Abemaciclib Verzenio for Stage IV
Luckylegs and friends on Abemaciclib - I am bumping the Verzenio discussion in the hopes that more people have started abemaciclib. We need to get a community going. I have not started abemaciclib but it is on my short list. Like many I am very interested in how people do on this treatment do, both as a monotherapy and in combination with hormone suppression and other treatment. I am hoping that this thread can capture the experience of everyone on Abemaciclib in whatever combination. This is a very important treatment option that we all need to be evaluating.
I would expect more people on the drug given the significant advantages of abemaciclib over the first generation CDK 4/6 inhibitors. However, the FDA has approved abemaciclib for only limited indications. We have not established its use as a first line treatment nor as something to switch to from Ibrance. At the same time, they haven't made it clear that the drug can and should be used after Ibrance. As a result, the setting for using abemaciclib is supremely unclear.
I believe abemaciclib can be used either instead of or after palbo/ribo depending on whether you view abemiciclib as another class of drug or the same class of drug with significant improvement. One can make arguments for either strategy. If you've already done palbo/ribo, it is certainly worth trying abemaciclib. If you haven't done palbo/ribo, the current guideline that you start with the first generation CDK 4/6 is reasonable, but not necessary IMO. A lot depends on the side effect profile you can tolerate the best as the drugs have significant differences in side effects and also whether you are at risk of brain mets. Abemaciclib is better at crossing the blood brain barrier.
The following summary of abemaciclib data taken from a thread started by Constantine on Inspire. I moved his entire discussion from three posts because it's that good. Thank you Constantine.
ABEMACICLIB (VERZENIO)
Preliminary data from a phase I study of abemaciclib [SABCS 2014] in patients with five different tumor types including HR-positive metastatic breast cancer, with I note a median of seven prior systemic therapies (outliers out to 11 lines) found an objective response rate of 19% and a disease control rate (including stable disease (SD) under RECIST definition of >24 weeks of ) of 81% for HR-positive MBC patients. This Phase I study was expanded to evaluate abemaciclib plus fulvestrant in HR-positive MBC [ASCO 2014.] with patients having a median of four prior systemic therapies (and outliers out to the eight line), finding an objective response rate of 62% confirmed PRs.
A subsequent Phase I study [Tolaney et al, J Clin Oncol 2015;33(Suppl 1).] of abemaciclib in combination with different endocrine therapies for HR-positive MBC (median lines of treatment = 3, with outliers out to 8) demonstrated a disease control rate (CR + PR + SD) was 67% for those on abemaciclib + AI therapy, and 75% for those on abemaciclib + tamoxifen.
The phase II MONARCH-1 trial evaluated abemaciclib MONOTHERAPY in HR-positive, HER2-negative MBC patients with a median of 3 lines of prior therapy for advanced disease, including a median of 2 lines of chemotherapy (as opposed to endocrine or biological therapy) for advanced disease, yielding an objective response rate (ORR) of 17.4% and a clinical benefit rate (CBR) of 42.4%.
What's important to remember about MONARCH-1 is that many women in the study had already received multiple lines of endocrine treatment (median 3 - 5 previous lines in the metastatic setting, with outliers beyond that), developed resistance and were refractory to all of these treatments, AND progressed, many of whom also received chemotherapy, and these results were for MONOTHERAPY in a heavily pretreated population, which as I determined through examination of historical controls with any other agent achieves at best only 10 to 20% clinical benefit rates - half of that achieved by single-agent abemaciclib, and with responses of short duration.
Hence, the collective results of these trial, including MONARCH 1 (MONARCH-2 (with letrozole) and MONARCH-3 (with fulvestrant) are exceptionally exciting breakthrough in breast cancer therapeutics.
BREAKTHROUGH SURVIVAL
In addition, for me, the overall survival (OS) of these heavily pretreated MBC patients was 17 months, and that compares to historical control I review from all clinical trials to date, as significantly better than other survival results, which are usually are at best 13 months. Thus, consider that for the current champ, eribulin chemotherapy in this setting, the EMBRACE trial achieved a median overall survival (OS) was 13 months, we clearly have here a major advance and improvement in overall survival in the highly challenging later-line settings (past at least 3 lines of therapy).
