Ribociclib v. Palbociclib: Let The Games Begin

zarovka

Novartis has developed a CDK 4/6 inhbitor called ribociclib. It's Novartis' answer to palbociclib. Sales of palbociclib in just the first quarter of 2016 were ~$400M, so each of the major drug companies is trying to develop a CDK 4/6 inhibitor. There is another drug in development called abemaciclib which is also a CDK 4/6 inhibitor but not currently expected to compete with palbociclib as strongly as ribociclib in the breast cancer space. I am interested if anyone knows why.

The ribociclib trials are called MonaLEEsa because the code name for the drug is LEE011. There are many active ribociclib trials with different targets and drug combinations. MonaLEEsa-2 is a trial that evaluates letrozol and ribociclib on hormone receptive positive stage IV breast cancer.

Novartis stopped MONALESSA2 a month ago because they reached the primary endpoint of clinically meaningful improvement early. Novartis has not released the results of the trial yet. They are only saying that they are stopping the trial because the results are good enough to allow them to get FDA approval.

There is at least one person in MONALEESA-2 on this forum doing exceptionally well. She doesn't know if she was taking the placebo or not, but it would seem likely she is on ribociclib.

The MONALESSA-2 trial is interesting because it looked only at patients who had been diagnosed stage IV denovo and who had liver or lung mets.

Ribociclib has the same mechanism of action as palbociclib, but it's a different molecule. Perhaps it will work a little better for some people or have fewer side effects for others? I think of people like artist who had a good response but debilitating SE's of uncertain provenance. Perhaps this is a tweak to our protocol that would allow Artist to continue inhibiting those CDK 4/6 inhibitors.

(Artist - i hope you got a car that will last a long time, as I expect you will need it.)

I also think of the folks in Canada trying to get access to these CDK 4/6 inhibitors. The MONALESSA trials (which continue with different targets and drug combinations) may be another way to get access to this class of drugs.

It sounds like Novartis thinks it has what it needs to obtain FDA approval as of May. It takes 6-12 months to obtain FDA approval. So we may all be able to worry about what CDK 4/6 inhibitor to take by 2017. If anyone would like to start worrying now, let this be the thread.

The big thing we need to know is what exactly were the results of MONALESSA-2 ... please post anything you hear. All Novartis is saying right now is that they met the endpoint that will allow them to begin the FDA approval process.

For those of you who want to dive right in, here is a summary of the upcoming deluge of CDK 4/6 inhibitors and related treatment combinations. We may become wistful for the days when got to choose between hormone therapy and chemotherapy. This is going to get very interesting but very confusing... certainly lots to talk about on BCO!

artistatheart

Wow Z, That is very interesting news for sure. Especially if it works with a different molecule. My first problem with Palbociclib was that in combo with Femara elevated my liver enzymes dramatically. We are still not sure it it was Palbo, Femara or the combo. I am on Palbo with Arimidex right now and have a blood draw in two weeks to check the enzymes. Even more exciting is that is was only tried on De novo with liver or lung mets. You are fantastic at sharing research here and I appreciate it beyond words. i will look at what I can find too and post. Z, I got a sweet GMC Acadia with not all but a lot of luxury and safety features. Like I boasted an another thread, I am going to drive it until the fenders fall off!

zarovka

Great choice! GMC's last a long time.

Interested in how your blood draw goes.

Bestbird

zarovka, thank you for your usual excellent summary and insight! I believe Abemaciclib holds great promise as well, as it is a monotherapy that evidently can pass the blood brain barrier. It will indeed be interesting to see what transpires!

artistatheart

Z, my last GMC that I just traded in lasted 14 years, 200,000 miles and was still running fine. I was just getting nervous about it's age.....Cosmetically it was a little beat up but not bad.

Thanks for more info Bestbird! Hope all is well!

zarovka

I am going to continue to post comparisons between the three CDK 4/6 inhibitors in development here. It turns out abemaciclib is a serious contender in the developing CDK 4/6 Inhibitor bake off so I will include what I find about abemaciclib.

This video from MSKCC summarizing metastatic breast treatment research results from ASCO has been posted on other threads but it gets into a lot of detail about the state of all three CDK 4/6 inhbitors (palbociclib, ribociclib and abemaciclib). It is by far the best overview of both MBC treatement options and the kinase inhibitors that I have found. Dr. Dickler is very interested in abemaciclib and discusses the outcomes of early trials at length.

