Posted on: Jan 1, 2018 05:03AM - edited Jun 18, 2018 12:19AM by zarovka
Posted on: Jan 1, 2018 05:03AM - edited Jun 18, 2018 12:19AM by zarovka
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.
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.
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).
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.
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.
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.
Abemaciclib continues to be available through Lilly's attractive Expanded Access Program (EAP):
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.
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.
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)
Jan 12, 2018 11:27AM cure-ious wrote:
LMWL- Thanks for posting the MORPHEUS trial- it has different arms that include Atezo (immunotherapy) with Akt inhibitor, BRAF inhibitor, or fulvestrant/AI, and I like that there is a triplet combo one can go onto if one does not respond, or has too many SEs, in the trial arm they are assigned. Is already recruiting in some locations, and slated to come to Memorial Sloan Kettering, UCSF, and UCLA, etc
Jan 12, 2018 03:40PM spicedlife wrote:
Alright then Z,
I think I am doing pretty good so far. The nausea has calmed down a bit. I know that when I have extreme anxiety that my stomach is always upset. I either have no anxiety or extreme but that is another topic. Before the mets I was doing so so well....no IBS and was Isleeping through the night. Miy counselor said that I am probably in shock and that is natural considering my issues with a mental health diagnosis. So it would be normal to have anxiety, ptsd, etc. and she said I am the strongest woman she has ever helped and that we will get through this too. ::) If you knew my story that is a big assurance.
I've had one episode of explosive diarrhea. It was yesterday and I took loperamide and I am okay now. The problem is I have no clue what I will do when I go back to wrok on Tuesday. I would never make it the bathroom. I sat on a double folded thick towel the rest of the day. If any of you have ideas please let me know. I have to have a solution to the diarrhea before it happens.
I wonder about some other things that y'all might have some knowledge about:
What do you eat for breakfast? I am not getting any protien w/ bkfst right now so I thougt I would add a half of a scoop of protien powder with water and drink that? It is vegan because I am lactose intolerant. I like to meal prep on the weekends so that I have the best nutrition possible.
How do I fix my sleep? I take ambien and it works like a charm until now. I exercise 30 minutes a day and get good cardio. I keep my room dark, I have an aromatherpy diffuser that I put lavender eo in.I have tried the Calm app and it really helps me go to sleep but I wake up every two hours and I eat. and that is unhelpful.
I forgot to tell you that I now have a sore inside of my mouth and of course extreme dry mouth.
Thank you for listening to me and now I am going to catch up reading your messages for the last few days so that I will be up to date with whats going on!
Jan 12, 2018 04:07PM zarovka wrote:
Shock panic and trauma are pretty the norm after the initial diagnosis and then we get to go through it all again with each progression. Ah MBC, the gift that keeps giving. Pretty much all MBC patients exhibit PTSD signs. My point is that don't let the shock etc itself freak you out and make you more stressed. What's not to be stressed about ... you have crazy growths trying to disable primary organs. At the same time we all eventually get periods of respite from the panic. I hope that being on a cutting edge drug that is best in class may give you some confidence and peace.
They have diapers for that situation. Losing control of one's bowels is common in very late stages of MBC, yet the tougher among us go to wedding etc. wearing diapers. I am going to be hiding in a closet at that point, but Depends and a clean up kit may be one solution to get you through work. As Cure-ious points out, the data suggests that the diarrhea resolves with time. Your gut biome takes time to adjust to this new agent but it appears that it eventually does. I wish I had some time to study what abemaciclib might actually be doing in the gut.
You may be doing the best you can on your own with sleep. Those are all the standard tricks. You might consider asking for referral to a palliative care doctor. It's a specialty that looks at treating these side effects of treatment and they may have prescription meds. However, I am seeing evidence of high levels of stress. The fear and panic may be something you just have to work through. Your counselor may be the best avenue to a good night sleep. I like that lady.
Another reason to see a palliative care doctor is the dry mouth. I don't like dry mouth because I think it is the tip of the iceberg of a larger systemic problem. I had it myself with ultimately serious consequence. It's basically a sign of systemic dehydration. In my cause the cause was very different so I can't help you sleuth the source of this. I am wondering about a drug interaction or supplement that isn't doing what you think it is.
You are doing great with so many pieces slightly out of place. I would start with building some confidence that you are on the track ... because you are. Once you see path forward leading in the right direction, some of these issues will become more manageable.
Jan 12, 2018 05:16PM spicedlife wrote:
Z, thank you so much. You rock! For the I can wear the diaper and by that time my body should have it figured out. I will check out the palliative care. Jenny
Jan 13, 2018 01:45AM JFL wrote:
Spiced life, I work full time and feel for you with the whole work predicament with Abe side effects. I expect to be on Abe sometime in the not too distant future and that is my main concern. I eat yogurt with 2T of flax seed and a banana for breakfast. Flax seed is a good source of protein and can also be added to oatmeal or cereal. That goes for nuts as well. I also sometimes eat a cold cereal called Ezekiel which has a high amount of plant-based "whole" proteins from the sprouted grains it contains.
Z and Cure-ious - I read a disturbing article yesterday about how dietary xenoestrogens, including genistien from soy, can directly counteract the mechanism of action of Ibrance/Femara, in very small amounts. Have you heard about this?!
Jan 13, 2018 02:19AM cure-ious wrote:
JFL- I posted to this on another thread, basically our bodies are highly depleted of estrogen, and so we should avoid any estrogen-like compounds, which are found in plants like soy (no soy supplements for us) and are also in plastic wraps, microwaving plastic, etc is not a good idea. However, keep in mind that these drugs have huge effects in clinical trials, and the individuals in these trials are eating normal diets like the rest of us. Stay away from environmental estrogens as much as possible, but I think this story is over-blown...
Jan 13, 2018 02:25AM - edited Jan 13, 2018 02:28AM by zarovka
hmm. it's a theoretical benchtop study but it does make sense. we know that ibrance doesn't work as single agent. if the hormone suppression is not working because estrogen is replaced by xenoestrogens then ibrance won't work. the relevance goes beyond letrozol ibrance since keeping estrogen low is a key piece of MBC treatment generally.
that said, xenoestrogens are hard to avoid. possible sources go way beyond soy. it seems you already eat very well. i could clean up my act a bit.
thanks for the reminder.
Jan 13, 2018 02:45AM JFL wrote:
What is so deflating about the article is that it is just another reminder that we have limited control over some of the environmental factors. I do try to stay away from BPA, plastics, pots and pans with coating, etc, but there is no way to fully avoid all these potential pitfalls. I also stopped consuming the isolated soy isoflavones and other potent soy-derived supplements/products after I was originally diagnosed 11 years ago but do still eat soy foods such as miso, tofu and edamame.
Jan 13, 2018 11:49AM - edited Jan 13, 2018 11:58AM by jnprsn
I am on week 2 of Verzenio. Diarrhea, but not terrible. Depression due to progression.
Ibrance treated me well for 2 years. Good luck to all those on or starting Verzenio. My Oncologist told me that a recent study said it was very good for bone mets so that is my hope.