So these are the results of Quality Improvement Initiative program that outlines the need for education representing five cancer centers in four states: Ohio, North Carolina, Tennessee and Kentucky.

 

The QI program began in late 2024 and ended in early 2026. Each center reviewed patients with stage II and stage III hormone receptor-positive/HER2-negative breast cancer receiving surgery. 167 patients at baseline. Final number of patients is 98. And they were able to identify gaps in identifying patients with high-risk disease and offering adjuvant therapy.

 

So you see in the plot on the left, the percent of patients with documented assessment of risk recurrence. And then afterward you see the – or sorry, on the right, you see the percent of patients with high-risk disease treated with a CDK4/6 inhibitor. Low at baseline 45.3%, 80.3% in the final numbers.

 

Defining High-Risk HR+/HER2- EBC

 

So how do we define high-risk hormone receptor-positive early-stage breast cancer? Typically and historically, we've used tumor size, nodal status and grade to inform recurrence risk and improve the prognostic accuracy of gene expression signatures. Higher prolife - proliferation metrics like Ki67 and lower estrogen receptor levels have historically been associated with increased risk of recurrence.

 

So failure of preoperative endocrine therapy to suppress Ki67, which has been an interesting space. We actually have a trial that's looking at that exact approach at the moment, but it predicts poor outcome with adjuvant therapy if you're not able to suppress the Ki67.

 

Luminal B tumors, HER2-enriched and basal-like are all considered high-risk hormone receptor-positive/HER2-negative breast cancers. And endocrine therapy resistance is a key feature of high-risk hormone receptor-positive/HER2-negative early-stage breast cancer that recurs within the first two to five years of hormone therapy treatment, or hormone therapy-based treatment.

 

Risk of Distant Recurrence After 5 Yr of Endocrine Therapy

 

So what is the risk of distant recurrence after five years of endocrine therapy? Here are the results of a meta-analysis of patients with ER-positive/HER2-negative early-stage breast cancer diagnosed between 1976 and 2011, who received five years of endocrine therapy and were disease-free at five years. So this is a more than 70,000 patient experience. And in the updated analysis, the 20-year risk of distant recurrence was a third lower for patients with node-negative/ER-positive breast cancer diagnosed after when compared to before 2000. And you can see those numbers here in the table below.

 

Treatment of HR+/HER2- EBC

 

What about the treatment for hormone receptor-positive/HER2-negative early-stage breast cancer? We've recently, you know, seen that the role potentially of oral SERD in the curative intent setting. But historically, we have relied exclusively on tamoxifen and aromatase inhibitors with/or without ovarian suppression, depending on the clinical situation. And we have data looking at extended therapy for five versus 10 years. And we now have genomic assays that help inform those clinical decisions.

 

Chemotherapy. The benefit depends on the risk for recurrence and the biology of disease. And again, those decisions are now largely informed by genomic assays. But there's still an unmet need. So identifying patients with hormone receptor-positive breast cancer who have primary endocrine resistance and preventing or delaying recurrence with additional therapies.

 

So here you see on the right, the meta-analysis of five years of aromatase inhibitor versus five years of tamoxifen and the recurrence risk. Just to look at the y-axis there, it's a zero to 50% risk there. So 22.7% with tamoxifen, 19.1% with aromatase inhibitor therapy.

 

Let's Look at a Patient Case

 

Patient Case 1: Woman With Grade 3 ILC and 2 Positive Nodes

 

So let's look at a patient case. So patient case number one is a 58-year-old woman who is postmenopausal. She presents with a 3.5 centimeter right breast mass and one suspicious lymph node. The initial breast biopsy reveals invasive lobular carcinoma. That's grade 3 with the following biomarkers, ER 80%, PR 30% and HER2-negative by IHC. I would give my fellows a stern lecture if they just told me it was HER2-negative these days, without telling me more information about that. But let's just say it was zero by IHC.

 

Fine-needle aspiration of palpable right axillary lymph node reveals adenocarcinoma of the breast. So biopsy-proven lymph node. She gets genetic testing. There is no germline BRCA mutation or any other underlying mutation. She undergoes upfront lumpectomy with sentinel lymph node biopsy. It reveals a four centime - four centimeter invasive lobular cancer with two of three involved lymph nodes, so T2N1.

 

She does have an oncotype genomic assay and the recurrence score is 26, which indicates that there is a role for chemotherapy here. So she receives TC, which again is docetaxel and cyclophosphamide for four cycles and then gets adjuvant radiation. She returns to the clinic now to discuss continued adjuvant treatment.

 

Pretest 1

 

So in addition to extended duration adjuvant endocrine therapy, what additional systemic therapy would be an appropriate – appropriate treatment for this patient? And it's just the patient's details are summarized there in the yellow box. So what additional systemic therapy would you recommend for this patient treated with chemotherapy, who has two lymph nodes involved. Is it:

 

1. None, endocrine therapy alone;
2. Abemaciclib only;
3. Ribociclib only;
4. Abemaciclib or ribociclib;
5. Abemaciclib, palbociclib or ribociclib.

 

Please vote. So almost half of you voted for abemaciclib or ribociclib.

 

Adjuvant EBC Trials With CDK4/6 Inhibitors

 

So here the – here's a summary table of the adjuvant early-stage breast cancer clinical trials with CDK4/6 inhibitors. There's a red box around monarchE and NATALEE because that's where the current clinical indication lies with abemaciclib and ribociclib, respectively. There have been two trials looking at palbociclib in the adjuvant setting, PENELOPE-B and PALLAS. Those were negative trials. So pal – palbociclib is not currently approved in the adjuvant setting.

 

When you look at – and this is not intended to suggest any kind of cross-study comparison, because they were very different patient populations that were enrolled in monarchE versus NATALEE. Just to remind you that they're both phase III registration studies that led to the FDA approval.

 

In monarchE, patients had high-risk disease, and we'll talk about how that was defined. That were node-positive with one other risk factor like size, grade, Ki67, whereas NATALEE included patients who had node-negative disease who were stage II or stage III. The duration of the CDK4/6 inhibitor is different for each study. In monarchE, it's two years. In NATALEE, it's three years.

 

Primary endpoints for both studies were invasive-disease free survival. monarchE has a little bit longer duration of – of median follow up. And we keep getting updates from both of these trials as the follow up continues.

 

monarchE: Adjuvant Abemaciclib + ET in High-Risk Node-Positive, HR+/HER2- EBC

 

So let's go over monarchE, which again is the study looking at adjuvant endocrine therapy plus or minus abemaciclib in patients with high-risk node-positive, hormone receptor-positive early-stage breast cancer. They could be pre or postmenopausal.

 

There were two different cohorts here with very different defining characteristics. So in cohort one, which was 91% of the patients, they had to have had at least four lymph nodes involved, or they could have one to three lymph nodes involved, plus some other high-risk feature including histologic grade 3 and/or tumor greater than five centimeters. So very high-risk population defined by conventional clinical characteristics there in cohort one.

 

In cohort two, you could have one to three positive lymph nodes. Ki67 of greater than or equal to 20%. So for cohort two, Ki67 could render you eligible for that group, grade 1 to 2 and tumor size less than 5%. The primary endpoint for this study was invasive disease-free survival, and patients were stratified by prior chemotherapy, menopausal status and region.

 

monarchE: iDFS

 

So here's the bottom line. And that chemotherapy point is important, right? Because the majority of patients on both monarchE and NATALEE received chemotherapy. So there are already sort of self-determined to be a high-risk population by virtue of them requiring chemotherapy.

 

So here's the invasive-disease free survival. You see a hazard ratio of 0.734 with a median follow-up of 76 months. So we have a long follow-up with this study. Now you see the separation of the curves relatively early on and of course favoring the abemaciclib combination here.

 

monarchE: OS in ITT (Key Secondary Endpoint)

 

What about overall survival? Well, it's probably still a little bit early to see those iDFS events translate into overall survival. But the hazard ratio is 0.84 here with a confidence interval in that upper limit to the confidence interval is less than one. So there is an early signal of survival benefit. So far it's 1.8% is the delta. But again, I think further follow-up will be more informative because it's a little bit early to see a survival advantage here.

 

monarchE: Safety

 

What about safety? I imagine that most of you have quite a bit of experience using abemaciclib in both the metastatic and the curative intent setting. Diarrhea is a common side effect, particularly in those first two months. I'm very lucky, we have a patient facing clinical pharmacist who does a lot of education with our patients. We have a low threshold to start Imodium, and we do a lot of education around that. And it's really most prominent within the first two months.

 

And if they can get through that period, then the diarrhea seems to dissipate thereafter, but otherwise very well tolerated, as you can see here.

 

Few dose – sorry, a few discontinuations, 18.5%. Only 8.9% after dose reductions. Just under 50% of patients had dose reductions and 61.7% had dose holds. So you can make some adjustments depending on the patient experience. I rarely have to do dose reductions, and I have only once ever discontinued drug for a patient. It was because of fatigue. It wasn't because of diarrhea. So I think with the right education it's actually extremely well tolerated.

