Alpelisib
Since I had some progression, looks like I will be moving off of Ibrance+fulvestrant. My MO wants me to join a Phase II trial for alpelisib + fulvestrant or letrozole. It is for patients with a PIK3CA mutation, HR+, HER2- who have progressed on or after CDK 4/6 (Ibrance, for example) inhibitor treatment. Wondering if anyone else has ever taken alpelisib.
Hugs, Susan
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I haven't, but just today read about this on another thread. Penny-78 posted a link. I'll try to find it but if you check her username for recent posts it should be there. I wrote it down to try to help me remember to follow updates on this.
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Here is the link that Penny-78 shared.
https://www.eurekalert.org/pub_releases/2018-06/uo...
Here is a link about a trial similar to what you describe, I think.
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There is info on the Ibrance topic. https://community.breastcancer.org/forum/8/topics/...
This link is from Penny-78. https://www.eurekalert.org/pub_releases/2018-06/uo... * Edited to show this link is about a different medicine.
these two are from cure-ious
https://clinicaltrials.gov/ct2/show/NCT02077933
https://clinicaltrials.gov/ct2/show/NCT02077933
I just read them today and wrote down this medicine to try and help me remember to follow updates on this.
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Thanks Muddling! Will post here when I learn more.
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Muddling,
Looks like the link from Penny-78 is for Alisertib, an Aurora A inhibitor. That also sounds very promising as a way to increase the efficacy of PI3 kinase drugs.
The clinical trial from cure-ious is for Alpelisib.
I know! The two drugs have such similar names!
Thanks for the links!
Hugs, Susan
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Susan, thank you for clearing that up. I was fooled too 😅 anyhow, were you tested for the PIK3CA mutation or did you get enroll as a generic MBC patient? Also, I was wondering what does your MO think of the possibility of you getting still fulvestrant in the mix and not letrozole when that not working was the reason for moving onto a new tx?
Thank you for keeping us updated on new drugs.
Daniel
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Susan, thank you for clearing that up. I was fooled too 😅 anyhow, were you tested for the PIK3CA mutation or did you get enroll as a generic MBC patient? Also, I was wondering what does your MO think of the possibility of you getting still fulvestrant in the mix and not letrozole when that not working was the reason for moving onto a new tx?
Thank you for keeping us updated on new drugs.
Daniel
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Now I feel really stupid.
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Hi Susan - I have also been presented with the alpelisib trial (with fulvestrant in my case) as an option as I have just progressed on Palbociclib/Letrozole. The only information I have been able to find is not good. The trials with two other similar drugs (Taselisib and Buparlisib) have been shut-down due to negative side effects and not-convincing early result.
Given the comments about PIK3CA dugs in general not being quite ready, I am inclined to pass on this trial. Let me know if you learn new information about Alpelisib that sounds more promising. Thanks!
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I would also be curious to know if testing for PIK3CA mutation is offered to the generic MBC patient in the States or if its reserved to trials. In Italy they told us the only genetic mutation currently tested is BRCA1/2. I think they might be years behind y'all here.
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Sary, Thanks for the information about the other failed trials. Extremely important information. I will talk to my MO about it this morning. My MO is head of clinical trials here so she will know about the others.
Daniel86, Metastatic patients here usually get a complete genetic panel done of the tumor as well as original healthy tissue. Helps to make treatment decisions, particularly now that they are coming out with so many targeted therapies. They test for, I believe, 500mutations. Many of these mutations are not currently associated with a specific illness but they keep the results in the event that future research makes an association.
Other choices she gave me were Gedatolisib (PI3K+mTOR) and NKTR-102 (targets brain mets).
Hugs, Susan
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SusaninSF: If it were me, I would also be concerned that the most promising combinations are not yet out for PI3K inhibitors, and hope that combinatios with AuroraA kinase inhibitor might come out in short order, based on the preclinical studies.
But also, there is evidence that the CDK4,6 inhibitors don't work after using PI3K/mTORC inhibitor, and it seems you have not had really long treatment with CDK4,6 as yet (unless your cancer genetics indicates that you have an RB mutation or won't respond), so what about the Abemaciclib-Keytruda combo trial? Abemaciclib works on brain mets, and the Keytruda seems to be making a bigger response to the drug...
https://www.onclive.com/onclive-tv/dr-tolaney-on-a...
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Thanks Cure-ious for the informed comments! I have been on Ibrance, a CDK4,6 inhibitor, with Faslodex for almost two years.
