Abemaciclib Verzenio for Stage IV
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piggy: i am thinking much like you. but i don't want to overly-alarm you either: most people do just fine on thyroid replacement, or with insulin shots. and side-effects OTHER than the endocrine ones seem to be reversible at this point, with aggressive steroid treatments.
i certainly will look deeper into this, especially the immunologic memory thing. and i do know of one oncologist who uses immunotherapy only every 4 months (rather than every three weeks); that might make sense: i found out on drugbank.ca that keytruda stays in the body for 4 months after administration, at of-course ever-declining (it gets slowly broken down, not eliminated via, say, feces or urine) levels. i also know some oncologists still use it at the 2mg/kg dose rather than the flat dose of 200mg. the keynote trials have shown that both response and toxicity mostly seem to be flat across a certain range of dosing (2, 3, and 10 mg/kg) but I still recoil from the idea of having almost twice the (probably-)effective dose infused into me every three weeks.
for those of you who haven't started verzenio yet, or only started recently, or are using it with endocrine therapy (which has shown to make the response more durable) and are responding well, i would suggest waiting another six months and evaluating the new JPCE data then before potentially adding keytruda. it has been shown that a 3-4 lead-in with verzenio-only probably gets better (or at least quicker, or perhaps more dramatic, for those who need that) results than starting both at the same time. that effect may "wash out" over time, of course.
on the other hand, in melanoma, adding keytruda after the optimal verzenio-response window is no longer (very) effective. so that is the part i am struggling with: i am well into that window, and may soon be past it, since i am using verzenio as monotherapy.
another thing to keep in mind is that there may be other good keytruda combos coming up, for those who, say, only have bone mets and therefore time to wait. there's at least one promising trial i have heard about that one would not qualify for any more if one were to take keytruda now. i'll try to get details. (sorry i am so vague today; i am intellectually exhausted.)
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this is NOT the trial i am alluding to above, but it is an interesting one involving keytruda (pembro) that i would strongly consider if i still (or again) had a tumor in the breast or on the chest wall:
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Hello all,
I got my blood test results after a month on the Faslodex/Verzenio combo. The first good news I have had in a year and a half. My CA 27 29 dropped from 873 to 814. That's the good news.
The bad news is that I have to stay on Verzenio. I had been bitching to the Onc that the side effects were awful and that I hated this drug. Eating was a big issue because everything tasted like shit and I didn't feel good most of the time. I had the blood draw on Wednesday so he said take a week off and we will see what the results are and then decide whether to continue or not. It only took a day for me to start to feel normal again and yesterday, Friday, I was able to eat food and enjoy it. So I have my reprieve until Monday. I will take advantage of this little vaca. He also said that a break can sometimes make the side effects lessen when you go back on and that there was no harm in taking the break.
Anyway, the good thing is the rapid response that I have experienced (and have others) on Verzenio despite the icky side effects. It works.
Chats
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Piggy, I hadn't realized the prospects of making it out 10 years is already 20%? if you can make it ten years on existing treatments, by that time surely you could make another 20+ on what will be availalble in a decade!
Also, for Luce, remember that probiotics in the bifidobacterium strains class are like a low dose of immunotherapy, and synergize with immunotherapy-
http://science.sciencemag.org/content/early/2015/1...
-So, assuming this does work, you could start slow by adding bifido to your Abemaciclib. Your immune cells have to be activated by traversing the gut, and apparently these bacteria are critical for this but also rather limiting ..
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cure-ious: yep, probiotics, especially bifidobacteria, are crucial, according to numerous studies. i have been taking mixed probiotics for years (as well as home-fermenting), and 5 bifido strains since last november. remember, i am the one who bought that $200 supplement?--i went through two bottles of those, then switched to cheaper/lower doses bifidobacteria supplements. am planning on ordering the expensive one again, though, ones i am out of my three current ones. no point skimping.
along the same lines, antibiotics past and current seem to reduce effectiveness of immunotherapy, yet another reason to take those probiotics. and don't forget: we get IV antibiotics during and after every surgery. there is no opting out of that, i have found. and they are flat-dosed for much heavier people than myself.