 

NATALEE: Adjuvant Ribociclib + ET in Intermediate- to High-Risk HR+/HER2- EBC

 

So that's a summary of a 10,000 foot view of monarchE. What about NATALEE? So again this is a study with a different definition of high-risk patients that enrolled both pre and postmenopausal women and men with hormone receptor-positive/HER2-negative breast cancer stage IIA. I mean, I'm not going to read all those criteria there. You can read those yourself there on the left.

 

But patients were randomized to receive a nonsteroidal aromatase inhibitor with or without ovarian suppression, plus or minus ribociclib. Primary endpoint here again is invasive disease free survival. These are huge efforts. This was a study that enrolled over 5,100 patients with high-risk disease.

 

Patients could qualify for this study, unlike monarchE, where we just saw that the nodal involvement was critical. Eligibility criterion here, patients with high-risk node-negative disease could enroll. And there's a nice table that we'll show you in a minute.

 

NATALEE: iDFS

 

So here's the invasive disease-free survival for NATALEE. Not as much follow up as we saw with monarchE, but a 4.5% delta at five years, trend toward improvement in overall survival. But again, it's not mature enough data probably to actually reflect the potential survival advantage here.

 

NATALEE: iDFS in Node-Negative Subgroup

 

And that high-risk node-negative subgroup, is there a benefit in that group as well? And here you see that post-hoc analysis in this population of 5.7% benefit at 60 months of five years. So very consi – consistent rather with the intent-to-treat population.

 

NATALEE: Safety

 

So here's the safety profile. So ribociclib was discontinued due to an adverse event in just under 20% of patients with most discontinuations occurring early on. The average was in four months for the non-steroidal alone arm. The discontinuation due to adverse events was 4% of patients.

 

With ribociclib plus the non-steroidal versus non-steroidal alone, most common, any grade adverse events leading to discontinuation were liver-related, so a higher rate of liver enzyme derangements in the experimental arm, arthralgias very similar across the two arms not surprisingly, because the nonsteroidal aromatase inhibitor backbone.

 

QTc interval impact is a notable issue potentially with this drug. So you have to do EKG at baseline. And more recently, in this past year, they've modified the recommendation. So you just have to do it at baseline and then at two weeks. So we used to do it at two weeks and then again at four weeks. We're not doing it as often now. So just the baseline in two weeks.

 

And this dose 400 milligrams, which is lower than the 600 milligrams which is used in the metastatic setting, had lower rates of dose-dependent toxicity when compared to the pooled analyses of the MONALEESA trials from the metastatic setting.

 

Select Ongoing Trials With CDK4/6 Inhibitors in EBC

 

Here are selected ongoing trials with CDK4/6 inhibitors in the early-stage breast cancer setting, ADAPTlate, POETIC-A, ADAPTcycle and NoLEEta looking at various combinations of abemaciclib with endocrine therapy or ribociclib with endocrine therapy in different populations with high-risk early-stage breast cancer.

 

Individualizing Care With CDK4/6 Inhibitors

 

Approvals and Recommendations: Adjuvant CDK4/6i + ET

 

All right. So here are the approvals and recommendations around abemaciclib and ribociclib in the adjuvant setting. You can see the FDA versus ASCO versus NCCN. FDA approval for adjuvant abemaciclib is in node-positive patients who are at high-risk of recurrence. Originally it was approved using the Ki67 cut-off of 20% that was used in the clinical trial. And then they dropped that. So it's a little bit more generic now.

 

The ASCO guideline is a little bit more prescriptive and aligned with the clinical trial design in that it's for patients who are at high-risk of recurrence with at least four nodes, or one to three lymph nodes in the high-risk features that were outlined previously.

 

NCCN, high-risk of recurrence with at least four nodes, one to three lymph nodes, and the very prescriptive recommendation that's very aligned with the study design.

 

In terms of adjuvant ribociclib. So the FDA approval is for stage II or III hormone receptor-positive early-stage breast cancer at high risk of recurrence. So a very general approval. ASCO recommends for stage II or III breast cancer who would have met criteria for participating in NATALEE. So again aligned with the eligibility.

 

NCCN is a little bit more prescriptive in that it's recommended for patients with node-positive disease and for patients with node-negative disease who have those high-risk features, including tumor size greater than five centimeters or two to five centimeters grade 2, high genomic risk, high Ki67 or grade 3. So a little – little bit more prescriptive there.

 

Adjuvant CDK4/6 Inhibitors Are NOT Interchangeable

 

So the adjuvant CDK4/6 inhibitors are not interchangeable. The inclusion criteria are very distinct. The duration of follow-up for the two studies are very distinct. And patients who qualify for both abemaciclib and ribociclib, you should consider patient-specific factors including the endocrine therapy backbone, prior treatment tolerance, duration of treatment, concurrent medications and/or disease states.

 

And in my mind, again, the majority of patients in these studies received chemotherapy. So it's not a replacement for chemotherapy, which is a common tumor board discussion that we have at our – at our site. In these two studies, the majority of patients receive prior chemotherapy.

 

monarchE and NATALEE Trial Populations

 

I love this table. This is a table that we actually have posted up in our clinic area where you can see where patients – because it does get a little confusing, quite frankly. So you can see very clearly what option people potentially qualify for the green being the eligible categories and the purple being ineligible. So the T1N0, they're ineligible for both CDK4/6 inhibitor options, for example.

 

I love this table. Again, we have it posted in our clinic space, and I think people really find that helpful when they're thinking about which one to offer.

 

MonarchE and NATALEE Checklists

 

Here's a checklist for monarchE versus NATALEE. You can review patients. The monarchE is a little bit more straightforward because it's primarily dependent on the nodal status. The NATALEE checklist is just a little bit more involved, just slightly with all of those eligibility criteria there.

 

So if you get yes for any of the statements, that means that they're eligible. Personally, I prefer the table though.

 

Treatment Algorithm for Adjuvant Targeted Therapy in HR+/HER2- EBC

 

Treatment algorithm for adjuvant targeted therapy for hormone receptor-positive/HER2-negative. If they have a germline BRCA mutation in their high-risk, then you should offer olaparib. The OlympiA study again did include patients with hormone receptor-positive breast cancer who had a known or suspected germline BRCA mutation. But for the majority of our patients who are BRCA wild-type and who aren't candidates for olaparib, if they have node-positive lymph nodes and they have high-risk features, than they would potentially be candidates for ribociclib with endocrine therapy.

 

If they have four or more positive lymph nodes, they are candidates for either CDK4/6 inhibitor and then it becomes a more nuanced conversation with patients. If they have one to three positive lymph nodes and they are grade 3 or greater than or equal to five centimeters, they have either option. If they don't meet those criteria, then they are candidates for ribociclib potentially.

 

Patient Specific Considerations

 

So here are some of the patient-specific considerations for those patients who qualify for either option. The dosing, the schedule, the toxicity profile, prior exposures, allowance of tamox - tamoxifen with abemaciclib. You cannot give tamoxifen with ribociclib because of the VTE risk. But otherwise there's overlap. Not surprisingly for the aromatase inhibitor, again, there are different durations. Hepatic adjustments are required for both of those medications.

 

NATALEE and monarchE: Tolerability and QoL

 

Quality of life scores are maintained over time on treatment for both trials. But they didn't capture early events. So the first quality of life measurement was at three months. So again with abemaciclib, diarrhea which might impact quality of life is an issue for the first two months. So if you're checking at month three, presumably the majority of patients would have overcome that side effect.

 

NCCN Guidelines Version 3.2026 Invasive Breast Cancer

 

Here are the NCCN guidelines. I don't know. Do you want to read those, Bill?

 

Dr. Gradishar: No, I don't.

 

Dr. McArthur: Okay. You can look them up, but they reflect really what we've just already talked about.

 

Let's Revisit Our Case

 

Patient Case 1: Woman With Grade 3 ILC and 2 Positive Nodes

 

So let's revisit our case. Again, this is a woman who's 58, postmenopausal, 3.5 centimeter mass, one suspicious lymph node, biopsy proven invasive lobular cancer. It's high grade. ER-positive, HER2-negative. Biopsy proven lymph node. BRCA testing is negative so not an olaparib candidate. She undergoes lumpectomy and lymph node – sentinel lymph node biopsy. It's four centimeters. Two or three nodes are involved.

 

The oncotype recurrence score is high at 26. So she gets chemotherapy followed by radiation. And now she wants to talk about adjuvant endocrine therapy.

 

Posttest 1

 

So for this patient with a high-risk node-positive disease, what extended duration adjuvant endocrine therapy would you recommend? Would it be:

 

1. None, endocrine therapy alone;
2. Abemaciclib only;
3. Ribociclib only;
4. Either abemaciclib or ribociclib; or
5. Any of the three CDK4/6 inhibitors.

 

Vote now and see if I convinced you.

 

Yay! Okay. So 66.7% chose either abemaciclib or ribociclib. And I – and I agree with that – that choice because she has node-positive disease. She has all the high-risk features that would qualify her for either strategy.