Here are just a couple of things that came up in the podcast and are related to conversations on this forum.

abemaciclib may be indicated in place of palbo when neutrophils are low. Abemaciclib targets CDK4 more than CDK6. It is the CDK6 inhibition that slams the bone marrow. It has had very good preliminary results with almost no impact on neutrophil counts on people who were pre-treated with taxane based chemo therapies.

I think of lovesmaltese and a couple other folks who could not stay on palbociclib. Apparently you get to trade low neutrophil count for a serious case of the runs with this drug. But we stage IV folks are used to having to choose the lesser of two evils. Eli Lilly has an expanded access program which may allow your doctor to apply for abemaciclib before it is FDA approved if you are responding to palbociclib but cannot tolerate the drug long term.

there is a small phase II trial testing ribociclib on patients who progressed on palbociclib. For those of us wondering what happens next should we progress on ibrance, that trial is something to keep an eye on and possibly participate in.

She didn't feel that immunotherapy looked highly promising for hormone receptor positive breast cancer. Immunotherapy works best when the cancer has a high number of mutations and looks very different from a normal cell. Triple negative cancer appears to have the best targets for immunotherapy because it is genetically the most different from a normal cell. That said, she noted that research is proceeding on immunotherapy drugs and hormone receptor positive cancer.

Always interested in what other people learn about these drugs.

>Z<

Anonymous

http://www.dana-farber.org/Research/Clinical-Trials/Clinical-Trial.aspx?tid=4231Z,

This is on my list to discuss at the end of the month with my MO- Here is some more info I found as well

https://www.youtube.com/watch?v=EymHUM6UVKo

Edited to add clinical trial at Dana Farber

Emily-Louise

Hey guys,

I took part in the Monaleesa-7 trial here in Australia, after bone mets in June 2015.

Its a double blind placebo trial, combined with Zolidex and Tamoxifen, due to my white cell count my oncologist was confident I was on the drug, however I had no side affects, with 14 months of stable bone mets.

I had progression to my liver last week and begin Taxol/Carbo mix, feeling very overwhelmed.

Emily-Louise

This is the one to watch……

http://www.independent.co.uk/life-style/health-and-families/health-news/cancer-treatment-using-nanotechnology-tested-with-astounding-results-a6930841.html

alnhaysmom

This is my first post. I was diagnosed in February with stage IV breast cancer with extensive mets to my lung and bones. I started out on AC and then Taxol to zap it down, and then switched on to a clinical trial with Ribociclib and tamoxifen. I was on the trial for 2 months with no side effects at all. After my scans came back it showed good shrinkage in my tumor and lymph nodes, but progression in my bone mets. The Dr feels it's likely that this was caused by a tamoxifen flare up, but I was pulled from the trial and switched to Paclociclib and Letrazole. I am only 10 days in on this treatment, but again no side effects other than moderate fatigue. I am already noticing some shrinkage in the tumor, and hoping the scans will confirm its working next week. I'd love to hear of anyone else's experiences with this treatment

zarovka

Thank you all for the updates on the ribociclib trial! Please keep it coming.

Ainhaysmom - Tribe Ibrance has an active dialog going on at this thread. Please join us there. Tamoxifen flare is apparently a thing. Fortunately you have a very similar alternative to try. Many people, including myself, have done very well on ibrance and letrozol.

>Z<

zarovka

Ribociclib a new CD4/6 inhibitor interim analysis Ribociclib plus letrozole was associated with significantly higher rates of overall response and clinical benefit than was placebo plus letrozole..