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piggy: i agree with cure-ious: if you have bone-mets only or have a slow-growing tumors that are well controlled with current therapies, why rush into anything whose protocol is surely going to be much-adjusted before its prime-time? the guineapig-treatments are for people like me: my prognosis was measured in weeks, before verzenio. it was too short, and i too sick, to even get into any trials, according to my oncologist.
but for people who want to try some of these never combos: please know that clinical trials are not the only way. your oncologist can help you (try to) access promising medications your insurance may refuse to pay for through compassionate-care patient-assistance programs. it is how i have gotten my last two medications, both of which my insurance had denied.
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verzenio update: i re-escalated my dose to the original 200 mg a few days ago. i am fine so far. i am optimistic i may be able to tolerate the standard monotherapy dose now. i was much sicker and in much worse physical shape overall in january and february, when i reacted to it with violent, incessant grade-4 diarrhea. i was also still on cyclophosphamide that first month, which had its own side effects (nausea, inappetance, changes in taste) similar to but much worse than verzenio's by itself. since targeted therapy interacts directly with tumor cells, and my tumor load is massive, i thought it was best to (try to) take the highest does i can tolerate while i am responding. i am finding this medication very tolerable at this point and only dread the day it quits working for me. as for enjoying food less, that may be a good thing: i intend to stay slender, since that may improve my prognosis, and staying slender may no longer be as effortless as it has been all my life now that i am in medical menopause. there is a difference between being thin and cachexic (and cachexia is a metabolic disease-state that can't be reversed or fixed by mainlining ensure or eating ice-cream), and thin is good. in fact, long-term calorie restriction would probably be a good idea for many of us. i understand that food is one of the few potential sources of pleasure still available for some of us (me included: i am mostly housebound and single, and unable to pursue my passions, so my life has gotten very small), but i am happy trading off my acute palate (i was a cook at an integrative/holistic health center before this) for a longer life, especially if a medication that is easy compared to chemo (on cyclo, eating was impossible or all but impossible at times) can give me that. thankful, too.
(so i am sticking to mostly vegetables, combined with low-to moderate protein, plenty of fat, and medium carbs (no processed foods), with an apple thrown in at times. i am absolutely convinced that "clean" keto (which is low-to-moderate in protein, NOT high protein) would prolong my survival (as is my naturopathic oncologist, and she has been doing this for 20 years) by having me run on ketones rather than glucose and by keeping my blood-glucose as low and even as possible, but i am not prepared to cut back on vegetables to stay under 15-20g of carbs a day.)
my nail changes and hair thinning seemed to be transient, too, and are much better now. i'll keep an eye on those things on the upped dose. not that i care, but to be able to report back.
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So, Luce, your comment interested me to go look at clinical trials with immunotherapy included. Its slow going, but will post some for comments from you and others:
Here is the MORPHEUS trial where they combine Atezolizumab (immuno) with different MEK/ERK-type inhibitors, and is started or will start soon at a lot of sites, but there is no CDK4,6 inhibitor thrown into the mix: https://clinicaltrials.gov/ct2/show/study/NCT03280...
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Chats - It's not right that you have to feel that bad to see a response, but I am so glad to hear you are responding. Please keep checking in and letting us know how you feel.
Luce - Congrats on successful move to the higher dose. I was just pondering the fact that my Abraxane SE's change as my overall health improves. In my case, a healthy liver is going to metabolize the Abraxane very differently. For one thing, I will metabolize it faster, clear the drug faster, and get a lower effective dose. Lots of things to ponder ...
BTW I have finally gotten my mind around the fact that a ketogenic diet is not necessarily a high protein diet ... sorry for some obtuse posts previously. We're on the same page nutrition-wise. Good nutrition and diet can be as powerful as any single line of treatment. I would not see yourself as on a monotherapy necessarily ...