 

Posttest 1: Rationale

 

All right.

 

Interactive Case Discussion

 

Case Discussion

 

Interactive case discussion. Who am I – am I interacting with you, Bill? Is that what's happening?

 

So 62-year-old postmenopausal woman diagnosed with hormone receptor-positive/HER2-negative. In this case, it's ductal carcinoma invasive, grade 3 tumor of 5.2 centimeters. Three axillary lymph nodes involved, high Ki67 at 28%. She underwent mastectomy with clear margins. She started adjuvant endocrine therapy with an aromatase inhibitor. She has hypertension and good performance status.

 

Given her high-risk features, would you consider adding a CDK4/6 inhibitor to her adjuvant treatment plan? Joanne's nodding.

 

Dr. Joanne Mortimer (City of Hope National Medical Center): Yes.

 

Dr. Gradishar: Yeah.

 

Dr. McArthur: Right. She's a huge tumor. High Ki67, high nodes or a large number of nodal burden. What factors support this decision? Well, I just outlined them. And are there any additional assessments you would perform before initiating therapy? Do you have a preferred – so this is a patient would you agree, who would be a candidate for potentially either abemaciclib or ribociclib? So what would you like to see before initiating therapy?

 

I want to see the EKG, of course, if I was considering ribociclib and, you know, she has hypertension. Is there any underlying cardiac issues that we need to be aware of? Is there anything…

 

Dr. Gradishar: That hypertension alone though wouldn't be a…

 

Dr. McArthur: The hypertension wouldn't be a contraindication, absolutely.

 

Dr. Gradishar: And you alluded to a moment ago if the – if a patient had a BRCA 1 or 2 mutation. So would you just comment if she happened to have that, how would you integrate a PARP inhibitor?

 

Dr. McArthur: Well, that is a very challenging question. So you – so I would – with the survival advantage with PARP inhibitor therapy and high-risk hormone receptor-positive disease, I would want to offer her a PARP inhibitor. I would think about potentially for a year. I – because she is so high-risk, I would think about sequencing PARP inhibitor for a year followed by CDK4/6 inhibitor therapy.

 

You know, technically you could start CDK4/6 inhibitor therapy within a year of surgery. So it sort of falls within the allowance of the clinical trials. But how would you approach it? Joanne, would you do this?

 

Dr. Mortimer: I would do exactly that. Yes.

 

Dr. Gradishar: Yeah. And I think the only caveat is you don't want to do it concurrently.

 

Dr. McArthur: Right. Right. Do you have any concerns about hypertension? We already acknowledge that hypertension and isolation wouldn't influence your decision-making here.

 

Case Discussion

 

All right. So Barbara, 50-year-old, 3.2 centimeter grade 2, one positive node. So less burden of disease here both in the primary tumor and the nodal involvement. She had breast conserving surgery followed by radiation. She started adjuvant endocrine therapy with tamoxifen. She has no significant comorbidities and maintains an active lifestyle with a good functional status. Given her clinical profile and the goal of reducing recurrence risk, would you consider adding a CDK4/6 inhibitor therapy to her adjuvant treatment plan?

 

So she's on tamoxifen. So you can't give ribociclib because of the increased VTE risk when co-administered. So would you give abemaciclib here? Bill, what do you think?

 

Dr. Gradishar: Well, it would – she would fit the criteria where she could receive it. I think it would be a discussion with the patient. You know, it is a three-year lift and she does have a positive node. So it would be a discussion.

 

Dr. McArthur: Two years for abema.

 

Dr. Gradishar: I'm sorry. Yeah. So it would be – you know, it's going to be more than just taking tamoxifen.

 

Dr. McArthur: Yeah.

 

Dr. Gradishar: But she fits – she fits the criteria.

 

Dr. Mortimer: Would you switch her endocrine therapy so she's not getting tamoxifen with abemaciclib?

 

Dr. Gradishar: Well, then you would have to make her ovarian suppressor.

 

Dr. Mortimer: Yeah.

 

Dr. Gradishar: So there's a lot of hoops to jump through. And you know, the potential side effect profile of what you're doing to her could make her lifestyle a little different. So I think again, discussion. What do you – what would you do? What would you do? Would you make her postmenopausal?

 

Dr. Mortimer: I would probably make her postmenopausal because she's 15, she's premenopausal. So I mean, that would make me want to be more aggressive with her because she's premenopausal, probably, although she's older. I mean, the data for young women with breast cancer is that women under the age of 40 do worse, regardless of how aggressively you treat them. But she's still premenopausal. So I would probably consider for ovarian suppression and an AI with – with a CDK4/6 inhibitor.

 

Dr. McArthur: I – this is someone I might consider for AMH testing, right? Perimenopausal, one node involved, RxPONDER. Those sort of provocative to inform decisions about chemotherapy potentially. And that might in turn inform my enthusiasm for more aggressive adjuvant endocrine therapy. But on the surface, I probably wouldn't switch her from tamoxifen at this point assuming she's going to go into menopause at some point in the next few years. I probably wait until she went into natural menopause, but I think this outlines that there can be several different, totally appropriate approaches to a case like this.

 

Got Questions?

 

All right. If you have questions, submit your questions now to have your questions answered at the end of the symposium. I'll hand it over to you, Bill.

 

Aligning Available MBC Treatment With Current NCCN Guidelines and Expert Recommendations

 

Dr. Gradishar: All right. Thanks so much. All right. So fasten your seatbelts, because there's a fair bit to go through with this segment.

 

Poll 4

 

And we start, of course, with a polling question. How confident are you in your ability to optimally select and personalize CDK4/6 inhibitor in the treatment of advanced breast cancer, considering the patient's presentation factors such as prior treatment comorbidities, visceral crisis, etc., and it spans from not confident at all to completely confident.

 

All right. So we've sort of spanned the spectrum of not confident to confident with a lot of people right in the middle.

 

Pretest 2

 

Based on current guidelines, which of the following patients with hormone receptor-positive/HER2-negative breast cancer would be most suited for treatment with imlunestrant plus abemaciclib?

 

1. Those with de novo untreated advanced breast cancer;
2. Those with advanced breast cancer with an ESR mutation and progressive disease after first-line AI therapy;
3. Those with advanced breast cancer with an ESR mutation with progressive disease on or after first-line treatment with a CDK4/6 inhibitor and an AI; or
4. Those with advanced breast cancer with an early recurrence less than 12 months after adjuvant treatment with the CD4/6 inhibitor and an AI.

 

Okay, so we'll come back to this.

 

Evolving Landscape in HR+ mBC

 

All right. So one of the things that's happened over the last, you know, basically five to seven years is, you know, whereas many of us, Joanne and I particularly – you're younger.

 

Dr. Mortimer: Thank you.

 

Dr. Gradishar: We were sort of stuck around 2002 for a decade. There was nothing going on between the AIs, fulvestrant. And then we started to see the integration of targeted therapies, first with everolimus, and then in – in the last couple of years, it seems like every six months there's something new in the ER-positive space, whether it's a new SERD, whether it's a combinatorial strategy with a targeted therapy, as recently as last week with vepdeg.

 

And then, of course, the antibody drug conjugates have been demonstrated to have activity in this setting.

 

NCCN Guidelines Version 3.2026 Invasive Breast Cancer

 

I'm a fan of anything that's got really small fonts. So if you look at the guidelines, you can see there are many different options that you can utilize that are justified by clinical trials. We still view AIs plus the CD4/6 inhibitor as our general first-line choice, with the exception if there are, you know, certain circumstances where a patient is a rapid progressor through adjuvant therapy as a PI3 kinase mutation. You might think about triplet therapy, but again, you're pretty familiar with that.

 

Treatment Algorithm for HR+/HER2- MBC

 

And how these things sort of fall out. Again, another very busy slide. But it really highlights my last comment. And that is that when you look at patients in the first-line setting, we still think of a CD4/6 inhibitor, plus endocrine therapy as our choice for the majority of patients, a small sliver might get a PI3 kinase inhibitor based on INAVO120.

 

And then thereafter we start looking for mutations that help inform our decision-making. So again, from Heather, you heard about the necessity of always thinking, does a patient harbor a germline mutation? Might they be a candidate for a PARP inhibitor? But in the endocrine space, we're looking for PI3 kinase mutations. We're looking for ESR mutations or anything in that pathway. The PI3 kinase, AKT, mTOR pathway, that would justify using a targeted therapy or one of the newer SERDs.

 

And then once we get past that, then we start getting into some of the antibody drug conjugates, which is not really the subject of what we're talking about tonight.

 

CDK4/6 Inhibitors + ET: PFS in 1L and 2L Treatment

 

On a single slide, if you look at basically thousands of patients and years of clinical trial development, there's a consistency across the trials. Three drugs, you know, palbociclib, ribociclib, abemaciclib. You combine them with endocrine therapy in metastatic disease. You get a significant incremental improvement in PFS, whether it's in the first-line setting or the second-line setting. The magnitude of that PFS increment is much larger when you're doing it in the first-line setting than the second-line setting, but it's consistent across the trials.