HIGH TOLERABILITY
The major limiting constraint with all CDK4/6 inhibitors to date, like palbociclib (Ibrance), is their most common adverse effect, that of myelotoxicity via neutropenia (low WBC neutrophils), with palbociclib (Ibrance inducing some degree of neutropenia in over half of women on it, with associated dose interruptions and sometimes dose reductions, a toxicity that so fat from the available data seems to also afflict ribociclib.
But abemaciclib (Verzenio) evades a good deal of this because although strictly a CDK4/6 inhibitor, it is more specific in inhibiting CDK4, that is it is CDK4-selective, and myelotoxicity including neutropenia is primarily associated with CDK6, making the incidence of neutropenia on abemaciclib significantly lower and more manageable.
CLINICAL LESSONS ON ABEMACICLIB (VERZENIO)
And unlike palbociclib (Ibrance):
1. abemaciclib has strong single-agent activity in HR–positive MBC,
2. has durable response in later line settings,
3. a good tolerability profile with reduced neutropenia, and
4. to date the highest OS in these challenging heavily pretreated settings of any oncotherapeutic agent, whether endocrine therapy, chemotherapy, or biological therapy.
SOME NUANCES
1. The ESMO-reported MONARCH 3 Trial found an response rate of 48.2% for all patients, BUT for the subgroup of patients with measurable disease, a response rate (ORR) of 59.2%, these being the highest ever response rates achieved to date for ANY endocrine therapy in breast cancer.
2. And although data needs to mature further for survival outcomes, it is anticipated based on exploratory analyses that PFS will weigh in at an improvement of close to 12 months, again an extraordinary gain.
3. In addition, Verzenio was most effective in challenging populations like those with visceral metastases (especially liver) and those with rapidly recurrent (short disease-free-interval (DFS)) patients.
4. Finally, 16 patients across two of the three MONARCH trials were NED (complete response (CR)), likely to increase once the MONARCH-3 data matures, more still I anticipate when results are reported from the MONARCH PLUS and other trials.
DIARRHEA AND ITS MANAGEMENT
To put the adverse events into a bit of perspective, although it is true that with Verzenio, all-grade diarrhea was between 86 - 90%, yet serious (Grade 3+) incidence was 13 - 20% but this is aggregated across the trials, and note further that diarrhea incidence is concentrated during the first month, and more narrowly the MTO (median time to onset) of the first diarrhea event was 6 days, lasting a median duration of just 6 days for Grade 3. Furthermore, for the most recent MONARCH-3 RCT, grade 4 diarrhea was zero, and grade 3 diarrhea was just 9.5%.
An aggressive proactive regimen of:
- high-dose loperamide/Imodium (4 mg but NOT ever de-escalated down to 2mg (and up to 16 -32 mg daily);
- "Big Pink" (Petpto Bismol Extra Strength) used in "priming" mode (started on day 4 and also used for immediate relief during loperamide dosing;
- budesonide (Symbicort) for recalcitrant cases;
PLUS "adjunct interventions:
- high-dose probiotic (28 billion microorganism count in two divided doses), and
- electrolyte powder (most of the refractory diarrhea was analyzed to be secondary to disturbed microflora and electrolyte imbalances)
- at least 12 8 oz glasses of fluid daily, 8 of which should be electrolyte-enhanced
brought the rate of diarrhea-related drug omission or dose reduction down from 22% (MONARCH 1 and 2) to under 1 - 2% in the cohorts run by my research teams in India and the Middle East.
NOTE: We found that the adjunct interventions of Big Pink, high-dose probiotic, electrolyte rebalancing, and assured fluid intake were at least important as the conventional agents, and in cases that seem intractable, converted to success, given that therapy-driven diarrhea inevitably causes GI tract flora, and electrolyte, imbalances, aggravated by inadequate hydration. Also critical was "through-and-through" loperamide dosing: 4 mg at each episode, but NOT de-escalating - as current protocols do - down to 2 mg after first (that de-escalation regimen we found indifferently effective, with large numbers of failures.
And although not reported to date, I note that in the MONARCH 3 trials the incidence of ANY grade diarrhea dropped to just 2% (courtesy of data provided by Levi Garraway at Lilly).