>Z<
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Just want to report back that I have been on the Faslodex/Verzenio combo now for 12 days and have not had any diarrhea, or other side effects, for that matter. I've been eating normally and not taking any Imodium, since there is no need. I will be going in for blood work this would week, so I will know if my neutrophils have dropped or not, but I feel very well, so I don't expect to see anything in the blood tests that would keep my off the medicine.
My onc did start me on a lowered dose of Verzenio- 100gm instead of the 150mg that were in the trials. Onc feels that the trial dose is not always necessary, or even the best one, for some patients. The bigger concern is that I have already been on Faslodex once several years ago, so we don't know if it will work again. My appetite and energy are good, and while I have a few twinges in the liver area, no real pain. Crossing my fingers.
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sandilee: so glad you are giving it another try! the lowered dose was highly effective for me and had very little side effects: a bit of diarrhea 2-3 times a week that became gradually less also. the full dose had initially been very hard on me. my oncologist said i'd have been dropped from any trial with the diarrhea i had. the lowering of the dose made all the difference, so i am confident it will for you, too. and i agree that the maximum dose may not be the best dose anyway. (with most medications, i would actually go for the lowest dose, or metronomic dosing, or even microdosing.) i only decided to go up to 200 because i am feeling so much better thanks to verzenio that i believe i can tolerate it now. and so far--5 days in-- i am. i've only had a small bout of diarrhea once. i am GUESSING/hoping that the higher dose MIGHT be even more effective in me, since i have a high tumor load and am on monotherapy. (nice one, zarovka, but i recurred on the best diet i can think of (for me), a low-moderate protein/no-sugar/no grain paleo one. keto is the only long-term one (i love longo's FMD as intevention) that still makes sense to me (in cancer or a few other medical conditions, NOT as a regular long-term diet. but, yes, we have cancer, so may have to take extreme measures that wouldn't be optimal/healthy for people who don't: chemo, endocrine blockers, targeted therapy, etc. i view (but don't currently practice) diet the same way) and that i haven't tried.)
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possibly of interest to some folks here:
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Hello Ladies, I am considering Verzenio post Y90 treatment on the left liver lobe.I am concerned about V increasing the liver enzymes and bilirubin. So, a two part question, has anyone experienced this and on what dosage? Also, did you change dosages and did the values drop? I have stable lung mets and liver mets and chemos have not been effective so perhaps a hormonal again. I'd did well on Ibrance for 20 months.
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really interesting. i will try this if/when i become verzenio-resistant (or if i decide to add keytruda, after all), maybe sooner if i can get one of my oncologists on board (not likely, since they only do standard-of-care). i hear IV would be ideal:
https://www.cell.com/cell/fulltext/S0092-8674(18)30586-5
in plain english:
https://www.sciencedaily.com/releases/2018/06/180601134720.htm
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Hi Luce,
A vilified italian oncologist Tullio Simoncini has been curing terminal cancer patients with on the tumor site injections of 5% bicarbonate of soda for the past forty years.
He is very explicit about the cause of all cancers ( systemic Candida albicans infestation that has turned into a fungus, capable of mutating and regenerating via spores, hard to destroy as it's part of our biodome and innocuous when held in check by a healthy immune system that gets weakened by the abuse of sugar, simple carbs, junk foods and antibiotics in our food supply.) while most MO consider candida a consequence of cancer and a suppressed immune system, he believes that candida is the cause of a compromised immune system which precedes all diseases, including cancer
He is very honest about the cancers that he can and can't treat because of his inability to reach them. Unfortunately I have mets to the bones and both him and the allopathic MO's have no means of delivering the meds or bicarbonate to the bones.
Im so glad to read more and more reports on how the bicarbonate is making a huge difference. They are not ready yet to admit that is the bicarbonate that's effective....and that we can do without the other very expensive and toxic stuff....
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yes, thank you, i was/am aware of him. the interesting part is that mainstream oncology is catching up, and that there's an implicit link to drug resistance and to immunotherapy.
one might infer that other google-able ways of alkalinizing the tumor environment may also work. i'll certainly look into that for myself.
i personally don't subscribe to his fungus theory, at least not for all cancers. but he clearly is on to something with the baking soda.