My MO said they've been seeing amazing results with Alpelisib. She also said that the other two PI3K trials were not conducted in conjunction with good side effect management so a lot of people got off too early.
I had never heard about PI3K/mTOR inhibitors effecting CDK4,6 efficacy.
Have my scans on Monday. Hoping they will be good and I can stay on Ibrance+Faslodex as this treatment has been very easy for me.
Will take a good look at the Abemaciclib+Keytruda trial!
Hugs, Susan
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Hi again SusaninSF,
Here are the links: recent preclinical data indicate that PI3K/mTORC1 inhibitors work far better when combined with Aurora A kinase inhibitor (the one tested most in clinical trials is called Alisertib).
https://breastcancer-news.com/2018/06/29/aurora-ki...
I'm really interested to hear that your MO sees great results with Alpelisib, because so far most PI3K trials have reported only a few months advantage, and as you mention the SEs are challenging. We all know we need the PI3K pathway inhibitors, especially once the cancer has become resistant to anti-estrogens, but in general all the trials have been disappointing, we still only have affinitor FDA-approved, and the data indicates that it would be better to take the Alpelisib in combination with Alisertib.
My suggestion to consider the Keytruda with Abemaciclib trial is because 1) Recent papers indicate that you would want CDK4,6 drugs to come before PI3K/mTOR inhibitors in your treatment sequence, and/or taken at the same time, but there was one report that found that PI3K inhibitor-resistant cells are not sensitive to CDK4.6 inhibition, so you would not want these drugs in the reverse order; 2) Abemaciclib seems to be the strongest CDK4,6 inhibitor and goes after brain mets; 3) the preliminary data that have been released at 6 months indicate that the Keytruda- Abemaciclib combination (ORR about 28%) was maybe 2-3x better than Abemaciclib alone, which suggests that the combination is working (!!), and so this is maybe a good chance to try some immunotherapy (see link below). The data supporting this combination come from preclinical studies showing that CDK4,6 inhibitors make breast cancer sensitive to immunotherapy; and 4) we don't yet have a trial option that includes with mTOR/PI3K like Alpelisib in combination with a drug like Alisertib, These drug names are so similar!!, they have to make new names!!!
So, who knows, but its something to discuss with your MO. Any further info you get on Alpelisib trial results would be much appreciated!!
A link about the Keytruda-Abemaciclib trial; https://www.onclive.com/onclive-tv/dr-tolaney-on-a...
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Here is an excellent discussion of the current state of the PI3K inhibitors. Many cancers respond to them, its the SEs and especially time to progression that could be better. Works best in PI3K mutant cancers, does not work in FGFR-amplified cancers.
https://www.onclive.com/publications/oncology-live...
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Great links Cure-ious! Love that onclive.com site.
The other factor is that I have PTSD about IVs so haven't been on an IV treatment yet.
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Well, I think that is an excellent idea, avoid chemo as long as possible! Also keep an eye out for CDK7 or CDK12 inhibitors, CDK7 will come first and preclinical data indicate it should be excellent for ER-positive and probably all subtypes of MBC. With CDK7 drugs they may also inhibit some CDK12, and with CDK12 kinase inhibitor there would probably be some overlap of mTOR kinase inhibition. So that is potentially another route to mTOR inhibition. I hope we can play this game for a long time. Is your doctor at UCSF? Rugo or Muenster?
PS Oh, I see that you would not be eligible for the trial because have not had prior chemo. Hhmm...I did see one clinical trial that combines Aurora Kinase inhibitor with mTORC inhibitor for solid tumors, however it also needs prior chemo/no other good options. I will we could just order up the drug combo we want to try next.
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Seems like clinical trials for CDK7 inhibitors started their phase 1 last year. They're dosing with Faslodex and as a monotherapy. Unfortunately they appear to be going the IV route for administration.
https://clinicaltrials.gov/ct2/show/NCT03134638
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Thanks, Daniel, I did not know that!! Hhmm, they are strongly pushing for ER-positive patients who have just failed CDK4.6 inhibitor with an AI. They exclude any chemo or really any treatment after Ibrance-Femara, so it seems in this trial version they are gunning to become a secondline therapy? I wouldn't blame them since it really unclear what to choose for secondline!! And, yes, it seems to be an hour long IV drip that would initially be twice a month, then monthly. So when will we hear if its doing anything great?! and what are the SEs?!