ACTIVITY IN LOBULAR CARCINOMA
The trials largely fail to report to date differential invasive-type stats, but the impression from conversations with some principals is that lobular breast cancer subjects are unlikely to experience significant decrement, and I also extrapolate from some hints surrounding the PELOPS (Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study) Trial another CDK4/6 inhibitor palbociclib (Ibrance), as well as from some molecular considerations (the p27 gene is a key regulator of certain types of progression (G1 to S-phase) and it appears that lobular carcinomas tend to have higher p27 which in a complex way under contextual effects can have either positive or negative effects on phase progression), but we have to await sub-group analysis to report on this issue explicitly. I am cautiously confidant of little differential outcome, which I think may be confirmed across the general class of CDK inhibitors. In addition, both the lobular and the ductal groups appear to have benefited from the addition of palbociclib (Ibrance) in the PALOMA-/TRIO-18 Trial, but I note that the difference observed in PFS in that trial is likely to be an artificial artifact of the small patient in the subgroup with lobular carcinoma arm (n = 18/19) compared to n = 117 in the ductal subgroup, so this is a small sample size effect not a robust finding, an impression in agreement with that of the principal investigators (Richard Finn and UCLA and colleagues). As we learn more about lobular BC and abemaciclib in particular, I will offer further clarifications.
DEGREE OF DIFFERENCE - IBRANCE v VERZENIO
Given the dramatic 14-fold (!) greater CDK4 activity in abemaciclib (Verzenio) compared to palbociclib (Ibrance) and ribociclib (Kisqali), as MONARCH 3 lead author Angelo Di Leo has established and noted in interview, and other consequent fundamental molecular pathway differences, I view these as only shared-class (CDK), but therapeutically distinct, agents, more like the difference between third-generation capecitabine (Xeloda) versus first-generation 5-FU although these are both fluoropyrimidines.
So: More different than same as witness also the high degree of relative invariance of efficacy and durable response in later-line treatments for Verzenio compared to that of Ibrance (see my original posting, above). These differences are sufficient warrant for me to classify palbociclib (Ibrance) as a first-generation CDK inhibitor, and abemaciclib (Verzenio) as a second-generation CDK inhibitor. The devil - as always - is in the details.
CNS (BRAIN) ACTIVITY
We have preclinical data [Raub et al. Drug Metab Dispos. 2015] of the cross-BBB (blood-brain barrier) capability of Verzenio, as witness the remarkable benefit in GBM (glioblastoma, being even non-inferior to temozolomide (TMZ), the standard of care in cross-BBB activity, and this although not a human clinical, was an in vivo, not just in vitro, study. And the Dana-Farber JPBO human clinical trial (I3Y-MC-JPBO) under Sara Tolaney is investigating single-agent abemaciclib in patients with ER+/HER2+ brain metastases, where I fully expect clinically relevant CNS benefit to be confirmed, with first phase interim results reported in June at ASCO 2017 showing 2 patients (8.7%) out of 23 having confirmed partial response (PR).
I should point out that there has been some provisional data on palbociclib (Ibrance) having potential cross-BBB activity in brain metastasis, but I hasten to note that strong in vivo data show a 10-fold greater cross-BBB activity for abemaciclib than palbociclib, with abemaciclib brain levels being more efficient at substantially lower doses than palbociclib and also active for longer duration, and finally abemaciclib was active as monotherapy, palbociclib was not.
Finally, as to leptomeningeal metastases, no explicit data bears on this question directly, but as to date all agents active in brain metastases have also been active in leptomeningeal metastases, activity would be expected.
THE ISSUE OF SWITCHING
It remains an open question whether patients who have progressed on or after another CDK inhibitor like palbociclib (Ibrance) may derive significant benefit from continuance of CDK4/6 inhibition by using a following CDK inhibitor like abemaciclib (Verzenio), with many in-progress trials like TRINITI-120 (and NCT0185719319 and NCT0263204521, among others) exploring the issue. But there is some plausible extrapolation from some preclinical data which has suggested non–cross-resistance among CDK4/6 inhibitors. A Barts Cancer Institute study reported at SABCS 2016 found that some palbociclib(Ibrance)- and ribociclib(Kisqali)-resistant cell clones were sensitive to abemaciclib (Verzenio).