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I'm chewing two Gaviscon tablets a day, just to handle the indigestion these drugs give me- they are highly alkaline- does that count? Not sure what the goal is, or how far does any oral alkaline pill reach into liver or other tissue?
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cure-ious: your guess is better than mine. i haven't dug yet; the study merely piqued my interest and like most everything with MBC, leaves more questions than answers. but a factor like that may make the difference between long-term responders to a medication and those who stop responding. i'll look into this further (maybe by contacting the grad student re. dosing, any may try some such strategy when i become resistant. i mean, most things some of us (can) do at this point fall under "desperation oncology".
interestingly, that despised-by-me ('cos i don't like its restriction of the vegetables i love to eat) "clean keto" diet may wok for the reasons that study elucidates.
any, yes, senescent cells are a pesky problem. verzenio may not extend our lives because some of the more aggressive cells and stem-cell-like cells in our tumors might just go to sleep during treatment, then roar awake when discontinued. one of the many papers i have recently skimmed speculated about that.
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cure-ious: from robert gillies, phd, who first made the baking soda-immunotherapy connection:
"An Atkins diet supplemented with sodium bicarbonate and Tums will help both verzenio and Keytruda."
(my q had been: hi, i am 46 and have stage-4 breast cancer with mets in pleura, lungs, pericardium, omentum, lymph nodes, spine, ribs, pelvis.... i read the baking soda study that was based on a previous study by you. any advice on how i could implement this? ketogenic diet? baking soda? i am currently on verzenio and it is working well for me. when i started it in january, my life expectancy was measured in weeks. now i am okay until/unless verzenio quits on me. i have the option to add keytruda to get a more durable response but am afraid of its side effects. an autoimmune condition is the last thing i need. thanks for your time and any advice you may have for me!)
now, i would NOT recommend an atkins diet, but clean keto, which is restricted in proteins and tailored to the individual (some people can't have beef, say, because it raises IGF-1 in them.) but his point is that yes, a ketogenic diet works for the purpose/effect described in the mouse study.
here is more on his qualifications:
https://moffitt.org/research-science/researchers/robert-gillies/#research
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cure-ious:
this, to make cancer cells less chemo-/immunotherapy-resistant by stopping them from going into quiescence, a state of temporary dormancy in which they are protected from cytotoxic substances and hidden from the immune system, is the goal. so, presumably, this approach is to be combined with a targeted therapy, immunotherapy, chemo, or a combination thereof::
https://www.sciencedaily.com/releases/2018/06/1806...
The researchers show that in acidic conditions protein motors propel lysosomes carrying mTOR away from the area around the nucleus, where they're ordinarily located. This separates mTOR from a protein required for its activation, RHEB, which continues to hang around at that location. Lacking one of its key activation signals, mTOR remains dormant, suspending the synthesis of proteins -- including the components of the cell's molecular clock -- along with most metabolic activity.
"Cells don't want to make proteins or other biomolecules when they're under stress," says Dang. "They want to slow things down and only awaken when things return to normal."
The researchers show that baking soda can reverse this effect. When given to mice in their drinking water, it surprisingly sufficed to neutralize the acidity of hypoxic patches in tumors. This sent lysosomes zipping back to the nuclear periphery in cells -- where RHEB was waiting -- and restored the activity of mTOR.
All this is relevant to cancer because researchers have long known that quiescent cells cannot typically be killed by chemotherapy. Notably, Dang and his team also found that T cell activation, which is essential to most immunotherapies, is similarly compromised under acidic conditions.
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cure-ious: i have never had a single TUMS in my life, and recoil from all prescription OTC drugs. but given the above, i'll probably add an antacid. not sure how to integrate baking soda. i wrote to another person involved in the study quoted and am hoping for dosage advice. presumably, neither will work very well without a ketogenic diet (which has numerous anti-tumor mechanisms--i read and instantly forgot a pretty good study a few days ago that explained them; maybe i'll look for it and post it, for those that may be interested in its mechanisms-- one of which is keeping the cell and environment alkaline), and i am still wrestling with the idea of a ketogenic diet. i am quasi-paleo, but that isn't even close to true medical keto.