 

And then, of course, not all the trials demonstrated a survival benefit. You know, that was more or less demonstrated only in a handful of trials. And you can argue about what the reason for that is. But nonetheless, those are the results. But they were very consistent trials, all the registration trials in terms of their results.

 

P-Verify: Comparative OS and PFS With 1L CDK4/6 Inhibitors

 

So even though not all three drugs showed a survival benefit, if you go through – go to real-world evidence and sort of compile the data from lots of patients, you know, looking at data sets from Flatiron or wherever you might get them.

 

And you can look at, you know, what really goes on in the real world, not just patients who go on clinical trials, which way – may be much more select in terms of who we choose. You know, the lines are overlapping, whether you're looking at palbociclib, ribociclib, abemaciclib with respect to either progression-free survival or overall survival.

 

So I'm not discounting the results of the registration trials, but you could make an argument that all three drugs have a very similar activity and efficacy in patients with advanced disease.

 

SONIA: PFS1 With CDK4/6i as 1L or 2L Treatment of ABC

 

We've always used – certainly in the United States, we try to use a CD4/6 inhibitor in the metastatic disease setting early. But the question has been raised, particularly in Europe, about whether you could delay the use of a CD4/6 inhibitor until after the first progression, and would you, in some way, be compromising overall patient outcome.

 

And that was really the subject of the SONIA trial, which is demonstrated here, where patients either got first-line CD4/6 inhibitor and endocrine therapy, or they went on endocrine therapy and didn't really start the CD4/6 inhibitor until the second-line.

 

And if you look at PFS1, perhaps not surprising if you think back to the registration trials, the PFS is going to be longer in combination with the CD4/6 inhibitor.

 

SONIA: OS and PFS2

 

But when you look at the PFS2, it looks, you know, not so different. And most importantly, do you get to a different place if you do the sequence differently. In other words, don't start with the CD4/6 inhibitor first, wait until the progression happens and then initiate it. If you look at the survival, it's overlapping.

 

So this could be an argument, not one that we've adopted uniformly or embraced necessarily, because we'd like to push out PFS as long as possible before we have to make a switch. But if you were so inclined, for whatever reason, you're not necessarily compromising overall outcome.

 

RIGHT Choice: Ribociclib + ET vs Combination CT in Aggressive HR+/HER2- Advanced Breast Cancer

 

There have been a variety of trials, and I'm going to fly through a number of them, that have looked at the question of combining endocrine therapy with a CD4/6 inhibitor compared to chemotherapy, either given as monotherapy or given in combination. And the RIGHT Choice trial, which looked at ribociclib plus a CD4/6 inhibitor with or without GnRH agonist for those that were premenopausal, compared that to doublet therapy with the chemotherapy choices that were shown in the grey box.

 

RIGHT Choice: PFS (Primary Endpoint)

 

And what this trial demonstrated in a population of patients who were ER-positive and hormone receptor-negative is not only was there more than equivalence, the – the actual endocrine combination was superior with respect to PFS and by a lot. So it almost doubled the time until patients went from 12 to basically 22 months before progression.

 

So that old dogma that, you know, if you have metastatic disease or even what might be viewed as more threatening metastatic disease, you must give chemo or you must give combination chemotherapy, that has been discounted multiple times now based on this trial and others.

 

ABIGAIL: Phase II Abemaciclib With or Without Induction Paclitaxel in HR+ Metastatic Breast Cancer

 

The ABIGAIL trial shown here is a smaller experience, but it was interesting in the sense that it looked at a lead in of chemotherapy in one treatment arm. Again, hormone receptor-positive/HER2-negative metastatic disease. No prior therapy. Patients either got an AI with abemaciclib, or they got paclitaxel as a lead in, and then went on to the combo of a CD4/6 inhibitor and endocrine therapy.

 

And the primary endpoint was looking at the 12-week objective response rate and then a variety of secondary endpoints.

 

ABIGAIL: 12-Wk ORR

 

And if you sort of look at the top part of the table and you look at the CR and PR rate again, which was the primary endpoint of the study, you're getting more with endocrine therapy than you were with the patients who started out with Taxol sequenced with endocrine therapy. And that was again a significant uptick in the response rate.

 

AMBER: Abemaciclib + ET vs Chemotherapy in Untreated HR+/HER2- ABC With High Tumor Burden

 

The AMBER trial looked at abemaciclib plus endocrine therapy versus chemotherapy, again in patients with hormone receptor-positive/HER2-negative disease. This was a trial of about 180 patients, equal number in both arms. And again, not unlike the RIGHT Choice trial, you're seeing that there's an almost a doubling of the PFS favoring optimal endocrine therapy with a CD4/6 inhibitor, as well as an uptick in the objective response rate. And for the patients who did respond to therapy, the duration of that response was longer with endocrine therapy.

 

PADMA: ET + Palbociclib vs Standard Chemotherapy in High-Risk HR+/HER2- MBC

 

So a variety of trials that have addressed this in the PADMA trial also looking at endocrine therapy plus palbociclib versus standard chemotherapy in patients with high-risk disease. And again, the combo was endocrine and palbociclib with or without a GnRH agonist, depending on whether or not you were premenopausal and physician's choice of chemotherapy.

 

And again, that could have been any of a number of single agents that you see a taxane, an anthracycline, cape or vinorelbine.

 

PADMA: TTF, PFS, and OS

 

And same thing. So there's a consistent finding in all these experiences that with optimal endocrine therapy as a first-line treatment, you're doubling the PFS or more, in this case, going from basically eight months to 19 months. So again, a clear indication that endocrine therapy can be highly effective.

 

PALMIRA: 2L ET ± Palbociclib Maintenance in HR+/HER2- ABC After 1L Palbociclib + ET

 

The PALMIRA trial looked at patients with hormone receptor-positive/HER2-negative advanced disease. And they could have had progressive disease on first-line palbociclib and endocrine therapy, or palbociclib-based adjuvant therapy, which they receive for greater than 12 months, at which point they were switched to palbociclib with a different endocrine therapy. So we're starting to get into this switch concept of switching CD4/6 inhibitors or not, or switching the endocrine therapy, or simply just giving them monotherapy with a different endocrine agent.

 

And in this case, I would submit even though there is on the right a suggestion. Maybe there's a separation between the curves, it's not particularly impressive.

 

I mean, if you look at the medians, you're talking about, you know, a handful of days that separates these. But the data is what it is. And when you go out to landmark time points at six and 12 months, particularly six, there's more patients without progressive disease.

 

MAINTAIN: Switching ET ± Ribociclib for HR+/HER2- mBC After Progression on Previous ET + CDK4/6i

 

The MAINTAIN trial was another experience looking at the switch cons - switch concept, where patients were randomized after having received a prior CD4/6 inhibitor. In the first-line setting, most of the patients having received palbociclib were randomized to either a different endocrine therapy or a different endocrine therapy with ribociclib.

 

MAINTAIN: PFS

 

And this trial suggested, again, a signal that there was an incremental improvement in the time to PFS of about two months, favoring the switch to ribociclib and endocrine therapy.

 

And although, we're not talking about a lot of the other things you could do, you know, you interrogate the tumor for ESR mutations, PI3 kinase mutations, etc. If you had a patient who had responded well to a prior CD4/6 inhibitor and you really didn't have any other target that you could consider, the MAINTAIN trial would, of course, be supportive of thinking about a switch trial, perhaps.

 

MAINTAIN: Responses

 

So again, you can look at the overall response rate, the clinical benefit rate. And there is a suggestion that a signal that you're getting some benefit by going on to another CD4/6 inhibitor.

 

postMONARCH: Abemaciclib + FULV vs FULV for HR+/HER2- ABC After Progression on CDK4/6i + ET

 

And then perhaps the biggest experience of all was the postMONARCH trial. And again, these were patients who had developed progressive disease on first-line therapy with a CD4/6 inhibitor and an aromatase inhibitor for advanced disease, or a recurrence after adjuvant therapy. And at that point, they were switched to abemaciclib plus fulvestrant or fulvestrant plus placebo.

 

postMONARCH: PFS

 

And the primary endpoint was PFS. And again, there's a signal. A statistician would tell you it's statistically significant. You know, I can't in my heart tell you that I'm overly excited about this. But I would have the same caveat. If you had somebody that had responded very well to whatever they had been on before, meaning they were endocrine sensitive and you didn't have another target, this is certainly a strategy that one could consider based on postMONARCH and MAINTAIN.

 

postMONARCH: PFS in Biomarker-Evaluable Patient Population

 

And again, you can look at whether patients had ESR mutations or not. PI3 kinase, AKT, PTEN abnormalities in their pathway in sort of the forest plot on the bottom. And again, the patients who were getting abemaciclib seem to have a somewhat better outcome.

 

PADA-1: Switching to Palbociclib + Fulv vs Continuing AI Therapy in ER+/HER2- MBC With Rising ESR1 Mutations

 

And the PADA-1 trial, again, built on this experience, but in this case, looking for the emergence of a mutation before there was clinical evidence of disease progression. So you're not seeing anything on imaging. And upon change, with the emergence of an ESR mutation, changing therapy, going from an aromatase inhibitor to fulvestrant. And did that make any difference in terms of overall outcome?