For patients now on Ibrance (or Kisqali) but who have NOT PROGRESSED , is it motivated to switch to abemaciclib (Verzenio)? This is an issue that needs to be thrashed about candidly with your oncology team and is a highly individual decision, but my own sense at this time is that it may be more optimal in the long run to stay the course, and consider abemaciclib (Verzenio) for recourse upon progression either off-label until the FDA expands its approval, or on one of the many abemaciclib (Verzenio) clinical trials available.
I would however entertain some specialized exceptions in which a switch now, off of Ibrance or Kisqali, onto abemaciclib (Verzenio), might be motivated; for example:
1. If a patient is experiencing repeated difficult-to-manage neutropenia, occasioning multiple drug interruptions or reductions (neutropenia being dramatically less with abemaciclib (Verzenio)), but the patient must weigh the associated countervailing issue of higher incidence - but still manageable I would argue - diarrhea on abemaciclib (Verzenio).
2. If a patient is in advanced later-line setting (say, more than 5 to 7 lines or so of treatment in the metastatic setting already completed), where it is suspected that abemaciclib (Verzenio) may be somewhat more consistent and durable in response and benefit in such challenging contexts. This is a difficult one to judgment-call, and I would tend to want to weigh each patient's circumstance and their complex treatment history and individual pathology to assist in the decision, since we have no hard data to be dispositive on this decision.
Yes, these are arguable and have to be intensively debated (as in a tumor board setting), but they are not wholly unreasonable. Outside of these exceptions, however, I do not see sufficient motivation to prematurely abandon Ibrance or Kisqali, as these have strong track records of efficacy and should be push to progression.
FDA APPROVAL
Abemaciclib is currently approved ...
1. as combination therapy with fulvestrant (Faslodex) for the treatment of women with HR+/HER2- advanced or metastatic breast cancer who experience disease progression AFTER ENDOCRINE therapy.
2. as monotherapy for the treatment of women with HR+/HER2- advanced or metastatic breast cancer who experience disease progression AFTER ENDOCRINE therapy AND prior CHEMOTHERAPY in the metastatic setting.
(Z) MO's have latitude to prescribe outside of these indications and there are strong arguments for doing so. My MO appears to have wide latitude to prescribe Abemaciclib and get insurance approval in other settings.
EXPANDED ACCESS:
Abemaciclib continues to be available through Lilly's attractive Expanded Access Program (EAP):
https://clinicaltrials.gov/ct2/show/NCT02792725?term=abemaciclib&rank=24
which is active and recruiting currently in several US locations (California, Florida, Minnesota, Missouri, Texas, and West Virginia), more being added. However that is for patients who have not as yet progressed on a previous CDK inhibitor like palbociclib (Ibrance), that is, for "switchers" who may want to explore the improved benefits of abemaciclib (Verzenio) over Ibrance (assuming the patient meet the other trial criteria); but not for patients who have already progressed on Ibrance.
RECHALLENGE
In several cases I have known, I counseled that although someone progressed on Ibrance, to reintroduce it after a hiatus of 3 - 6 months, and in many cases this washout appeared to resensitize the tumor cells to Ibrance, which upon re-introduction was newly effective. It is a variant of a trick I have counseled and seen working not infrequently with other agents like capecitabine (Xeloda) where after progression on it, I advised a trial on a new metronomic schedule (low-dose, continuous, daily, capecitabine) and seen again it newly effective despite previous progression, just by this shift I schedule (there is some provisional data for this, but not decisive). But these are beyond convention and reserved for highly special circumstances.
MARKERS THAT PREDICT RESPONSE TO CDK 4/6 INHIBITION
I am not convinced that there is any biomarker - protein or otherwise - that reliably identifies responsivity to CDK inhibitors, and Fabrice Andre of the Institut Gustave Roussy and colleagues, as reported in their presentation at ASCO 2017, were unable to identify any such biomarkers of response: neither Rb levels, p16 protein levels, Ki-67 cell proliferation, CDKN2A, CCND1, nor even ESR1 gene expression, all the usual suspects, and others, had any response-predictive value whatsoever. To date the only established biomarker for response to CDK4/6 inhibitors, remain hormone receptor positivity (HR+). Of course not everyone responds, but response rates remain historical high - and higher than any other treatment to date - and as long as one is HR+, one has the potential to benefit from a CDK inhibitor.