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Interesting conversation ... thanks. Recovering well from gamma knife on Tuesday. Declined dexamethadeath. Controlling inflammation, I hope, with Longo/Gundry nutritional strategies. Doing well. More latter when I can take the ice pack off my eyes for longer periods ...
>Z<
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Z!! You made it to the other side!! The Rest & Recovery Phase awaits you!!! Soft music, hydrate, and ...
maybe some fabric art therapy? Here is a link to Sue Carlson's serendipity quilts, I am trying to make a (smaller) whale in-between my bits of grant-writing.
Luce- Fantastic insight from the researcher! So, he thinks that actual antacids will help and get through to the acidic patches, well, that's easy enough, but how much is too much?
The loss of circadian rhythms in tumors is a real problem for them, new research shows that adding compounds that restore circadian patterns kills cancer cells, and the compounds used in this research are forming the basis for a new category of anti-cancer drug..
https://www.cancer.gov/news-events/cancer-currents...
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z: get well fast!
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cure-ious: yes, that is exactly what the ketogenic diet and antacids do: restore cancer cells circadium rhythms and getting them out of quiesence, so that they are accessible to chemotherapeutic agents and immunotherapy again. no other drugs needed. (although i would LOVE a pill that would spare me going on a ketogenic and calorie-restricted diet. once one does that, one has to pretty much give up on getting pleasure from food, and can never indulge freely again, not even in the allowed foods other than MCT or coconut oil. pretty sad; i don't even like coconut oil in anything but a thai curry, and find MCT oil ethically objectionable.) i am actually thinking that this mechanism is one of the main reasons ketogenic diets work for cancer, not any starvation of cancer cells by the diet per se.
i have no idea how many antacids and how much baking soda may be enough or too much. in the absence of a ketogenic diet (which does what the antacids are meant to do pretty much by itself), i would guess "too much" doesn't really apply with regards to affecting tumors (but it most likely does apply with regards to general health, kidney function, and such, although i haven't looked into that yet). perhaps you'd be willing to dig deeper and ask dr. g for further advice (on dosing, or an actual protocol, or if antacids may help in absence of a ketogenic diet)? i was surprised i got any advice at all, since non-treating physicians are generally reluctant to give it to strangers.
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Just popping in for a quick note. I have found that brushing my tongue when I brush my teeth and even at odd times seems to clear the icky taste that I have in my mouth. Dead taste bud cells?
I am back on V since Monday and it's not too terrible. Hope that the side effects don't get any worse.
I was also starting to use baking soda and water - primarily to quell the upset stomach feeling and acid feeling but if it also helps the V then I will make it a daily dose.
Chats
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chats: i don't know what dose you are on (i am guessing 150), but should your side-effects get worse again, i'd recommend reducing the dose over taking a break. there might be a rebound effect when taking breaks. i have been playing around with dose and for me, the 50mg difference is huge with regards to side effects. not so much on diarrhea anymore (i have diarrhea one to three days a week on either dose at this point, but am definitely paying attention should that gradually get worse on the higher dose i am currently on), but that queasy feeling and lack of appetite and food just being unappealing is MUCH worse on the higher dose. i used to love food but on the higher dose, have to force myself to eat. on the lower dose, i still like and enjoy food. i may utilize the higher dose's side effect to play around with a ketogenic diet, since those foods are pretty unenjoyable (to me) anyway, and i have no strong cravings for more enjoyable fare that may be forbidden when trying to get into and stay in ketosis.
i also may buy TUMS but need to ask my doctors about the increase in calcium first (and do my own research). but, yeah, to alkalinize tumor and tumor environment, that's probably the way to go. i think baking soda can be hard on the kidneys but haven't looked into that yet. i may try to determine the least-harmful dose and add that also. and now we may know why that expensive japanese water-alkalinizing machine that someone wanted to lend me a few years ago actually might work, by alkalanizing tumor cells and environment, since an acidic environment (lactate) forms a sort-of shield around tumors, it seems. i used to think alkaline water was bs, since the stomach is so acidic anyway, and because no one could actually explain the science behind it to me. makes a lot more sense now.
