FGFR1 amplification
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Interesting article, Sandi. I hadn't seen that one. Unfortunately, I didn't have stellar results on Afinitor/Aromasin but hopefully you will fare differently if you go the Aromasin / Afinitor route. I do suspect that some sort of cocktail of 3 meds (such as an FGFR inhibitor, hormone therapy and the right targeted therapy) may hold promise. The biggest obstacle there may be tolerability on 3 medications though.
My perspective on stopping Xeloda and moving into a trial is that "a bird in the hand is worth two in the bush". If it were me, I would stay on a medication that is working, particularly Xeloda that has such tolerable side effects. Why risk progression and/or harsh side effects on a trial when one is taking a medication that is working? The trial med may not work and trials have such long washout periods. A patient could be in a very different state if, God forbid, the trial treatment doesn't work. It could be possible that the patient would no longer be a candidate for Xeloda by the time one has moved on from a trial that doesn't work. My FGFR inhibitor trial had two separate washout periods - the first one was 3 weeks after my prior treatment failed before I could have a required biopsy and the second one was 4 weeks of washout before I could take the trial drug. There was no way to overlap these two. There were 3 separate stages of the trial application process that involved filing and then waiting, filing and then waiting. There were about 2 months of delays in between those 2 washout periods (red tape among the various parties involved). My delays were shorter than most as I become very pushy (friendly yet annoying and persistent) with following up with all stakeholders on all sides to push things through. Also, the fact that my DH is an attending physician at my medical center expedited my biopsy by several weeks. I can't even imagine what type of delays others face who don't have the temperament, energy, capacity or motivation to push the various doctors, day after day, until something is finally done and who don't have the connection I have. Between my 2 washout periods, I took Halaven for 6 weeks, which is not enough time for it to even start working. Average TTR (time to response) for Halaven is 9-12 weeks or so if my memory serves me. My scan showed a small bit of progression after starting Halaven compared with my prior scan. However, I was off treatment for a long time after my prior scan and it is possible I got much worse during that time and that Halaven was improving the situation from when it bottomed out. I will never know. The FGFR inhibitor I took had a lot of toxicity and intolerable side effects. I stayed on the trial for 2 months until I was kicked out because it wasn't working but there were two others on BCO at the time in one of the two erdafitinib trials and both dropped out early within less than a month or so because they couldn't handle the side effects. Afinitor has some tough side effects as well.
If Xeloda is working, enjoy and appreciate that!!! You always have the future to go for a trial and to try Afinitor/Aromasin. What I have learned over the years, seeing many women come and go on BCO, is that we don't have the luxury to "save" or postpone treatments for a rainy day. Often the rainy day never comes for one reason or another. My perspective is that if it is working and tolerable, then stick with it.
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I agree with JFL. And if standard treatments will do the job for a while, that gives us more time to see how trial drugs pan out, and some even become available outside of a trial.
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JFL and Shetland. You both are right. My MO is saying the same thing in regards to washout period, esp for those of us who have aggressive liver mets. She worries about a trial especially if tx is working.
It is good to hear from those who have done the trial route and have a different perspective. I needed to hear that. Do you have any regrets or maybe you had no choice..
I feel myself screaming for better drugs to keep us going with quality of life.
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Agreed with everybody, though I might move around on treatments if they were all readily available outside of trials
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Murfy- That is very interesting about the infammatory state of the tumor microenvironment!
I was taking Celebrex for a year, ostensibly to block any incipient PI3K cells (which are COX2-dependent) from popping up, but mostly because these NSAIDs have been shown to boost immunotherapy/immune system killing to cancer cells.
https://www.drugdiscoverytrends.com/partnering-nsa...
https://www.sciencedaily.com/releases/2017/07/1707...
Similarly, cdk4,6 inhibitors are known pre-clinically to also boost immunotherapy responses, so I was hoping that the Celebrex would synergize with the Ibrance, since I have no access to immunotherapy.
However, in the meantime a report came out showing that nsaids have a paradoxical effect on PI3k MBC, making them more aggressive, so I got nervous and dropped Celebrex -however I don't know if I have a PI3K mutation to even worry about...
And I miss the Celebrex, because it was helping so much with my arthritic joint pain.