Constantine Kaniklidis
Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)
Oncology Reviewer, Current Oncology [journal]
Society for Integrative Oncology (SIO)
Member, European Association for Cancer Research (EACR)
Comments
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Tons of information, thanks Z for publishing this! I hope Constantine continues to provide updates through 2018 and beyond. It is shocking to realize how little is settled about best treatments following standard firstline therapy
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Z - thanks for starting this thread and for the info you posted. I don't know all the clinical words and stuff in the information but here we go.
A little background on my bc coming back to my bones (just in the pelvis) and I don't know the specifics of tumor sizes or anything. This is a totally different language than my initial bc in 2012 so I will be learning. I started jogging in October. By that I mean jog 1 minute, walk 2 minutes and repeat 7 times. Did it every other day and increased VERY gradually. I never made it past the 6 minute jog , 1 minute walk, repeat 3 times because the pain was intolerable.
I just had 3 weeks of writing go away and I'm not repeating it. !!!
I am going to get my 3rd Faslodex shot today and I start the Verzenio today. I have taken off work for the next month because I expect the side effects to be that bad because of the information cards they sent me. It is a chemo pill and I am supposed to wear gloves to take each pill and dispose of them in a sealed container.
I am happy to give you my experience on this new journey. I plan to give it a try for a month and see if I can work and have a life while doing this treatment. I will also get bone strenghtening infusions every three months. The doctors have said that I can continue this treatment plan as long as it works or as long as my body will tolerate it.
I don't know how we are supposed to know if it is working. Do I do that with scans, bloodwork, just wait until I have a new symptom? I will get as much information as I can when I go to the onc today.
I did the femara for 21/2 years after my initial bc treatment but I had to stop it because of the side effects. One other thing is that I never had any type of scan other than my initial scans when I was initially diagnosed.
I hope some other people will post here with their experience too.
Have a wonderful day dear sweet sisters! Jenny
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Z, Thank you for starting this thread! I am hoping that this is going to be my next treatment. My mo has 3 patients who started this drug. He is very concerned about the diahrea. He said he would let me know in February what he thought. I told him that I thought he should talk to more of his patients about that, because I for one, would welcome diarrhea over concrete rocks!
Spiced, I am hoping that this treatment really works for you.
Hugs and prayers,
Claudia
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Hi all --
Been meaning to jump in since I'm on Abemaciclib. I know everyone's experience is different, but I just want to emphasize that the side effects are minimal. Yes, the diarrhea can be bad, but once you figure out what irritates your stomach, you just avoid those foods (for me, it's raw vegetables and sometimes acidic foods). If I'm going out to eat and am worried, I'll take a pre-emptive lorapamide. All my stomach issues are food-related. If things get bad, I'll just do a BRAT diet for a day or two. Interestingly, I went on a trip to Europe in September and had no issues. Must be something in the water.
Spiced: why are they telling you to wear gloves? I've handled Abemaciclib daily for almost a year with no issues. No one ever mentioned drugs.
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Mazie73....I am SO glad you posted. I have been worried the most about the stomach issues as I have IBS and just recently got my issues with that under control. I wasn't told to wear gloves but that is what t he directions that came with the drug said to do. I also read that around 90% of the people on the drug have the terrible stomach problems for the first month.
When I told my onc that I plan on being off work for the next month to get used to the drug he said I was basically crazy to do that. My words, not his. He said that he has people on the drug and they are just fine. So I am thrilled to read that you are doing so well. I haven't found any patient reviews about this drug on the internet until Z directed me here. Again, thank you for posting!
I got my Faslodex shot yesterday and infusion for strong bones (can't remember the name of it) and I will take my first pill tonight.
Love and good day to you all, Jenny
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Question: What about a rebound effect with Abemaciclib? What if I don't tolerate it or don't respond or it stops working (which it eventually will) and I discontinue it, will there be a rebound effect? I suspect that yes, there will be. I have read that that may be the reason overall survival benefits haven't been proven yet: people have longer progression-free survival on those drugs, but once they discontinue, there is a rebound effect and consequently they die sooner off the drug than they otherwise might have.
Some of these studies are finished. Does anyone know about whether any rebound effect was investigated after?
Thanks!
Dec. 2016:
TARGETED ONCOLOGY: Does the dosing schedule have anything to do with its efficacy?