Plus only offered at Dana-Farber and in Texas. Well, if it does anything great, it should move to more trials and more locations..
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Cure-ious,
Xeloda is technically chemo and was on that for more than two years. My MO is Hope Rugo. Really love her!
Hugs, Susan
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Yeah, wow, she is amazing, I see her clips on onc-live all the time. So now is even more interesting to consider that she thinks Alpelisib is great and that the numbers would be looking even better if people knew how to handle the SEs and would stop dropping it prematurely. I would be very interested to hear her comments on the Aurora A kinase inhibitor study (which was also done at UCSF), and what she hears about keytruda-abemaciclib, since she is clearly very tuned in to the results coming from clinical trials.. thanks!!
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Just got my scan results and there was more progression in my lungs.
1. Increased size and number of nodules throughout the right pleural space consistent with metastatic disease
2. Increased right pleural effusion
I have had slightly worse trouble breathing and small amount of coughing but nothing too bad.
Hope still wants me to go on the trial for Alpelisib but she said I would not be able to change from Faslodex to Letrozole because the trial is specified as Alpelisib + Faslodex. I asked her about Abemaciclib and also suggested Afinitor + exemestane. She's in Australia so I will have to wait for her reply.
Worried.
- Susan
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Ah, well it is time for a change, I'm so sorry you have to face it alone without Dr. Rugo, however on the upside, you do have one of the best ONCs on the planet!! And access to the very best drugs on the planet as well. The challenge is to make the best decision as to what is available at this time, of course, so you can move forward. (I have a dual mindset about scans, of course I don't want them and my MO doesn't feel the need to do them unless one is having symptoms, but by then it could be awful so I insist on them AND sweat through them, but would rather know asap if I have to change.)
So you have had Tamoxifen, Xeloda and Ibrance:Faslodex over the past four years. And are considering Alpelisib-Faslodex (a trial), Abemaciclib monotherapy (or with Keytruda in the trial?), or the Affinitor-Aromasin combo. Is there a reason you don't want to stay on Faslodex? And are there other options to consider? Time to do some research, the CDK7 trial Daniel brought up might be another possibility..
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So, for Alpelisib in SOLAR-1, there was a great response rate, and median progression-free survival 9 months, meaning half of the patients went longer than that. It is also in a trial with nabpaclitaxel (PFS 13 months), so I guess it could come at a later step, with chemotherapy. However, she must sense that now is the time to hit that PI3K pathway.
There are reports that combination of Alpelisib with CDK4.6 inhibitors is synergistic
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41555...
- can you get Alpelisib-Abemaciclib?
OK, not trying to be cute, and she won't find it funny, but why can't we just add in the AuroraA kinase inhibitor and some immunotherapy?!
Alpelisib-Abemaciclib-Alisertib-Atezolizumab!!!!
PS For comparison, the PFS from the phase 3 Bolero-2 trial (affinitor-aromasin) was a similar 7.8 months, but Dr. Rugo may have the sense that Alpelisib is a better drug, esp if she thinks people have needlessly dropped out because their side effects were not handled properly..
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What a tongue twister that one is! They really do have to stop naming drug that start with the letter "A".
Cure-ious, I'm curious how you know so much. Are you a cancer researcher?
I've been so mad at myself for not pushing harder to switch treatments when I initially showed progression three months ago. Hope thought the progression was too small to warrant a switch. I argued that progression is progression so why wait until it it a big progression. I should have stuck to my guns. I think I also have some metastasis to my ribs near my lung tumors. Have some pain and something showed up in the bone scan but they weren't sure if it was anything. Even the best doctors can make the wrong call. We need to always advocate for ourselves.
Thank you SO much for your continued research and feedback!
Hugs, Susan
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Oh, waiting is probably always a good idea, if the progression is not too bad, so you followed her advice and that's is a good thing!! It's not so bad progression and you are delaying the time that the cancer will mutate again to escape the next drug. It's the smart way to go, I'm sure my mets were happily growing away for a couple years undetected before it caused my blood calcium levels to rise- but sometime progression is very aggressive, so that's why I want to have screens even if no new symptoms
One question for now is if it is true or not that once you go onto PI3K inhibitor, that progression afterwards will mean the cancer will no longer be sensitive to CDK4,6 inhibitors. If so you could be missing out on possible benefit of Abemaciclib and/or Abemaciclib/Keytruda- on the other hand, there is no guarantee that they will work, compared with the certainty that you need a PI3K inhibitor. It's awful that they don't know with more clarity or speed if we will respond to a given drug or combo!