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the cost of my verzenio co-pay has jumped to 6000 a month, does anyone else have the same problems, any grants, foundations, money? This amount is not doable! Suggestions please......And it seems to be working clean scan and tumor markers down. Stage 4 with brain mets.....
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Hi MKDF77-
Welcome to BCO, we're sorry you find yourself here, but we hope this community can be a place of support. The financial aspects of breast cancer are difficult to manage, we sympathize with your situation! We have a forum that might be helpful to you: https://community.breastcancer.org/forum/113. We sincerely hope you're able to find some financial help, so that you can continue your treatment!
The Mods
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luce,
I did a bit of digging and this is from Constantine Kaniklidis on the rebound issue.
ABEMACICLIB (VERZENIO) PLUS PEMBROLIZUMAB (KEYTRUDA)
As I noted in these forums, SABCS 2017 provides further promising benefits of combining abemaciclib (Verzenio) with the checkpoint inhibitor pembrolizumab (Keytruda), where early hints the JPCE trial suggest benefit in pretreated ER+ disease without adding any additional toxicity, to be confirmed by the final report due this February 2018.
REBOUND: EVERYTHING YOU HEARD IS WRONG
Now, I'll take up the issues of REBOUND, via showing key fallacies in the literature discussing this much garbled concept, and it's even more mangled implications:
FALLACY 1: Ki-67 REBOUND IS THE SAME AS OR IMPLIES TUMOR GROWTH REBOUND
As to so-called rebound effect, there layers upon layers of confusions and misperceptions about this, due to garbled understanding by both the lead investigator (Cynthia Ma) of the NeoPalAna trial , who herself misstates the matter, and by Sara Hurvitz who both incorrectly interprets Ma's conclusions as well as herself garbling key distinctions. Although the claim - once understood properly - is empirical but only hypothesis-generating since as I will show below no one has any reliable evidence of it, nonetheless regardless of what further robust trial evidence ever shows, right now we can unambiguously reject Hurvitz's notion that the trial referred to (NeoPalAna) even remotely suggests that "the TUMOR may actually rebound". Wrong.
Hurvitz (mind you: "overreach" in interviews is common among oncologists, making rather sweeping ifHurvitz (mind you: "overreach" in interviews is common among oncologists, making rather sweeping if not soaring statements that in a journal NO Editor or Reviewer (like myself) would EVER tolerate!), and Ma conflate illicitly the concept of Ki-67 REBOUND - if indeed this is eventually validated independently in robust cross-confirmative trials, which it has NOT been to date - and the concept of TUMOR GROWTH REBOUND, that is, a clinically relevant and measurable increase in aggregate tumor volume post-termination.
These are NOT remotely the same. Ki-67 rebound is simply an increase after terminating an agent, transiently or durably, to higher levels than it exhibited while on the active agent, and it in addition just reflects the fact that the rate of proliferation has increased above the levels that the agent was able to lower them (Ki-67) to when active. It DOES NOT follow from such a increase (aka, rebound) that there is necessarily any true DISEASE PROGRESSION (which definitionally means an increase in total tumor volume). Ki-67 often spikes in such circumstances but may not lead to clinically significant worsening in measurable tumor burden (cells are simply proliferating faster, relative to a previous threshold, not uncommon in the "off-periods" of any agents cycle).NOTE: Fueling the confusion is a commonly cited MD Anderson study [Bashour et al. J Cancer. 2017] which claims rapid disease progression following the discontinuation of CDK4/6 inhibitor therapy. It shows no such thing, being only a hypothesis-generating speculation based, moreover on a case series of exactly 4 (FOUR!) patients (and only TWO (!) of which suffer compromised survival). Note however, that although two of the patients who developed rapid disease progression after CDK4/6i withdrawal were lost prematurely early (before 6 months post-treatment), the other two actually proceeded to follow the expected natural history of the disease (one even surviving over two years after CDK4/6 inhibitory therapy discontinuation), so that is a wash. But it does not diminish the ultimate methodological compromise, that deducing anything from a population of TWO aberrant natural disease histories is rather an act of extreme chutzpah and lacks ANY compelling status.