Hurvitz: The continuous dosing may be related to the single-agent efficacy. There is some data that suggest that during that off week, when you're allowing the white cells to recover, the tumor may actually rebound and increase in cell cycling. That was shown in another neoadjuvant study looking at palbociclib (Ibrance), which was led by Dr. Cynthia Ma. We will be looking at the 4-month biopsy samples and selected tumor samples of when patients have been off of abemaciclib for a period of time to see if we are also seeing that rebound effect in patients after being off of abemaciclib.0 -
luce - that is an interesting comment indeed.
thank you all for reporting in. many are monitoring this thread.
>Z<
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Spiced: Everyone's different, but the only time I've had really bad stomach problems is when I've eaten raw vegetables. Even nibbling a bit of carrot while slicing it to make a stir fry caused problems (and I won't even mention the time I ate a fresh spring roll — previously my fave easy dinner snack — and then realized my mistake. But, the stomach problems have never lasted more than an hour and medication always makes everything better. Yes, it's totally unpleasant, and painful, but temporary. I tried OTC medications initially (Immodium, Pepto Bismol), but ultimately got prescriptions — Loperamide (2 mg) and Lomotil (2.5-0.025). My oncologist said the side effects go away for some people. I'm still waiting!
Luce: Due to scheduling with my clinical trial, there have been three or four cycles when I've been off Abemaciclib for a week. But the tumor size/number and tumor markers have consistently decreased. I'll ask my oncologist about that study and see what she says. She's the lead researcher for the trial I'm on and is a big fan of Abemaciclib. My appointment is on Monday, so I'll post her response Monday evening or Tuesday morning. I know there are a few other questions I want to ask based on what people have posted.
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Mazie - I am on the edge of my seat to hear whether your oncologist sees a rebound effect. It may be something that is hidden by the shortness of the prescribe breaks relative to the time on the drug. I have read that it is important that the amount of time on ibrance should be at least 2X the amount of time off. This is very important to understand but the kind of things that they wouldn't discuss with patients.
>Z<
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I haven't posted on this site in a very long time, but have been reading the last few months.. I hope that my story will give some hope to those who have just begun this journney that none of us want to be on.
I've had a long history with breast cancer, beginning in 1975 - I was 34 - when I had a mastectomy, chemo and radiation. After 5 years, I thought I was cancer free. Well, that wasn't to be. In 2004, I had another mastectomy and reconstruction (Diep) on both breasts. I took Armidex for five years, and thought now I was surely done with this disease. Again, not to be!! In 2012, I experienced a great deal of back pain which led to my diagnosis of MBC in the bones. I thought it was a death sentence,as it surely would have been in 1975. I'm happy to say that I have been treated for 5 years at MSK. I took letrozole for 3 + years and received monthly denosumab injections. During that time I continued to work part time-3 days a week- and was able to continue my usual life style. My Pet scan indicated that there was some progression in the bones. I then participated in a clinical trial for GDC-0810, an estrogen degrader, for a year until I had progression to the liver.
Last January I began the Monarch trial which included Faslodex,abemaciclib and another drug, LY3023414, a PI3K/mTOR inhibitor. I was not able to tolerate the LY3023414. I developed a rash all over my body which even scared my doctor and nurses. I continued on the regimen with Faslodex and abemaciclib and bi-monthly denosumab injections and have justed started cycle 14. Part of the regimen is regular CT and MRI scans- every 2 months for the first year, then every 3 months. I have had a good response to this treatment as my liver lesions have shrunk. I have found this regimen very easy to tolerate. My nurses know how to give the Faslodex shots so that they are relatvely painless. I also learned on this site ways to make them more tolerable. As for the abemaciclib, I have had few issues. There is the possibility of stomach issues and diarrhea, but I have been able to manage that with Imodium. Fatigue seems to be the same as with other regimens. My biggest issue is that my taste has been affected so that some foods are hard for me to tolerate, especially those which are acidic. A very common side effect is dry mouth, and I developed that early in treatment. I encourage those of you starting Verzenio to be hopeful that you will be able to tolerate this easily and not to be afraid to start it. Feel free to PM me with any questions or concerns you might have. I am 76 years old and plan to be around a lot longer!!
Marie
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Marie - thank you for your post. I appreciate the time you took to detail your protocol and remarkable response. We see a variety of experiences on abemaciclib, particularly with respect to side effects. I am glad it has been very tolerable for you. Please keep us updated and have a healthy 2018!
