefit from HER2-targeted therapy. In future studies, different combinations of mutations in patients and their treatment with different combinations of drugs need to be considered."
The report further indicates those with both Her2 and Her3 mutants may be less likely to respond, and those with low tumor mutation burden do better than those with high. Sounds like you may already be a very strong responder beyond the expected pfs?
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Hi Shetland, Thanks for popping back in! Oh how I love hearing you are still NEAD!!! I did a bit of reading in the neratinib thread, my main take away was watch out for big D. I didn't read the whole thread and missed the details of your initial problems with this drug. Did you start on 240mg? Glad you are feeling well at 160 and still seeing great results.
I am just finishing my week at 160mg and will go to 200mg next week. So far 2mg of immodium a day has been enough. Time will tell going forward. I see my mo on Tuesday. She is a lovely person and very smart, but I have to admit I questioned her judgement when it came to trying neratinib. After seeing you results I am much more hopeful this drug may work for me too.
Cure-ious, Thanks for your input, even though much of the report flies far over my head! One thing I did glean from it is that fulvestrant should be part of this tx. At last visit my mo was questioning that, but I'll bet she will likely have read this report in the meantime.
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Hi Jobur, I was focused on this report because they were trying to suss through the biomarkers (specific mutations) that would lead to success, and clearly Shetland is doing supremely well; that report was guessing/hoping for PFS around 6 months or so, but now Shetland is double that and still going, so she's going to push those numbers out there! I'd guess it should be paired with endocrine therapy because if the mutation was a cause of resistance, then when you block the mutant Her2 the cancer cells are going to go back to being estrogen-dependent. If the cancer was never ER-positive then you wouldn't do that obviously
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Cure-ious, my tests showed two alterations which, according to my DH, are next to each other on the gene: I767M and D769H. I believe it was the first one which one qualified me for the trial as it is considered to be an activating mutation. I know the researchers are very interested in how particular ERBB2 mutations may affect length of PFS and the development of resistance to neratinib. They will also do genomic testing to compare the list of all mutations found at the start of the trial to the list of mutations found later, to look for interactions.
I believe that as described in the research you quoted, this mutation developed under pressure from my letrozole treatment and caused resistance to letrozole. The ERBB2 mutations did not show up before that treatment, but did show up on the test done after progression on letrozole (with Ibrance), and there were no other mutations found that are known to cause resistance to hormonal therapies. I am glad I used Xeloda next though, as at that time I would have gotten neratinib monotherapy as in an earlier version of the trial, but now it is expected that PFS will be lengthened with Faslodex added. There was at least one trial with neratinib plus or minus fulvestrant. By the way, the most recent test did show tumor mutational burden high, and that had not been the case earlier. I tested at mbc diagnosis, at progression on Ibrance+Letrozole, and at progression on Xeloda.
My oncologist and the oncologist named as PI on the study at my institution are thrilled with my response. Interesting to me is that with both taxol and with Xeloda, I also had a dramatic response — swiftly to NEAD and got two years. And again with this combo, a swift and dramatic response. I'm hopeful that it could be beyond two years, in the way many Her2+ mbc patients get a long time on their anti-Her2 treatments.
Jobur, are you also on fulvestrant, or considering adding it? Yes, I started at 240, had terrible vomiting and diarrhea and ended up in the ER for fluids and electrolytes. (The trial nurse did not look out for me as she should have. I have a different one now.) More meds on board and tried again. Nope. Then I told them the only way I would give it another chance was to titrate up from 120. I found out later that after the ER episode the sponsor wanted to kick me off the trial, and my onc fought for me because she believed this was the right treatment for me. I love that woman. Now I’m sure the sponsor is glad to have me. Lol.
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Oh, Shetland, great call by the MO, you are solid gold to the trial sponsor!! And yeah this kind of response seems more like what people get from Her2 treatments.. What kind of test is used to pick up HER2 mutations- blood? tissue biopsy? So this is a mutation that develops as a result of some time on AI therapy, and is more commonly seen in lobular cancers? The other issue is that if the TMB stays high, you might become a great candidate for immunotherapy.
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I had both Foundation One tissue and Guardant 360 liquid (blood test) biopsies that showed the mutation. It does appear to develop during AI therapy, and confer resistance to it — a typical case of cancer finding a different pathway to use, and one that is more common in advanced ILC. I have read some papers advising that oncologists should always check for ERBB2 mutations with patients who have metastatic ILC. But I note that jobur has IDC, and she came up with an ERBB2 mutation, so I do think all ER+ patients who progress on AIs should get a genomic test. The tissue biopsies seem to be more sensitive.
I do have immunotherapy on my list of possibilities for the future. I would have expected to see microsatellite instability since a germline MSH6 mutation is, in my view, the main reason I ended up with premenopausal ILC, but that does not show up.
Cure-ious would you give me a reference or link to the report you were reading?
And yes, the faslodex is to stop the cancer from going back to using the ER pathway. Jobur, if your onc is not convinced and you would like papers to show her, I will dig out my folder of journal articles for you.
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I have been meaning to update this thread for some time in the hope it may help someone in the future.
Short story is Nerlynx (neratinib) did not work for me, but with a couple of caveats. The first being I was only on this drug for a very short time, slightly less than 2 cycles. I did continue to get Faslodex along with neratinib during that time, but scans and new pain showed quite a bit of progression to both liver and bone. The second being I took famotidine twice a day during my time on this drug. Although I religiously followed the timing spelled out in the prescribing info between when I took the acid reducer and when I took the neratinib I have to wonder if this caused the drug to be less effective. My heartburn was killer on this drug, even with the famotidine, so I quit taking it altogether during the last weeks I was on neratinib. During those weeks, D (which is one of the main ses of neratinib) was noticeably worse, which makes me wonder if the acid reducer was also reducing the effectiveness of the cancer drug. I did find at least one study where another acid reducer had this effect. Third caveat is that I took neratinib as a monotherapy (not counting Fas). Maybe it would have been more effective if used with other drugs?
I recently had a liquid biopsy through Foundation 1 that again showed the Erbb2 mutation, so the tissue biopsy of my liver that originally uncovered this mutation was not a fluke.
Shetland- I hope your current combo is still keeping you NEAD. I am looking forward to seeing the results of the SUMMIT trial when it completes in Sept.
BevJen- I *think* you are on some combo tx (sorry I can't remember what) to target this mutation. I hope you are doing well and will post your results, good or bad on this thread.
Best wishes to all~
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Jobur,
I'm not yet on any treatment dealing with the ERBB2 mutations that I have. I was on Ibrance and Faslodex, and in late January, I switched to Keytruda as a mono therapy. I was eligible for that because I have tumor mutation burden high. The jury is still out as to whether it's working or not.
The trial that Shetland is on may be on in my future, I don't know.
Take care,
Bev
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Shetland, Late to respond, but anyway, here is the link to that paper discussing Her2 mutations:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC70810...
They see different responses depending on the specific mutation, and indeed BOTH of yours are included in the list of the neratinib-sensitive ones:
HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I.
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