FALLACY 2: ASSUMING ALL CDK INHIBITORS ARE EQUAL
The NeoPalAna trial, being (a) a neoadjuvant trial, and (b) a palbociclib (Ibrance) trial, has ABSOLUTELY NOTHING to say about abemaciclib (Verzenio) nor about the metastatic setting. No extrapolation across these boundaries is licit. Despite falling into the umbrella class of CDK4/6 inhibitors, these are VERY different agents with their own unique modes of operation: abemaciclib (Verzenio), as opposed to the other approved CDK4/6 inhibitors, exhibits far stronger potency / selectivity for CDK4, rather than CDK6, likely driving both tumor cell senescence (terminal growth arrest, aka "proliferative arrest" resulting in non-dividing cells, hence senescence constitutes an effective tumor suppressor mechanism) and ultimate tumor regression. This is true of abemaciclib and of, to date, no other CDK inhibitor. And of course, palbociclib (Ibrance) and ribociclib (Kisqali) require "off-weeks" to permit recovery of bone marrow function, in contrast to abemaciclib (Verzenio) which can be and is dosed continuously no off-periods. (And of course all the other advantages I have dissected, including record-breaking median overall survival (OS) of almost two years).
FALLACY 3: REBOUND ACCOUNTS FOR TO-DATE NON-EMERGENCE OF OVERALL SURVIVAL
You may have picked up the the impression - left likely by the Hurvitz and Ma confusions - that the failure of an as-yet demonstrated overall survival advantage must be secondary to this rebound. Not so. Across all oncology in every malignancy type we have been for some while seeing a trend of increasing PFS and decreasing, or no demonstrated, OS, but this is due to a complex survival factor "located" between PFS and OS, known as POST-PROGRESSION SURVIVAL (PPS), which - very roughly - tracks how much subsequent lines of therapy may confound or suppress reliable determination of overall survival (OS). It's been shown that when post-progression survival is much longer, as it is known to be in the hormone-positive environment, and with targeted and immunotherapies, as opposed to chemotherapies, then OS becomes a weak endpoint for clinical trials. In addition, OS emergence requires far larger patient populations, and far longer follow-up periods, than PFS.Note further, in any event, the fact remains, as per the NeoAnaPal findings, that while patients who stopped palbociclib (Ibrance) two to four weeks before surgery showed a rebound in Ki67 when assessed at point of surgery, those who actually received palbociclib immediately before surgery did NOT. No rebound. And note that this is a "neoadjuvant thing" - having to do with what happens pre-resection (surgical intervention), and cannot be generalized out of this highly specialized context. And since the washout, as admitted by Ma, was abrogated on cycle 5 of palbociclib (Ibrance), and since as I have demonstrated elsewhere and in these forums, the long TTR (time to response) of palbociclib dictates deployment of at least 5 to 7 cycles to be a fair test of responsivity, the matter may be moot - EVEN IF CONFIRMED outside of this small and highly bounded trial (it was a single-arm Phase II trial with no comparator, and with all the limitations of such trials).
Finally, that while we at present lack data for overall survival from any of the phase III trials of CDK4/6 inhibitors (likely due to the confounding represented in the measure of post-progression survival (PPS)), nonetheless the doubling of PFS seen with the addition of CDK4/6 inhibitors to conventional endocrine therapies is unequivocally a breakthrough in the treatment of patients with metastatic HR+ breast cancer, not rivaled by any other agent to date.
Kind regards
Constantine
Constantine Kaniklidis
Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)0