>Z<
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Mazie and Marie, you have really helped to calm me down. Thank you! I started the Verzenio last night so I have only had two doses. I took Zofran 30 minutes before taking the pill and I ate eggs, bacon and toast. I got very nauseated but after an hour or so and drinking gingerale and soda crackers it had calmed back down. (Must have been the bacon....I usually don't eat bacon because it is very hard on my stomach...oops.....and once I finally got to sleep I slept very well. It was very hard to wake up but I don't know if that was caused by the verzenio or the faslodex.
This morning I took the Zofran 30 minutes before taking the pill and I also ate an egg, toast and apple cinnamon oatmeal. I have not had any nausea today. I have felt sleepy and spacey but that is all. So far I am thrilled.
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Spicedlife: What dosage are you taking? I can almost guarantee that any nausea was due to anxiety (or a lingering side effect of those awful Faslodex shots — I've vomited twice from the pain). Abemaciclib definitely shouldn't make you feel spacey. You might feel a little tired in the afternoon, but nothing you can't power through, or take a quick nap when needed.
Have they told you to take it with an hour of a meal?
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from constantine kaniklidis via inspire (i had posted some questions there):
Good questions, which in answering will I hope help to clarify the issue, and expose some rather clotted reasoning and invalid jumps to conclusions not supported by the data that many clinicians (Hurvitz, Ma, and others) are making:
STABLE DISEASE IN MONARCH 1 (ABEMACICLIB (VERZENIO)) TRIAL
As to your last (most recent) question, although secondary reporting sources sometimes omit, the stable disease rate was actually reported in the MONARCH 1 trial report (this is required by peer-reviewed journal standards that conform to RECIST reporting standards): CBR (clinical benefit rate: CR+PR+SD≥6 months) was 42.4%, of which 19.7% was the objective response rate (CR+PR) and 22.7% was the stable disease (SD) rate; this is a relatively high CBR for a median of three (out to 8) previous lines of metastatic therapies (any number of non-metastatic regimens allowed) that forms the subject population of the trial.
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 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)
Oncology Reviewer, Current Oncology [journal]
Society for Integrative Oncology (SIO)
Member, European Association for Cancer Research (EACR)0 -
Z- would this mean that it is better to take 75 mg for 21 days and be off for 7 days instead of 100 mg for 21 days and need to be off for 14 days to recover ANC for the next cycle?
Seems also that the rebound affect per Constantin may not be a clinical rebound in tumor burden?
thanks
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Luce...I'm a newbie. Can you tell me who Constantine is? In a nutshell?
Many thanks.
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azs40: i have no idea. i just went to the link in the first post of this thread. I'm actually wondering myself. could constantine be affiliated with lilly? the vociferous defense of abemaciclib on all counts makes me suspicious.0
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Constantine Kaniklidis, aka Edgerider, is an oncology researcher. He posts on www.inspire.com. He is research director of the No Surrender Breast Cancer Foundation Forum. Very informative posts.
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yes, that much is obvious. but he appears so biased, i am wondering if the foundation is independent or sponsored by some drug-maker?
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Love this guy Constantine-- please keep re-posting his insights!!
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I guess I don't see bias since I was so optimistic about Abemaciclib just from the reported properties (works on brain mets, has single-agent activity)- and I hope we see the data he is talking about in Feb about the final upshot of the phase 1 combo with Keytruda!
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I agree, his posts are informative but I can see why Luce would question motives. What I found interesting is that I could not find information on his credentials anywhere, not even on Linked In. May mean nothing but I must admit I find that decidedly odd for someone who is a researcher in the field. I spent many years in academia and trust me, thesefolks are typically not shy about listing the letters after their name. Just saying... 😉
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Wow. Deja vu. Constantine used to post on YSC boards 11 years ago when I was early stage with the same reaction - some loved his posts, others questioned his motives and identity. I really have no opinion - but he has been around stirring things up for a long time
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I found his info on LinkedIn
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The link isn’t working but I did find him on Linkedin. However, unlike most people on the site, particularly those with advanced degrees, I saw no reference to his education. This may mean nothing. I just find it odd. I do find his posts interesting and thought provoking.