 

PADA-1: PFS and PFS2

 

And again, there is some suggestion that if you act on the ESR mutation, and of course, this was a predecessor to SERENA-6, which we'll talk about. But if you look at the outcome of making that switch based on the emergence of an ESR mutation, you see an improvement in PFS, which seems to carry over, in fact, to the second progression – second progression after the initial one on the right.

 

So there is some suggestion that by acting on biology, molecular changes that are occurring, even in the absence of a clinical change on scans, that you may impact on patients.

 

EMBER-3: Imlunestrant ± Abemaciclib vs SoC for ER+/HER- ABC

 

The EMBER-3 trial was an effort to look at one of the newer SERDs in combination with abemaciclib or not versus standard of care endocrine therapy. So as you can see, this was a trial in pre and postmenopausal women with ER-positive/hormone receptor-negative disease. Prior treatment, they either had advanced disease or prior therapy with a recurrence less than or equal to 12 months of adjuvant AI with or without a CD4/6 inhibitor.

 

And they were randomized either to monotherapy with imlunestrant, the combination of abemaciclib and imlunestrant. So again, this is looking at least in a fraction of the patients at this idea of – of coming back at the patient with another CD4/6 inhibitor, in this case, abemaciclib or the standard of care arm, which would have been fulvestrant or exemestane.

 

EMBER-3: PFS (Primary Endpoint)

 

So if you look at the primary endpoint of PFS in the patients who received imlunestrant as monotherapy, not a doublet, with abemaciclib on the left. In the population with an ESR1 mutation, there was clearly an improvement favoring imlunestrant over monotherapy with either an AI or fulvestrant. Not a huge one, but nonetheless, it was significant.

 

If you look at the combination of imlunestrant/abemaciclib versus imlunestrant on the right, you also see that you get that effect across the entire population. And it was also seen in the ESR1 mutation – muted – mutated patients as well.

 

And the patients receiving monotherapy with imlunestrant, there wasn't any advantage in the wild-type to receiving monotherapy with imlunestrant.

 

EMBER-3: I+A vs I PFS by Previous CDK4/6i and ESR1 Mutation Status

 

So again, if you break it down by whether a patient had been treated with a prior CD4/6 inhibitor, because not the entire population had gotten a CD4/6 inhibitor. There is a benefit with coming back at the patient with imlunestrant plus abemaciclib. On the left, if you had an ESR mutation or not, there was a – there was evidence, certainly with the combination that you were getting a benefit.

 

And then in the patients without an ESR mutation on the bottom, imlunestrant plus abemaciclib was better than imlunestrant alone.

 

SERENA-6: CDK4/6i + Camizestrant or AI in ESR1m HR+/HER2- MBC in Patients Without PD on 1L CDK4/6i + AI

 

And then SERENA-6, which hit the news, you know, relatively recently in the sense that it went before ODAC and unfortunately didn't fare too well, even though it did get an approval in Europe. This was a trial that built on PADMA-1, looking at whether or not you could look at the emergence of a mutation in the absence of a clinical change based on scans that the patient had progressive disease.

 

So patients who had been on their initial therapy for at least six months started to get screened for the emergence of ESR mutations every two to three cycles. If you were ESR1 negative on your screen, you could continue to get screened. If you did have a mutation that emerged, you had – you were randomized between continuing on your current therapy with endocrine therapy plus a CD4/6 inhibitor, or making a change to camizestrant, one of the newer SERDs plus a CD4/6 inhibitor that you had been on.

 

And the primary endpoint was looking at PFS. And you might ask, “Well, how do you judge PFS if you haven't actually progressed yet on clinical exam?” And this was actually one of the pushbacks from the ODAC committee that the trial – you know, this was a novel marker. And also there wasn't a treatment arm that allowed you to get camizestrant at a later time point. So there were perhaps a few flaws in the trial design that contributed to its lack of success.

 

SERENA-6 Update: Survival and ESR1m ctDNA Outcomes

 

Even though when you look at the actual data and the primary endpoint on the left, there was an improvement on making a change from what you were on with the emergence of an ESR1 mutation in the absence of clinical evidence of disease progression. And if you look at a 12-month time point or a 24-month time point, more patients are without disease progression who receive camizestrant.

 

There's also a suggestion that that carried over into PFS2 and the chemotherapy-free period was longer in the patients who made that switch. But because of the reasons that I suggested to you a moment ago, this was debated a fair bit at the ODAC committee and ultimately by a six to three vote, it didn't get approved. There's still a chance it might, but it didn't get the thumbs up from the ODAC committee.

 

PATINA: Palbociclib + Anti-HER2 + Endocrine Therapy in Previously Treated HR+/HER2+ MBC

 

And then PATINA has changed how we think about treating patients with hormone receptor-positive/HER2-positive disease. We can have a much longer discussion about how we integrate newer antibody drug conjugates into this patient population. But if you think back not that long ago, that CLEOPATRA reigned as the best therapy that we would typically use in this setting.

 

In patients who are ER-positive, the question came up, could you further optimize the endocrine therapy? Because remember, if you're responding in CLEOPATRA, you stop the chemotherapy, you continue the trastuzumab. And then endocrine therapy can be concurrent with the trastuzumab plus/minus pertuzumab.

 

And the question became, could you optimize or further optimize endocrine therapy with a CD4/6 inhibitor, in this case, palbociclib.

 

PATINA: PFS and Interim OS

 

And as you recall, when Otto Metzger presented these data which are shown here, the PFS on the left, was significantly longer in the patients who had palbociclib integrated into their maintenance therapy with endocrine therapy. And it starts to look at – look like the best PFSs we're seeing with many of the other trials, a clear reduction in the odds of disease progression.

 

And furthermore, if you look at the response rate, there was also an uptick in that as well, 32 versus 25%. And the five-year overall survival is also going in the right direction, favoring the addition of palbociclib to endocrine therapy in this setting.

 

Considerations for Individualizing CDK4/6 Inhibitors for MBC

 

So when we individualize CD4/6 inhibitors for metastatic disease, again, not unlike some of the considerations for early-stage disease, but we have to take into account other things that are going on in the patient's life. There are other disease. What their response and benefit might have been to prior endocrine therapy? Do they have specific sites of disease, visceral disease, brain disease? We, of course, have to look at drug-drug interactions.

 

And again, the list is long. But we have to think about all of these things when we're making a decision – decision about the optimal combination in this setting.

 

Let's Revisit Our Question

 

Posttest 2

 

All right. So let's go back to our – our post-test number two. Based on current guidelines, which of the following patients with hormone receptor-positive/HER2-negative breast cancer would be most suited for treatment with imlunestrant plus abemaciclib. And rather than read them all because I've done that once, you can go ahead and choose. These are exactly the same as they were earlier.

 

All right. All right. Now, we'll talk a little bit about this.

 

Posttest 2: Rationale

 

So, you know, again, the EMBER-3 trial, it would – the ideal answer would be B. And if we can go back, do we – can we still bring up the – the voting result on the prior slide or is it gone forever? All right. So anyway, the correct answer – okay. So we were making an incremental improvement in the ideal patient population for this.

 

And it's really – the indication for the combo is those with advanced breast cancer with an ESR mutation and progressive disease on or after first-line treatment with an AI. And not everybody with an AI in this experience had gotten a prior CD4/6 inhibitor.

 

Case Discussion

 

All right. So we're going to go on to a couple of cases. The first is Naomi, a 60-year-old woman with hormone receptor-positive/HER2-negative metastatic breast cancer. She was initially treated with palbociclib in combination with letrozole. After three cycles, she developed grade 3 neutropenia that persisted despite dose reductions and treatment delays.

 

In addition, she reported increasing fatigue and difficulty maintaining her daily activities. And given the severity of her hematologic toxicity, her oncologist decided to discontinue palbociclib. So what treatment course would you consider next for Naomi? And what factors would come into your decision-making and why?

 

So I'll turn it to Joanne.

 

Dr. Mortimer: Okay. Yeah. So – so right now it looks like she only has grade 3 neutropenia, which – which is unusual with palbociclib, but it certainly happens. The concern you might have is, is something else going on, but it doesn't appear that she's anemic or thrombocytopenic that make – would make you worry about having a myelophthisic process. So, you know, it isn't certainly an option to switch to a different CDK4/6 inhibitor and continue her letrozole. I guess I'd be inclined to give her abemaciclib if that was the case.

 

Dr. Gradishar: How about you, Heather? Anything different?

 

Dr. McArthur: I agree with those comments. I would probably pick ribociclib here. I probably would have started with that in the first place if I was seeing this person at diagnosis. And that's just because of the statistically significant survival advantage. And we – when that data came out, we really pivoted from palbociclib to first-line ribociclib. And then in my mind, now with the imlunestrant/abema combo, which isn’t FDA approved yet, but we have in the US been able to access that combination. And it's ESR1 agnostic in my mind. I might save that for a second-line of therapy.