It's been very frustrating that no studies have been done to see if Celebrex can boost the Ibrance response-do you think it might?!
maybe I'll go back on it
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I found the Celebrex/cancer data quite convincing. As you mentioned, the data show that Celebrex may work in concert with immunotherapies on several levels to elicit anti-cancer effects. It is also a potent inhibitor of IL-6 (as well as COX and other pro-inflammatory mediators), and I'm going to stick to my interpretation of the graphs you posted that reducing said mediators enhances the effectiveness of Ibrance. I would further posit that Ibrance works down-stream of and, when inflammation is reduced, may attenuate activation of the PI3K pathway. I looked and there are clinical trials recruiting and underway to look at some of these parameters. Until we see those results, I'm going to start popping a nightly aspirin!
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OK, me too, I'm going back on Celebrex! And will research these inflammatory pathways you've been discussing..
Please post links to any clinical trials you think we should keep our eyes on
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Thanks..this is great information!
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here's an excellent review of drugs targeting the FGFR pathways in cancer
https://www.onclive.com/view/fgfr-alterations-emer...
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FGFR1-4 are tyrosine kinases and targeted by kinase inhibitors. But these 4 kinases are not all the same-FGFR1 amplifications are not inhibited by these drugs nearly as strongly as FGFR2-upregulated cancers are, for example.
So FGFR1 amplifications might need to be treated with drug combinations.
Sometimes this mutation can occur with high Cyclin D, which is an activator of CDK4,6 and very sensitive to Ibrance, so in that case it could be could be good to try an FGFR inhibitor plus Ibrance
There is a phase IB trial is investigating erdafitinib, fulvestrant (Faslodex), and palbociclib (Ibrance) in patients with recurrent or unresectable estrogen receptor—positive, HER2-negative, and FGFR-amplified breast cancer (NCT03238196).
https://clinicaltrials.gov/ct2/show/NCT03238196
Not too many sites for this trial and it's suspended (presumably due to covid) at some places, but it looks like UCSF is going to pick it up, which is a promising sign...
This is probably the trial Moissy tried
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Yes, that appears to be the trial Moissy tried. I am looking forward to hearing results on the combo treatment.
Another challenging thing about trials is that the side effect profile may not be quite accurate. The studies of erdafitinib used to obtain approval for it in urothelial cancer indicate it is very tolerable. The study reports make it sound like an easy drug at the doses I was taking and in many cases, people even took higher doses in the urothelial trials. I had some really harsh side effects and had a hard time with it. For erdafitinib, they start you at a certain dose and if your phosphate levels do not increase to dangerously high levels and if you do not experience retina detachment in your eyes, they will increase the dose one or two more times. I was surprised I was unable to do any dose increases and even had to reduce my dose and take a treatment break. I thought this drug would be a breeze. It is also an anti-angiogenic and decreases blood flow to the jaw and other bones so those on bisphosphonates or XGeva need to be careful about increased risk of ONJ, fracture of femur or other fractures. I question how realistic that is that the urothelial doses were so tolerable. When I did the trial, there was a TINY area on a piece of paper to write down the daily side effects. No one would make the side effect line that small unless whomever prepared the daily diary paper really didn't want anyone to write anything down or write more than one thing. Honestly, it seemed like an attempt to get people not to report side effects. Super shady. My trial was an NIH trial too. One would think trials would be run "cleanly" by the NIH.
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JFL- I was wondering about that! The study report I was looking at had very high levels of grade 3 side effects! and they said high phosphate levels in the blood were a direct consequence of the drug working, so if they don't go up, the docs will increase the drug. This whole category of drug is reminiscent of PI3K inhibitors, where a whole slew of drugs ultimately bit the dust due to toxicity. We ended up with Piqray, which is challenging enough! Because the FGFR pathway turns on the mTOR/PI3K/AKT pathway, maybe one of the mTOR or AKT drugs (like Ipatisertib, which is being tested with immunotherapy and faslodex in the MORPHEUS trial) will be helpful
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Yes, that is the trial I was on. My particular trial nurses did want to know every side effect I experienced daily, and I felt very well cared for, so I guess locations vary. When I had any unusual difficulty with side effects, they would email the trial doc right away and they encouraged me to call even on the weekend if I needed them. So in my particular case, I couldn’t have had better care from the trial staff. But due to my side effects, MO thought I would do better on a different treatment. And I did. But I don’t regret trying it. JFL, I did wonder also how the urethra cancer trials/treatment had such high dosages
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JFL...but what exactly were your side effects???
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Has anyone had successful treatment with Verzenio as a monotherapy with the FGFR1 amplification? Or how about Afinitor/Aromasin?
Just couldn't find any real world data.
