Oct 23, 2018 08:48AM pajim wrote:
Amy, thumbs up!
Posted on: Jan 1, 2018 03:03AM - edited Jun 17, 2018 09:19PM by zarovka
Posted on: Jan 1, 2018 03:03AM - edited Jun 17, 2018 09:19PM 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)
Oct 23, 2018 08:48AM pajim wrote:
Amy, thumbs up!
Oct 29, 2018 04:37PM - edited Oct 29, 2018 04:37PM by pajim
Ladies, is there anyone here who has been on this stuff for more than three months? Has the diarrhea stopped perchance?
Because for me at week 10, it's stopped. My stools aren't 'normal' but i haven't taken an Immodium in more than a week. I can feel the constipation re-asserting itself. I'm wondering if my experience is common
Oct 29, 2018 08:31PM AmyQ wrote:
I haven't completed an entire week on this stuff and it's been close to three weeks since I received my prescription. I can only take one dose, either AM or PM but not both without having stomach pains. I could handle minor stomach aches or pains but these are severe and intolerable so I take 200 mg when I'm feeling okay.
I don't have diarrhea probably because I'm not getting the full 400 mg daily. I wish I could answer your question, sorry.
Nov 7, 2018 09:34AM chatsworthgirl wrote:
I was started on 150 mg. Was on it for three months. Very difficult. I felt sick all the time and couldn't eat. Everything tasted like cardboard and food just made me sick to my stomach. I kept telling my onc that I needed a lower dose as I am very sensitive to drugs and I felt that since I was not a big person, that is, I only weigh about 130 and am five feet eight inches tall with very little body fat, that I just couldn't absorb the drug very well.
He finally agreed and put me on 100 mg. Much better. I can eat again and food tastes normal. I still get diarrhea sometimes but I am trying not to use Immodium and limit my dairy intake. I found that when I was eating yogurt (which is recommended for probiotics) and other dairy the diarrhea got worse.
However, with all the diarrhea I now have cracks at the anal opening from the damage done and having a hard time getting it to heal. Diarrhea causes this as the undigested food and enzymes are harmful to the anus. It's one thing after another.
I did get a very good response from the Verzenio. In the first three months my CA 27 dropped from 783 to 480. I got smaller drops after on the 100 mg but the most recent test shows me staying at about 325. Not thrilled that I am not still getting drops but I am about to have another scan to see if the little bugs are dead. Fingers crossed.
Nov 7, 2018 10:10AM chatsworthgirl wrote:
I am curious to know what everyone has experienced with their tumor markers on Verzenio. What were they before you started and what are they now. Also, since my Onc seems to think that two months at around 325 is stable. What is stable for you?
Nov 7, 2018 01:50PM AmyQ wrote:
I gave up on Verzinio last week. Took my AM dose and four hours later was vomiting and had diarrhea AT THE SAME TIME! Needless to say, I was mess and had to go to bed. My sweet husband cleaned up for me.
I wrote to my Oncologist and said I am Done with Verzenio. Besides vomiting and diarrhea, I had a stomach ache so vicious I wanted to die.
I see my Oncologist tomorrow so will see what she has in store for me.
Thanks for all your input. I will report back after seeing her.
Nov 7, 2018 06:24PM Hlarson wrote:
I have started Verzenio. I was on Eribulin and then switched. I started with 150 in the morning and at night. I was in it for 2 weeks along with anastrozole. After 2 weeks I was very weak and very sick. Could barely function. Dr pulled me off for a week then I started again. Once again at the 2 week mark I was weak and very sick. She pulled me off again for a week. I restart on Sunday at half the dose. I hope that the symptoms are releaves
Nov 7, 2018 08:13PM vlnrph wrote:
I had to insist on being allowed to try a lower dose. According to the package insert/prescribing information, this strategy was required in 20% of patients.
As a pharmacist, I used the argument that, while early phase trials determine the maximum tolerated amount (who are those people?), the minimum effective level has not been established. They would have changed me to Ibrance but I don't want to risk having blood abnormalities.
The data is so much better than for the others in the class, I want that advantage. I'm only on day 5 of 100mg bid however am feeling OK. If tolerated, I will rechallenge at the original strength.
Nov 8, 2018 09:14AM NouzayO wrote:
So as a pharmacist do you think it’ll be ok to mix the dose .. say take 100 mg in the morning and 150 at night??
Nov 8, 2018 04:23PM vlnrph wrote:
I might try 100/150mg am-pm for a couple weeks when I want to ease back into my original prescription early next year. I only lasted a week at the higher dose so have 14 tablets left...
For NouzayO, the main problem with your plan could be getting the pharmacy to dispense it that way! Those prefilled dose packs assume you’ll be taking the same strength both morning and evening.
However, if that’s what is tolerable and your doctor specifies that schedule, it makes sense to me