 

Case Discussion

 

Dr. Gradishar: Okay. All right. Second patient. Mei is a 74-year-old postmenopausal woman who was originally diagnosed with a T2N1M0 hormone receptor-positive/HER2-negative breast cancer at the age of 65. She underwent neoadjuvant chemo with an anthracycline and cyclophosphamide, followed by paclitaxel, had a right mastectomy and radiation therapy, and completed five years of endocrine therapy with letrozole, and has been free of any problems until recently, when she developed back pain and a dry cough. And a workup demonstrated that she had bone metastases, as well as suspicious lung nodules.

 

And a biopsy that was done confirm the recurrence of the original breast cancer that remained hormone receptor-positive/HER2-negative. And she does have a history of well-controlled hypertension, hypothyroidism and mild depression.

 

So what course of treatment would you recommend for Mei now, and what factors would go into your thought process and influence what you decided?

 

So I'll start with you this time, Heather.

 

Dr. McArthur: Yeah, I think my answer here would be exactly the same as it was with the prior case, which is that I would typically – in the absence of any contraindication, I would typically consider an AI-ribociclib combination upfront. I do start the AI first to establish tolerance of the backbone before I introduce the ribociclib. So I typically do it in a staggered fashion, typically a month after starting the AI, because if you don't get the foundation right, they just won't be compliant at all. And I don't see any contraindications for that.

 

And again, the statistically significant survival advantage with that approach and abema-based doublet options available at a later date.

 

Dr. Gradishar: Is there anything that makes you have to give an AI as opposed to fulvestrant?

 

Dr. Mortimer: I was going to say I would probably give her a – get a next-gen sequencing on her as well, and find out if she had an ESR1 mutation.

 

Dr. Gradishar: Okay.

 

Dr. Mortimer: I – I don't – I – so we have fulvestrant doublet combinations with other. So PIK3CA and other targeted agents. And the intramuscular injections I think is a quality of life issue. So I probably wouldn't start there for this patient.

 

Dr. Gradishar: You sort of have to play three dimensional chess, thinking about how you're going to use the currently available therapies going forward.

 

Got Questions

 

All right. Remember to submit your questions. And now I'm going to toss the baton to Joanne and she'll talk about management of AEs.

 

Managing AEs and Promoting Adherence and Persistence With CDK4/6i

 

Dr. McArthur: Thank you. Thank you, Bill. Thank you all.

 

Poll 5

 

Here's our first poll question. How confident are you in your ability to foster and support treatment adherence and persistence in patients receiving CDK4/6 inhibitors?

 

1. Not confident;
2. Slightly confident;
3. Moderately confident;
4. Confident; or
5. Very confident.

 

Okay, so we have – we have some work to do. Hopefully by the end of this, you'll be – all be in the high confidence.

 

How We Identify Adverse Effects of Therapeutic Agents

 

Which of the following is optimal management for a patient receiving adjuvant abemaciclib for a stage IIIA hormone receptor-positive/HER2-negative breast cancer with an elevated serum creatinine?

 

1. Assess renal function by measuring cytostatin C;
2. Hold abemaciclib and resolution and restart at the same dose;
3. Hold abemaciclib until resolution and restart at a reduced dose;
4. Discontinue abemaciclib and switch to ribociclib.

 

Wow. You guys are really smart. Okay.

 

How We Identify Adverse Effects of Therapeutic Agents

 

Okay, so we're going to talk about toxicity and, you know, how do we identify toxicity? You know, by and large it's from registration trials. And as you know, the patients who participate in these trials are usually pretty hale and hearty. And so real-world experience with patients with comorbidities really does identify additional adverse events with – with any drug.

 

The FDA also helps us identify adverse events and has an adverse event reporting system, which may identify toxicities. And the significance of this constant follow-up is that a third of newly approved drugs face safety concerns after approval.

 

So as we continue longer follow-up, you know, you think about bisphosphonates and ONJ or musculoskeletal problems with aromatase inhibitors. It's important to understand toxicity, though, because it helps us understand the biologic mechanisms of the disease and the treatment. It identifies other potential indications. It's important for dose and schedule modifications, and it requires management to help patients adhere to effective therapy, and toxicity may contribute to the expense of treatment.

 

Monitoring and Managing CDK4/6i-Induced Neutropenia

 

So the first and common toxicity is neutropenia. And this occurs with basically all three of the CDK4/6 inhibitors. And as you know, we check the – the – the CBC on a – on a day one of the cycle. And if the ANC is 1,000 or more, there's no need to change the dose of the drug.

 

If you have grade 3 toxicity between 500 and 1,000 granulocytes and they’re afebrile, you hold until they resolve to grade 2 and then continue at the same level. If it happens twice, then you do a dose reduction.

 

And patients who have grade 4 and ANC less than 500, you need to hold until it resolves. And those patients all require a dose reduction.

 

Roadmap for Managing Hematologic Toxicity With CDK4/6 Inhibitors

 

So the unique things about the neutropenia that you see with the CDK4/6 inhibitors is that it's seldom that you see an infection even when their granulocyte counts are low. So you don't need to do antibacterial prophylaxis and you don't need to give them GCSF. But it is a case that Dr. Gradishar presented. If somebody is persistently neutropenic and if you can't attribute it entirely to the CDK4/6 inhibitor, you want to make sure that the patient doesn't have a myelophthisic process, and usually they're anemic and thrombocytopenic at the same time.

 

monarchE Dose Reductions and Discontinuations

 

So we – Dr. McArthur talked a bit about dose reductions and discontinuations in – in the monarchE trial. So if we look at the number of dose reductions, there were 43% of patients required a dose reduction of abemaciclib and discontinuation from adverse events was as high as 18%.

 

If we look at the treatment and no dose reduction, the median duration of treatment was 23.7 months and 73% completed at least 18 months. For those individuals who had one or more dose reductions, the median duration of treatment was 23.7 months as well, and 76% completed at least 18 months of treatment.

 

So what this slide points out is that you have to monitor these patients. And dose reductions may be important in order to keep them on study, especially since the overall benefit observed in this population with dose reductions was seen even for the patients who had dose reductions and AE discontinuations.

 

Management of Abemaciclib-Induced Diarrhea

 

So one of the biggest problems we have in managing patients’ compliance on abemaciclib is diarrhea. And at the first sign of loose stools, we recommend that they take antidiarrheal such as loperamide. And patients who have less than four stools per day are considered grade 1, and you would not change their abemaciclib dose.

 

For those individuals who have four to six stools a day. If it doesn't resolve, you hold the drug and let it resolve. If it doesn't resolve, you may require a dose reduction further – further waiting. If it's a higher grade, grade 3s, which is seven or more stools a day compared to baseline, you want to hold again until you get to grade less than 1. And these folks require a dose reduction, as do patients who have grade 4 life-threatening diarrhea.

 

Renal Toxicity With Abemaciclib: Mechanism of Action

 

So the question that we asked about creatinine clearance or creatinine, it is common to see elevated creatinine in patients who are on abemaciclib. And this is not renal compromise. But abemaciclib interferes with the transporters that are – that are important in getting creatinine into the urine. And so when those are interfered with the creatinine, the blood is elevated.

 

Management of Renal Toxicities With Abemaciclib

 

And so most patients treated with abemaciclib will have an increase in serum creatinine during cycle one. And that may be stable throughout treatment and may even decline once treatment is discontinued, but know that the creatinine can be elevated as much as 15 to 41% higher than baseline.

 

If, however, you think that there's an acute renal injury, then you want to measure renal function, whether you're looking at BUN, which individually doesn't help, but cytostatin C or calculating a GFR is beneficial.

 

TRADE: Phase II Dose-Escalation Trial of Abemaciclib + ET in HR+/HER2- EBC Planned for Adjuvant Abemaciclib

 

So one of the big questions that's been raised is how – when you dose abemaciclib, can you sort of slowly introduce the drug and make it more tolerable? And this TRADE study addressed that issue that included 90 patients whose eligibility were the same as monarchE, and patients started with 50 milligrams twice a day of abemaciclib for the first two weeks, escalated to 100 twice a day for the second two weeks, and then the third two weeks were on full dose, 150 milligrams twice a day.

 

TRADE: Primary Endpoint (Composite Adverse Event Rate at 12 Wk)

 

And what they showed was that this sort of slow dose increase did result in a greater number of patients achieving their target dose than was seen in monarchE. So 71% of patients reached their target dose of 150 milligrams twice a day, and that was higher than observed with monarchE. But this is a phase II study. So it's really, you know, cross-study comparison is really not legitimate.

 

But I think it does point out that this is a strategy that that may be worth trying in patients as – as you're – as you're getting them on abemaciclib.

 

Six of the 89 patients on this study actually discontinued therapy, two withdrew consent and four withdrew because of toxicity.

 

NATALEE Dose Reductions and Discontinuations

 

So NATALEE also had dose reductions and discontinuations. The dose reductions were 27%. So somewhat less than monarchE, but discontinuation rate was – was pretty comparable, 19.7%. So dose reductions and – and adverse event discontinuations were common and they tended to occur early, but nonetheless, the – the trial still achieved a significant and durable invasive-disease free survival benefit through the five years.