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Nicole, the worst side effect was that my intestines went into a state of paralysis and I developed severe constipation, a side effect of severely elevated phosphate levels. Erdafitinib blocks certain kidney function which is thought to cause of the hyperphosphatemia. The drug seemed to stop the natural cramping process that pushes everything through the bowels. I went 10 days or something like that without a bowel movement and nothing worked after trying many things I researched myself and others recommended by my MO and the trial staff until finally milk of magnesia worked. After I finally had a bowel movement, I had continuing problems with the issue and never really felt too much relief. I have never felt pain like that in my life in my back, liver and belly but mostly my back in the kidney area. I was worried my bowels would become impacted and perforate. It was the scariest thing. I take a lot of fiber, yogurt, kombucha, probiotic supplements, apple cider vinegar, flax seed and eat a diet high in whole grains, fruits and vegetables and water and usually have no bowel issues due to my lifestyle. When my phosphate levels became dangerously high, I had to stop the drug and take something called sevelamer used in kidney dialysis patients to reduce phosphate levels. High phosphate levels is the goal of the drug to indicate it is working but mine were off the charts beyond the acceptable elevated ranges. Also, despite the fact the drug was clearly blowing my phosphate levels through the roof, it did nothing for the BC.
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Hi fellow FGFR-ers. I have recently had major progression on Faslodex/Ibrance and then Xeloda. I had a feeling my cancer wouldn't behave on such "tolerable" drugs, and now that has been confirmed by my latest scans.
I have to make the decision whether to switch to an IV chemo regimen, or possibly go on a Phase 1 FGFR trial using infigratinib as an FGFR inhibitor. I wish there were a better option. From what I can tell it seems like a lot of the drugs that attempt to control FGFR pathways are not particularly tolerable, and also not particularly effective. It seems like high phosphate levels are expected, and then you most likely end up taking drugs to control those. Also, there's constipation. It seems that one person even died in an earlier trial due to lack of blood flow to the intestines? Scary.
Anyway, I'm not really sure what I'm asking here, but I'd appreciate updates, words of wisdom, or insights from those who have tried FGFR inhibitors, or infigratinib in particular.
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Hi there all - I'd like to follow this thread too and hear people's experiences with FGFR inhibitors. I was ER+ (8/8) on primary but my cancer mutated to triple negative on spread. However I still have a FGFR1 mutation which I figure may be a hangover from my hormone positivity (as I understand it's much more common in hormone +) It also could have led to endocrine resistance even if I hadn't lost my receptors...Anyway, I'm about to start chemo but want to keep an eye on FGFR1 inhibitors as that could indeed still be driving my progression.
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My MO knows that I am seriously interested in a trial NCT 04024436. It is offered in several US states and countries. Phase 2.
It is a trial for oral FGFR inhibitor, Futibatinib. I would hopefully qualify for cohort 4. I have not had Faslodex. The requirement is a minimum of 10 copies of FGFR1 amp gene. I called F1, I have 13. Cohort 4 group specifically targets FGFR1 amp.
My MO said when I start to have progression, we would start immediately to apply for trial. I believe recruitment stops June 2021.
I do not have ESR1 or PK3 mutations from latest bx. The suspicion, but NOT confirmed, is FGFR1amp is the driver on my progression.
Just passing this info on to help others
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Thanks for passing that info along, SandiBeach. That's good that it's a phase 2 trial!
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My progression came on so fast that it was impossible to start the trial that I was interested in, NCT 04024436. Plus, I am now excluded due to > than 2 chemos.
Although I cannot say that FGFR1amp mutation caused progression while on Letrozole and Ibrance, I still have to keep that in mind.
Anyone else with this mutation and what treatments have you been on?
My recent liver bx again showed the FGFR1 amp and no ESR1 or PIC3 mutations.
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Very sorry to hear that, Sandi!!
Here is an excellent recent review of FGFR1 amplification, which is a common way that MBCs become resistant to I-F treatment, one report found it in 41% of those progressing in a Ribociclib-AI trial:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC79128...
Perhaps you might consider trying an AKT inhibitor like Ipatasertib in the MORPHEUS or other trials https://www.ncbi.nlm.nih.gov/pmc/articles/PMC79128...
Or alternatively an ADC like Trodelvy or Enhertu?
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Thank you Cure-ious! I have a running list..AKT inhib has been on my reading list. Don't see much research action on FGFR inhibitors for breast cancer.
My MO said not much success for Enhertu with HER2 1+ IHC..
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