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I've followed Constantine for a while. Constantine is a cancer consultant operating out of the middle east ?!!? (somewhere not the US and not europe) and a tireless reader of cancer papers. He is pretty solid and not associated with any drug company. He is a voracious reader and he does an excellent job at consolidating and making sense of what he reads. The limitation, of course, is in what he reads. I feel that, generally, the literature is highly influenced by drug companies. He amplifies a certain perspective shared by our entire research community. To his credit he is knowledgeable on complementary therapies and ready to mix up the standard protocols where it makes sense. I listen to him closely and learned a lot. I am not always in agreement, his data (taken from papers) is always sound but where it leads him can be debated.
>Z<
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What's the best method of monitoring if one is a responder, or at least stays stable on it? I don't have any easily-measurable tumor (even though my mets are everywhere: spine, ribs, pelvis, pleura, lung, omentum, lymph nodes, pericardium ...) and I don't want CT-scan radiation.
Is it true that it takes 3.7 months until a response shows, or did I misread something? Given the diarrhea, etc., this clearly is not a medication I want to be taking if I am amongst the 60% (I would be taking it as monotherapy) that derives no benefit. I care about the quality of my abbreviated life, and diarrhea (and possibly nausea, inappetence, weight loss) and fatigue are a big deal since I am already tired and rail-thin.
I'm just reading that CDK4 gain is seen in only 14% of luminal a breast cancers. (Mine is luminal a.) I may be missing or misunderstanding something here, but how does that make me a good candidate for a CDK 4 inhibitor?
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zarovka: and i agree that drug-company data of course makes their drugs look more favorable than they perhaps are, so i prefer to go with the independent-review numbers whenever possible. the objective-response rate in MONARCH1 is 17.4%, not the investigator-assessed 19.7%, for example.
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He is on linkedin. I just saw it.
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luce - Scanning is the gold standard for IDC. If you have ILC, TM markers are an important tool because scans are difficult to interpret. With ILC, doctors go with bloodwork and how you feel.
There are a few maverick doctors who do not scan much or at all and go by bloodwork and how the patient feels for all types of MBC. This approach works in tandem with the belief that there is no real advantage to catching progression early. The main argument for this strategy is that we don't have a lot of evidence that an aggressive treatment protocol results in longer overall survival. However, the argument has many counter arguments and the strategy takes cojones I have not been able to muster.
The behavior of TM's is specific to the individual and the cancer and the behavior of cancer can change with time so one cannot generalize about what they mean. I monitor my TM's with great care against my progression/regression in scans. I won't know what the mean for me until I have a couple more years of data, and even then, only scans provide the final verdict.
There are a number of other blood based tests, including ctDNA testing and CTC, which should/could offer some indication of what is going on. The problem is that they too are individual to the cancer and the individual and the cancer is changing with time, so you have to do them for a couple years and track them against your scans to see what they mean for you. Since these are generally not covered by insurance, it's an investment that you have to consider against other demands on your budget.
If you can convince someone to do MRI, then you can eliminate the radiation exposure. Given the difficulty of evaluating your mets with CT, you have a reasonable argument. It's more expensive and a bit of an ordeal for you but can be preferable. MRI of the liver is my current approach. This requires ignoring my bone mets for the moment.
Regarding response time, my conclusion is that Ibrance can take 5-9 months to get a response. Makes it very tricky to evaluate.
Regaring CDK expression statistic, I can't confirm those numbers independently but we are certainly seeing a higher response rate than 14% so the relationship between CDK expression and outcomes is weak. This is generally the case between biomarkers and the drugs theoretically associated with those biomarkers. This is why targeted therapy and precision medicine is moving sideways more than forward.
Pardon my french but the truth is that we don't know WTF these drugs are actually doing. We don't know that the supposed target is actually the mechanism of action. Abemaciclib, for example, has demonstrated PDL-1 inhibition in pre-clinical trials. We find over and over that the drugs that work well have immune modulating effects that were not understood during their development. My working hypothesis is that all cancer treatments (chemo, targetted, whatever) that give any sort of durable response work by activating the immune system.
For this reason, I agree that it is concerning that are tired and rail thin and that is a problem that needs to play a key role in your choice and decision making. Your doctors will waive this off as "just a side effect" but your overall health is the foundation of your healing.
I enjoy your comments and observations and I think the way you challenge the information you get will net huge rewards. I look forward to further discussion.
>Z<
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