 

So it's important as we have these patients on adjuvant – especially adjuvant therapy, that we – we work to – to keep them compliant and manage their toxicities accordingly.

 

QTc Prolongation With Ribociclib and Dose Modifications

 

So Heather talked about QTc prolongations which is a unique toxicity with ribociclib. And we do check the QTc prior to and two weeks after institution of ribociclib. And this slide just summarizes how we would monitor them. So if there is an increase of QTc of 60 milliseconds or more from baseline or consecutive QTc prolongations of more than 500, probably ribociclib should be discontinued. For less significant changes, holding the ribociclib and waiting to see the QTc goes less than 480 would be recommended.

 

Monitoring and Management of Ribociclib-Induced Hepatotoxicity in Advanced Breast Cancer

 

All right. So ribociclib is known to have some hepatotoxicity. And when we start patients on ribociclib, we do measure their liver functions every two weeks for the first two cycles. When we talk about liver function tests here, we're talking about transaminases. If there is an elevation in the bilirubin of twofold or more, you have to stop the drug. So other dose modifications are based on the transaminases. And so if they're less than three times the upper limit of normal, there's no need for dose adjustment.

 

A grade 2 is greater than three to five times the upper limit of normal. And in those cases, you would hold until it resolves to less than baseline, resume at the same level. But if it occurs twice, you need to lower the dose.

 

Grade 3 is five to 20 times the upper limit of normal, and you hold until it resolves to less than baseline grade and resume at a lower dose level. Patients who have grade 4, which is 20-fold increase in the upper limit of normal of their transaminases, should have their ribociclib permanently discontinued. And again, bilirubin, twice the upper limit of normal is considered a reason to discontinue the drug as well.

 

Real-world Studies vs Clinical Trials: VTE and Arterial Thromboses

 

I show this slide because when we started using these drugs, it was clear that venous thromboemboli and arterial thrombosis was a side effect. But this really highlights the importance of real-world data because as you see, the comparisons of clinical trial data versus real-world data incidents, it's much, much higher than what was seen in the – in the registration trials.

 

Monitoring, Managing and Mitigating VTE With Abemaciclib

 

And so patients should be aware that there – that clots and thrombosis are potential complications of these drugs. And so they should not be telling us about symptoms that are worrisome for pulmonary emboli or for thrombosis.

 

Thrombotic Events in Patients on CDK4/6 Inhibitors Summary

 

So thrombotic events in – in the CDK4/6 inhibitors really occurs with all three agents. It may be lower interestingly with ribociclib. It may also be increased in the concurrent use of tamoxifen. And there's an unclear relationship whether patients who have pre-existing comorbidities such as cardiovascular disease, whether they are at increased risk or not, but know that these are both venous and arterial clots, and they have been reported as fatal events in some cases.

 

Meta-analysis of CDK4/6 Inhibitor–Associated Interstitial Lung Disease

 

Interstitial lung disease is also a side effect of CDK4/6 inhibitors and presents, as you'd expect, with cough and abnormal imaging. There is a trial that looked at 12 randomized clinical trials with over 16,000 patients, most of whom were breast cancer patients. And they reported that the incidence of interstitial lung disease was 1.6% in the patients who got CDK4/6 inhibitor, compared to patients who were not receiving a CDK4/6 inhibitor.

 

It's interesting in the FDA follow-up data, it seems that abemaciclib has a higher incidence of interstitial lung disease than ribociclib or palbociclib. And interestingly, the time to developing the latency period is much shorter for abemaciclib, 50 days, compared to ribociclib of 253 days. So kind of just like T-DXd, we need to sort of be constantly aware of dyspnea, shortness of breath and – and exertion in our patients who are on CDK4/6 inhibitors.

 

Roadmap for Managing ILD/Pneumonitis With CDK4/6 Inhibitors

 

So we need to monitor them for worse pulmonary symptoms. And obviously, if they develop symptoms, we want to do a pulmonary workup with a CT scan and rule out other etiologies such as infection or tumor progression.

 

For grade 1 interstitial lung disease, there's no dose modification necessary. If there's a grade 2, though, you want to hold until their symptoms resolve, start them on prednisone one to two milligrams per kilogram until there’s – they – they resolve their symptoms to grade 1, and you can consider resuming them. But you may want to reduce the dose of the CDK4/6 inhibitor.

 

For patients who have grade 3/4 ILD, you want to discontinue the CDK4/6 inhibitor, initiate steroids and treat them accordingly.

 

Considerations for Switching CDK4/6 Inhibitors

 

So what are the considerations for switching CDK4/6 inhibitors? And I think – you know I think Dr. McArthur made this point. You know when you know how to manage toxicities and you're paying attention to the patient's symptoms, most of the toxicities are managed – are manageable with proactive monitoring and supportive care and guideline appropriate interruptions and dose reductions.

 

Ideally, you want to maintain the CDK4/6 inhibitor that you started so that you can, you know, keep – keep up the long-term therapeutic benefit of that agent.

 

Switching agents is – is appropriate in some indications, but it's reserved for severe, recurrent and unmanageable toxicities despite doing dose modification. And – and I think, you know, the strategies to optimize outcomes really, you have to – you have to identify these side effects early. Patients should be aware of what the side effects are, and you want to do a timely interruptions and dose reductions as indicated by symptoms.

 

Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention to Maximize Adherence

 

So this slide just summarizes the toxicities that we see with the CDK4/6 six inhibitors. Diarrhea is a common side effect mostly of – of abemaciclib but can occur with ribociclib as well. Hepatotoxicity. We measure liver function tests before starting treatment with ribociclib in Q2 two weeks for – for a month and may need to modify accordingly to their – to elevations. But liver function abnormalities also occur with abemaciclib.

 

Neutropenia occurs with all three of the CDK4/6 inhibitors. I put venous thromboemboli. It occurs with all three, but it seems to be more common with abemaciclib and perhaps less common with ribociclib. Interstitial lung disease occurs – has been reported most often with ribociclib and abemaciclib. QT prolongation with ribociclib and tamoxifen should not be used in patients with ribo – on ribociclib.

 

Key AEs With CDK4/6 Inhibitors: Monitoring and Prevention to Maximize Adherence

 

Fatigue is a very common side effect, and we know that when we put a CDK4/6 inhibitor added to an endocrine therapy, the fatigue is more common. And I put down exercise that because that really is the only data that shows any potential benefit. And it's – it’s largely in the chemotherapy population.

 

Elevated serum creatinine is due to interrupt – interference with the measurement of creatinine and not actual renal compromise. And then there are some times that there are skin changes that can occur. And these can be typical red rash drug reaction or even vitiligo which has been seen in patients who are on CDK4/6 inhibitors.

 

Optimizing Patient Education and Adherence

 

So, you know, I think we've talked about patient education and adherence, because we really want to make sure that the patients are partners in their care and that they understand what the potential side effects are. And it's also important that the caregivers and that the physicians are aware of all these potential side effects. And whether it's – so Dr. McArthur has a pharmacist who helps them with this toxicity. That is really an ideal situation.

 

But I think the more education we do or the patient, the caregiver and the physicians, the better we are able to continue therapy and adhere to treatment.

 

Acknowledging Potential Healthcare Disparities to Promote Adherence

 

I think we've talked about the importance of healthcare involvement in the adherence of patients on CDK4/6 inhibitors.

 

Resources for Optimizing the Use of CDK4/6 Inhibitors in HR+/HER2- Breast Cancer

 

So this slide, it has a QR code on it that has a number of resources that are available to help with managing CDK4/6 inhibitor treatment. It's an interactive tool to manage adverse events in these agents. And you see the site on the right. So feel free to take that.

 

Patient Support and Resources

 

And additionally, the NCCN does have patient support and resource guides for patients that are also available.

 

Let's Revisit Our Case

 

So let's revisit our case.

 

Posttest 3

 

So which of the following is the optimal management for a patient receiving adjuvant abemaciclib for stage IIIA hormone receptor-positive/HER2-negative breast cancer with an elevated serum creatinine. I'll let you guys answer again.

 

Oh, wow. We got 100%. Yay. Yay, team. Okay. Yeah.

 

Posttest 3

 

So – so, you know, I think this was – this was a side effect. I think a lot of people hadn't known until you used the drug for a while. But again, you know, the elevations in serum creatinine can be up as high as 41 – 40% higher than baseline.

 

Poll 6

 

Okay. So okay, so these are questions that we're not going to show, but could you – do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

Poll 7

 

Okay. And please take a moment to text in one key change that you plan to make in your clinical practice based on – on this educational program from today?

 

Interactive Case Discussion

 

Patient Receiving Abemaciclib Who Develops Shortness of Breadth After Treatment With CDK4/6 Inhibitors

 

And so this is my – my interactive case, which is obviously a real person, a 72-year-old with stage IV hormone receptor-positive/HER2-negative, invasive lobular breast cancer who had metastases to the peritoneum and bone. So she was rather atypical lobular breast cancer.

