Topic: Abemaciclib Verzenio for Stage IV

Forum: Stage IV/Metastatic Breast Cancer ONLY — Please respect that this forum is for members with stage IV/metastatic breast cancer ONLY. There is a separate forum for caregivers and friends: Caring for Someone with Stage IV or Mets.

Posted on: Jan 1, 2018 04:03AM - edited Jun 17, 2018 11:19PM by zarovka

Posted on: Jan 1, 2018 04:03AM - edited Jun 17, 2018 11:19PM by zarovka

zarovka wrote:

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)

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Jan 6, 2018 02:28PM - edited Jan 7, 2018 08:02AM by zarovka

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<

Ibrance/Letrozol Feb '16 -Sep '17. Adoptive Cell Therapy Oct 2017. Jan 2018 SBRT to sternum met and liver mets. Jan 2018 start Faslodex. Dx 12/28/2015, IDC, Left, 4cm, Stage IV, metastasized to bone/liver, Grade 3, ER+/PR-, HER2- Hormonal Therapy 1/16/2016 Femara (letrozole) Targeted Therapy 2/2/2016 Ibrance (palbociclib)
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Jan 6, 2018 06:52PM spicedlife wrote:

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.


Surgery 3/4/2012 Lumpectomy: Right; Lymph node removal: Right, Sentinel Surgery 4/15/2012 Lymph node removal: Right, Underarm/Axillary; Mastectomy: Right; Prophylactic mastectomy: Left; Reconstruction (left): DIEP flap; Reconstruction (right): DIEP flap Chemotherapy 6/3/2012 Cytoxan (cyclophosphamide), Taxotere (docetaxel) Hormonal Therapy 10/7/2012 Femara (letrozole) Surgery 11/4/2012 Reconstruction (left): DIEP flap, Nipple reconstruction; Reconstruction (right): DIEP flap, Nipple reconstruction Surgery 3/15/2013 Reconstruction (left): DIEP flap, Nipple reconstruction; Reconstruction (right): DIEP flap, Nipple reconstruction Dx 11/30/2017, IDC, Stage IV, metastasized to bone, Grade 2, 1/15 nodes, ER+/PR+, HER2-,
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Jan 7, 2018 03:33AM mazie73 wrote:

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?

​Currently on a clinical trial at UC San Diego Moores Cancer Center: Abemaciclib + Pi3 kinase inhibitor + Faslodex Dx 8/2013, IDC, Right, 3cm, Stage IIA, Grade 3, 0/7 nodes, ER+/PR+, HER2- Surgery 9/23/2013 Lymph node removal: Sentinel; Mastectomy: Right; Prophylactic mastectomy: Left Chemotherapy 1/28/2014 Cytoxan (cyclophosphamide), Taxotere (docetaxel) Surgery 5/15/2014 Reconstruction (left); Reconstruction (right) Hormonal Therapy 5/21/2014 Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Dx 12/2016, Stage IV, metastasized to bone/lungs, ER+/PR+, HER2- Hormonal Therapy 2/4/2017 Faslodex (fulvestrant), Zoladex (goserelin) Targeted Therapy Verzenio
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Jan 7, 2018 02:58PM luce wrote:

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)

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 7, 2018 04:35PM nkb wrote:

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

Dx 12/2011, ILC, Both breasts, 6cm+, Stage IIIC, Grade 2, 34/40 nodes, ER+/PR+, HER2- Surgery 2/3/2012 Lymph node removal; Lymph node removal (Left): Underarm/Axillary; Lymph node removal (Right): Underarm/Axillary; Mastectomy; Mastectomy (Left); Mastectomy (Right) Chemotherapy 2/27/2012 AC + T (Taxol) Radiation Therapy 9/10/2012 Hormonal Therapy 10/21/2012 Arimidex (anastrozole) Dx 5/2017, ILC, Stage IV, metastasized to bone, ER+/PR-, HER2- Hormonal Therapy 6/1/2017 Faslodex (fulvestrant) Targeted Therapy 6/1/2017 Ibrance (palbociclib) Targeted Therapy 3/13/2019 Afinitor (everolimus) Hormonal Therapy 3/13/2019 Aromasin (exemestane) Chemotherapy 3/10/2020 Xeloda (capecitabine)
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Jan 7, 2018 05:39PM azs40 wrote:

Luce...I'm a newbie. Can you tell me who Constantine is? In a nutshell?

Many thanks.

azs40 Dx 8/2008, IDC, Left, 1cm, Stage IIIA, Grade 2, 4/28 nodes, ER+/PR+, HER2- Dx 11/2017, Stage IV, ER+/PR-, HER2-
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Jan 7, 2018 06:19PM luce wrote:

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.
Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 7, 2018 07:46PM - edited Jan 7, 2018 07:54PM by sandibeach57

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.

DCIS (06&07)HR+Gr 3 Bil mx-rad-tamox. Oct 2016 Stage IV liver mets IDC ER+PR-HER2- Gr 3 AC then I/L 01/17- 03/20. Liver mets 03/20 ER+PR+HER2- Gr 3 Xeloda until 06/21. Liver mets June 2021 ER+PR+HER2-Gr 3 Taxol.(IHC 1+, FGFR1amp, ATM inver)
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Jan 7, 2018 10:30PM - edited Jan 7, 2018 10:30PM by luce

yes, that much is obvious. but he appears so biased, i am wondering if the foundation is independent or sponsored by some drug-maker?

Dx 12/12/2016, ILC/IDC, Left, Stage IV, metastasized to bone/lungs/other, Grade 2, 0/3 nodes, ER+/PR+, HER2-
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Jan 7, 2018 10:33PM cure-ious wrote:

Love this guy Constantine-- please keep re-posting his insights!!

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