But even if you do forgo CDK4,6 inhibitors, CDK7 and CDK12 drugs are coming along, and other combinations. Also, if they find that PI3K inhibitors work with Aurora A kinase inhibitors, you can go on that combination later and will most probably still respond. We can't worry too much about what lies ahead, because there are so many other trials, and maybe CAR-T will be able to eradicate the problem in a few years. A couple of women we already know about nowadays are seemingly cured of of their Stage IV MBC, and they were in really bad shape by the time they got the treatment that eradicated it, yet were still able to make a complete recovery.
I am a professor and do research in basic molecular genetics and cancer, but no clinical trial or drug expertise, no familiarity with medical procedures or treatments whatsoever. Never even knew anybody who had breast cancer. So I'm of limited value, but I do like keeping up with the new therapies under development, if only for the inspiration!!!!
PS If you go onto PI3K inhibitor, try to keep a schedule where you take a (water-only) fast starting in the early evening, it will do wonders to keep your blood sugar levels low, and high blood sugar is one of the main problems with those drugs. I just saw some reports on the benefits of evening fasting, they say you can eat whatever you want in daytime, just be sure to give your body the time it needs to burn it all off every night:
https://www.nytimes.com/2018/07/24/well/when-we-ea...
https://www.nytimes.com/2017/08/21/well/eat/the-ca...
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Ah! A professor and researcher!
Very good advice about the evening fasting. I read that article on Sunday but didn't make the connection with my treatment. My husband practices intermittent fasting so it should be relatively easy to implement. I have been on a low sugar/low carb diet for the past month. Recommended by my Chinese medicine doctor.
Hugs, Susan
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I have done the evening fasting, on and off, for several years- initially to lose weight, and it was good for about 10-15 lb weight loss for me, and it really stayed off. But more to the point, with the indigestion I had (which mostly went away with the weight loss), was so so much better not to go to bed with any food in my stomach,and I could finally get off of Prilosec, that was the immediate benefit. But there are many more benefits. For one thing, your body responds, and communicates between organs, to day-night and feeding schedules, so once you get a rhythm of fasting, then the body "anticipates" it, and it goes into fat-burning mode more quickly and more efficiently- also, your blood pressure and sugar levels drop in the evening, and having a big difference between the extremes (ie, the high-low numbers) is very helpful for synchronizing the rhythm and your bodys metabolic responses, so obviously if you head into sleep already in a reduced food and sugar state, then the lower your cells can drive the overall sugar level in the evening. Here they are using this in the medical clinics on diabetic patients, because it is a very straightforward way to drop blood sugar, does not require any weight loss, does not mandate any diet. You can eat what you want in the day, but just stop in early evening, preferably around the same time each day, and move to water, fizzy water, hot water, but that's it. Initially I got hungry later on, but that goes away quickly if you stick to it, and you can make sure you eat a big meal at 6-6:30, it was never as much of a problem as I imagined. And now if I ever do get hungry, I decide I should just go to sleep instead, breakfast comes soon enough. I get indigestion again from the Ibrance, so with the fasting I can handle it, no problem.
PS There was a report in the literature that the anti-diabetes drug metformin works literally about 1000X better in cells starved of sugar, compared with cells containing high sugar, which shows that it is way easier for the cells to lower sugar if they aren't starting from a high number in the first place. Instead, I think people imagine they take it to directly counteract a bunch of sugar/food they just ate, but clearing sugar takes a long time, is not immediate.
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I try not to eat anything after dinner. Sometimes, if I eat out, I forget to take my meds and have to eat a little something with my meds but that doesn't happen very often. So I generally go from 7pm to 7-8am without eating. I was thinking I would have to shorten that eating period to 6-8 hours. So maybe get rid of breakfast? I also got rid of my afternoon snack which was usually some kind of pastry or cookie. Have cut way back on sugar and carbs and I don't drink alcohol or do recreational drugs. Have already lost a few pounds and definitely feeling better except for the progression in my lungs.
Hoping to see Hope next week but still waiting for my appointment to be scheduled. Thanks to you, I'm primed with good questions!
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FYI - I have decided to do the trial (alpelisib and fulvestrant). I will start in a few weeks. I consulted with an oncologist at a leading research hospital in Canada and he said there are no drawbacks (other than potential for moreside effects). I also investigated SBRT (I have 3 lung mets and 1 new liver met) but no one was convinced of that route.
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