At the prospectively planned interim analysis, we found that postmenopausal women with HR-positive, HER2-negative advanced breast cancer who were receiving first-line treatment with ribociclib plus letrozole had a significantly longer duration of progression-free survival than did those receiving placebo plus letrozole, with a 44% lower relative risk of progression. The trial population included a high proportion of patients who had disease that was expected to be sensitive to endocrine therapy (i.e., those with newly diagnosed advanced breast cancer or with a disease-free interval of >24 months). However, the duration of progression-free survival was longer in all preplanned patient subgroups receiving ribociclib, including those with newly diagnosed or pretreated metastatic disease and those with or without liver or lung metastases. Further analyses of these subgroups are ongoing. Ribociclib plus letrozole was also associated with significantly higher rates of overall response and clinical benefit than was placebo plus letrozole, a finding that was consistent with observations from an earlier phase 1 trial.18
Most patients had an acceptable adverse-event profile with long-term administration of ribociclib plus letrozole, with 7.5% of patients requiring permanent discontinuation of both ribociclib and letrozole because of adverse events and similar percentages because of decisions made by either patients or physicians in the two groups. The majority of nonhematologic adverse events in the ribociclib group were of grade 1 or 2, and grade 3 or 4 events were reversible by dose interruptions and reductions, which allowed most patients to remain on treatment. Hematologic adverse events in the ribociclib group reflected on-target CDK4/6 inhibition, which resulted in reversible bone marrow stem-cell quiescence.26 Neutropenia occurred mainly within the first 4 weeks of treatment and resulted in five cases (1.5%) of febrile neutropenia in the ribociclib group. Grade 3 or 4 elevations in alanine and aspartate aminotransferase levels were reported in 9.3% and 5.7%, respectively, of patients receiving ribociclib in this study and have also been observed with other CDK4/6 inhibitors in combination with aromatase inhibitors.27-29 The majority of cases of liver-enzyme elevation were isolated and asymptomatic and were reversible with dose adjustment. Prolongation of the QTcF interval to more than 480 msec occurred in 3.3% of patients treated at the 600-mg dose of ribociclib, with changes mostly occurring within the first 4 weeks of treatment. Our protocol excluded patients who were deemed to be at high risk for prolongation of the QTc interval; during treatment, such prolongation was limited by proactive dose interruption or reduction, since this side effect is dose-dependent. In routine practice, careful monitoring should be implemented to limit the incidence of these events to the levels observed during this study.
In conclusion, this phase 3 trial showed significant prolongation of progression-free survival and higher rates of overall response with the addition of ribociclib to letrozole than with the addition of placebo to letrozole for first-line treatment in postmenopausal women with HR-positive, HER2-negative advanced breast cancer. The improvement in the duration of progression-free survival was associated with a higher rate of myelosuppression among patients in the ribociclib group.

ShetlandPony

Thank you, Z. That last line -- is it saying that low counts meant it was working?

Batfax

Sorry that I am not entirely sure whether this is the same trial my wife was on. She got on an A/A + ribociclib trial in August, but this week we found that in addition to some progression in the liver (less than 20% though, so she was clear for the trial) she had a new brain met, so the trial was donezo. After this and Ibrance/Letrozole failed in very short order, I've started to wonder whether her ER+ is somehow hormone therapy resistant. Hopeful Xeloda will work as Taxol did for 9 months.

zarovka

Shetland - This is the actual paper with all the details. I am guessing that low counts were associated with longer progression free survival, but they just stick that comment in at the end of the conclusion. I didn't see any detail or supporting data for this point in the paper so I am not 100% sure what it means or how significant the association was.

The results aren't fantastic relative to palbociclib. The trial has not hit median time to progression for letrozol at 18 months. IOW, more than half the women taking ribociclib still have not progressed. But they are close. Seems like about 40% of the women taking ribociclib had progressed. I don' think that ribociclib will exceed the ~24 month median time to progression achieved by palbociclib, and it may not even reach 24 months. The side effects, however, seemed like they might be milder.

I'd be interested in how other people read these interim results, in comparison to ibrance.

>Z<

Longtermsurvivor

Here's a related bco conversation on the MONALEESA-2 Phase III of Ribociclib:

Forum: Clinical Trials, Research Studies, News, and Study Results

Healing regards, all, STephanie

Longtermsurvivor

Important article on the difference between relative and absolute risks.

https://community.breastcancer.org/forum/73/topics...

If you have the stamina or interest, read Gerd Gigenzer's work on understanding risk and statistics. Great for the common reader.

healing regards, Stephanie

seagan

Thanks for starting this thread. I don't have anything to add about trials or experience, just glad to see more is being explored. I'm especially hoping they'll know soon about whether it makes sense to go on another CDK 4/6 inhibitor after progressing on palbociclib. Palbo seems to be working well for me so far in combination with Faslodex, but I do wonder what's next and am not keen to move to chemo. I noticed the small trial on ribociclib after palbo excludes those who were on Faslodex already, so I wouldn't qualify for that one.

Stephanie, thanks for the tip on Gizenzer's work. Always glad to learn more about interpreting risk and stats, and it's so easy to read things incorrectly or at least not fully.

zarovka

Seagan - the big question is definitely what happens next. hope it never comes up for you.

>Z<