 

On April 1st, 2024, she was started on letrozole and abemaciclib for her metastatic disease, and within two weeks the dose was reduced because of severe mucositis. And I think mucositis is certainly a side effect from the CDK4/6 inhibitors. This woman had incredibly severe mucositis, which I had never seen before with the CDK4/6 inhibitors. And – and so I dose reduced her. But within the next two weeks she was admitted with acute shortness of breath of three days duration. She had fatigue, fevers to 101 and a pulse ox of 85% - of 90% at rest, with a pulse of 85.

 

ILD With CDK4/6 Inhibitors

 

And here was her chest X-ray when she was admitted. So she had a bronchoscopy. She had cultures, cytology was negative, cultures were negative. And she was started on steroids.

 

So how often are you seeing ILD in your patients being treated with CDK4/6 six inhibitors?

 

Dr. Gradishar: Okay. Not very often.

 

Dr. McArthur: Rare. Yeah.

 

Dr. Mortimer: This was of course a physician.

 

Dr. McArthur: Of course.

 

Dr. Gradishar: Of course.

 

Dr. Mortimer: So, you know, the – the incidence seems to be – it's a little bit less than 2% from – from that meta-analysis or that series of 16 randomized clinical trials. And the other thing she demonstrates is, you know, the data seem to suggest that the time to developing interstitial lung disease is shorter with ribociclib than – I mean, with abemaciclib than ribociclib. But hers was incredibly short.

 

And I – I don't know that her mucositis should have made me think that she was having excessive toxicity from this drug because of her own metabolism. But nonetheless, within a month, she had rather significant ILD.

 

So are you seeing differences in – in rates and severity of ILD with different CDK4/6 inhibitors?

 

Dr. Gradishar: I don't see it very often, but I guess the other part of that, that I would be curious what your thought would be. I'd be pretty reluctant to try any other CD4/6 inhibitor in this woman.

 

Dr. Mortimer: You know, that's a really good point, Bill. And I'm going to tell you, I was with you on that. I mean, this woman was – was – was significantly compromised. And even though she got steroids and got better, she never returned to her normal baseline function, actually. And – and – and so she did not get a CDK4/6 inhibitor. She just continued on – on an aromatase inhibitor.

 

I guess I've seen ILD with all – all three of the CDK4/6 inhibitors. The first one I saw was – was with – was with palbociclib and it was a patient who was about 100 days on her – on her palbociclib shortly after the drug was approved. You know, but there is data that says that if you stop and go to a different one, they're not – they may not get ILD again. But in this lady's case, I – there's no way I was going to risk that.

 

So what about the mucositis? Do you guys want to comment on mucositis? That seems to be a really uncommon side effect.

 

Dr. McArthur: I was going to say I – I can't recall a patient with mucositis.

 

Dr. Gradishar: Yeah, same.

 

Dr. McArthur: Okay. I'm going to ask one other side effect question because it’s – there's a very scant literature for this, headaches on – on CDK4/6 inhibitors. I seem to see this with some regularity that tends to respond to dose reductions.

 

Dr. Gradishar: Well, I'll know what to do now when it happens.

 

Dr. Mortimer: Yes. Okay.

 

Dr. McArthur: It's probably not a toxicity that we capture very well or attend to.

 

Dr. Mortimer: Yeah, it's such a non-specific side effect. Okay. Okay, Bill, back to you.

 

Q&A

 

Dr. Gradishar: Have a seat. We're just – we have a few minutes left, and we want to take advantage of some of the questions that came in. Many from the virtual audience. And a couple will go right to you, Joanne. And that is, you know, you mentioned fatigue. It could be a question we ask about just about any therapy we give, including antibody drug conjugates. But is there any particular strategy or effective ways you have for mitigating above and beyond exercise?

 

Dr. Mortimer: Yeah, I have to say, there are patients that I do dose reduce who are significantly – who are significantly fatigued, especially if they threaten to stop their CDK4/6 inhibitors. So going from 600 to 400 on ribociclib in – in older patients. I think I'm inclined to do fairly regularly when they say they're about to become noncompliant.

 

Dr. Gradishar: And – and there was one other question on toxicity – well, there's others, but somebody was asking whether you see an increased risk of clotting in people on a CD4/6 inhibitor and who smoke.

 

Dr. Mortimer: Oh, gosh. You know, I wish I knew the answer to that. You know that study that looked at – at interstitial lung disease and – I mean, it looked at clots. It – it's not clear. It seems that patients who have cardiovascular disease may have an increased risk of clots and thrombosis, but they didn't see that – they didn't address smoking as a risk.

 

Dr. Gradishar: Yeah, good idea not to do it though. So question for you, Heather.

 

Dr. McArthur: Okay.

 

Dr. Gradishar: You know, we sort of – we're putting a blind eye to all the things on the slide showing all the targeted therapies, the combinations that are coming along. But there was a question about has everolimus left the room? I would submit maybe it's coming back through the doors.

 

Dr. McArthur: I think I see it sneaking in over there. It's – you know, it's never been my favorite medication because of the stomatitis mucositis issues. Although I know others, like Hope Rugo I know loves giving everolimus. I do think it is making a comeback based on the evERA study, looking at giredestrant. So one of the novel oral SERDs together with everolimus in a very impressive PFS improvement. The OS data was not yet mature, but the PFS improvement was pretty notable. And that's going to the FDA at the end of the year.

 

So I think we'll have another combination approval in that space. And especially it was enriched in the ESR1 mutation population, which really drove. They enriched for ESR1 mutations in that study.

 

Dr. Gradishar: I think we'll hear more about that trial on Monday or Tuesday. Some – some subset data. So I commented on the RIGHT Choice trial, which was one of the combo chemos versus a CD4/6 inhibitor and endocrine therapy. And the question really focuses on, you know, how do you decide somebody's got aggressive disease or is in a visceral crisis? And would that dissuade you from using endocrine therapy?

 

So I'll just make a comment. I mean, you know, this – visceral crisis has always been in the eye of the beholder, but it's not simply the presence of metastatic disease or having a few liver mets. It's where things are rapidly progressing. You may have bulky disease and, you know, even despite the RIGHT Choice data, I think you still have to be selective in who you use optimal endocrine therapy for despite what the RIGHT Choice tells you.

 

But I think it gives you permission based on that data and the other trials to try endocrine therapy, even if there is fairly diffuse metastatic disease.

 

Dr. McArthur: And I think we've forgotten about the abemaciclib monotherapy data, right, where it was very effective in patients who were at high-risk of visceral crisis. So I think there's a longitudinal narrative around the use of CDK4/6 in higher risk patients, even though it kind of gives us some anxiety, I think, to actually have the guts to do it, or you feel like you're not going to have enough time for it to reach steady state, etc..

 

Dr. Mortimer: Something that people have a lot of discomfort with, thinking that endocrine therapy is – is better than chemo.

 

Dr. Gradishar: So there's a lot of considerations into whether you choose, and despite your love of that table, monarchE versus NATALEE distinguishing, you know, the kind of patient that could go on either one of those drugs. But how about the duration of therapy? Does that ever – just that as a two versus three-year question.

 

Dr. Mortimer: Yeah. I have to say, when I have overlapped patients, we have discussion – I mean, obviously the patient is part of the discussion. It's two years versus three years. It's diarrhea versus no diarrhea and a lot of monitoring. I usually leave it to the patient. And those patients that are – are – fall into both groups of potentially getting ribo or abemaciclib.

 

Dr. McArthur: I mean, if it were me, I'd prefer to be on combination therapy for two years instead of three years. So I probably have some bias in how I direct my patients.

 

Dr. Gradishar: And how often have you found that you've had to switch among the – in the adjuvant setting or even the metastatic if they weren't tolerating it between the CD4/6 inhibitors.

 

Dr. McArthur: Very rarely, I would say. I think again, it's about the education and maybe in an academic environment, I have more time to spend on the education than, as I said, I have this patient-facing pharmacist. So there's a lot of education. But on occasion, I mean, I did have one patient who had one kidney and I was scared because their creatinine shot way up and I – on abemaciclib and I did the cystatin C. I had a patient who was on the monarchE study at our site. We had PALLAS and monarchE, and he was on the monarchE study, very high functioning person.

 

The fatigue was so profound, she just couldn't go to work anymore. And she was a very motivated person. But these are sort of anecdotes and not – I don't think, the general rule.

 

Dr. Mortimer: So I think the diarrhea is the hardest part of it because I have patients who like don't eat out anymore. They don't – they don't go to parties and eat because they're afraid they're going to have diarrhea. Then – and I find the diarrhea to be a disruption to – to many, many patients.

 

Dr. Gradishar: And patients actually tell me they enter a room trying to figure out where the bathroom is before they even have the urge to go. So that's sort of a limiting thing when you think about your lifestyle.

 

Dr. Mortimer: It doesn't make you stop the drug, but it's quality – it's a huge quality of life thing. So I actually think I'd go for three – three years of ribociclib.