This transcript has been edited for clarity.
Lidia Schapira, MD: This is the conclusion of my conversation with Dr. Antonio Wolff. The first half of our conversation, featured as episode 2 in this series, focused on DCIS and lower-risk early stage breast cancer. This second half of our conversation featured here, focuses on high-risk early stage breast cancer.
So let's turn our attention now to a different setting, and that is the higher risk, early-stage invasive cancer. And let me start by giving you a case to get you thinking about this. So now you're seeing a 42-year-old gynecologist, and she was just diagnosed a year ago with a node-positive infiltrating ductal carcinoma that was high grade. Let's say she had a KI67 greater than 30 and ER/PR-positive. She's just finished her local treatment. She had surgery, she had adjuvant chemotherapy, she had radiation, and she's about to begin her endocrine therapy with ovarian suppression and tamoxifen. And she just read the results of the monarchE study, and she wants to know if she should also abemaciclib. So with that case? Let me ask you first to explain the rationale for including a second agent like a CDK4/6 inhibitor in the adjuvant setting.
Antonio Wolff, MD: In the 1990s, when we were learning about the benefits from tamoxifen, a lot of the data actually were coming, not from individual trials, but from meta-analyses of a combination of clinical trials. And in fact, it took a metaanalysis to show that tamoxifen was equally efficacious in premenopausal women. Until 1995, we would only recommend tamoxifen for postmenopausal women, and it is an incredibly old drug. But is still today, one of the most successful interventions we have for patients with early-stage breast cancer, with the aromatase inhibitors offering an incremental benefit, particularly for patients with node-positive disease, but less so for patients with node-negative disease, where the survival benefit is less apparent.
And so that's part of, again, my part of my decision to become a medical oncologist in the breast cancer medical oncologist was the excitement about new knowledge with new interventions and in many ways for other diseases, for early on, for HER2-positive disease, for triple negative disease, we did not have much to do until the late 1990s and mid 2000s, when we learn more about the life-altering effects from anti-HER2 targeting.
And for many years, we had the sense that things were just fine for patients with ER-positive disease. Because we have tamoxifen, we had aromatase inhibitors where more and more we began to realize that even though the reduction in the risk of an event in terms of disease-free survival and then ultimately overall survival, the improvement in the hazard rates for recurrence was significant. We still have a substantial residual risk. It took us a while to begin to realize that actual risk of recurrence for patients with ER-positive disease persisted beyond five years. And where for patients with HER2-positive and triple-negative disease, most of the risk would be in the first five years or so. For ER-positive disease, actually, only half of that risk is in the first five years, and the residual half of their risk is from years five to lifetime. So we are beginning to recognize that for patients with ER-positive disease, in some ways, it's difficult to be able to tell them that they may be cured from their disease, and we continue to use the term they remain disease-free. So remind me of your question.
Schapira: The question is: [what is] the rationale for including these CDK4/6 inhibitors in the adjuvant setting? And I think what you've said is that they were found to be so effective in the metastatic or advanced cancer setting, that it's logical to think that they would be brought forward since we are still looking for ways of preventing or delaying late recurrences.
Wolff: Absolutely. And I think all of us expected it. I mean, for the most part, every time that we have done clinical trials in patients with advanced disease, and we see improvements in progression free and overall survival and the drugs become approved for patients with metastatic disease, that it's simply going to be a matter of time. Let's just launch the studies to show a clinically meaningful disease-free survival or invasive disease-free survival benefit. Let's aim for a hazard rate of 0.75, which implies a 25% reduction in the risk of recurrence. And it's just a matter of time, and we're going to see positive results.
Wolff: Lidia, would you allow me to say: I have no idea; is that OK? And I actually am joking when I say this, but I'm serious in the sense, actually, I tell my patients very often it's things like, I don't know, I don't think I know exactly what is happening.
There have been actually four trials of CDK4/6 inhibitors in the adjuvant study. Three of them have been reported with two of the drugs. The first one was the results around June of 2020 were the data, the press release for the financial markets of the data from monarchE showing that they had matched the primary objective. But then soon after, another data safety and monitoring release from PALLAS with palbociclib initially also triggered by the need to reform financial markets, that there were no benefits.
So early on, we had data and science by press release without seeing the actual data. We knew that the patient population of both studies were a little bit different in that in monarchE there was a much higher risk patient population. PALLAS included a patient population with ER-positive disease with a lower anatomic risk, and also included a number of patients in PALLAS that had node-negative disease. And that number was capped at about 1000 patients to make sure that we did not end up including a larger number of patients with lower risks that could ultimately make the study be underpowered.
For full disclosure, I have no financial interest in any of these three drugs, but I am on the steering committee of PALLAS, so I have been involved from the beginning in the design of policy, and I think many of us were surprised and disappointed in some ways. I remember writing about this, and I think the way I wrote it was, "the data from PALLAS was a mix of surprise and disappointment." But then we were compounded by the astonishment and hope when we had the data from monarchE with abemaciclib in the higher-risk population.
Even today, after those studies have been published, there have been publications with subsequent follow-up and essentially final analysis at least for PALLAS. And then, we have the data of Penelope-B for a higher-risk population with who had received neoadjuvant therapy and then had residual disease at surgery with ER-positive disease were then given a year of palbociclib versus not. So the same drug used for PALLAS and Penelope-B was also a negative trial. I don't think we know exactly what is happening.
There's a third study in both. So, Penelope-B was a year of post-neoadjuvant palbociclib. PALLAS with palbociclib and monarchE, with abemaciclib, two years of adjuvant therapy versus not. And we have a third study that has not yet reported, which is the NATALEE. NATALEE is the study with ribociclib for a longer duration of about three years of therapy, and I think we all awaited major interest the data from NATALEE.
Schapira: So, just to be clear, with our listener, PALLAS uses palbociclib, and NATALEE uses ribociclib, and monarchE uses abemaciclib. Correct. Now my final question to you is at the moment in the U.S. since October of 2001, when the FDA approved one of these drugs, only abemaciclib for use with either tamoxifen or aromatase inhibitors for patients at high risk of relapse, which they define as KI67 greater than 20 percent. This is now an open question, right? And patients will come to you with a recommendation for a recommendation. So, what is your practice? What is the Johns Hopkins group doing in general? Do you have this conversation, and do you limit the conversation to the use of just one of these drugs, abemaciclib which is FDA approved and for the duration that was given to these women in the study?
Wolff: Yeah. So this is a great question, and I'm going to make an advertisement here for all the listeners to actually go on the JCO website and download a rapid communication by Melanie Royce and FDA colleagues, which was published in the JCO a couple of weeks ago. It's available online. So, this is the FDA approval summary of abemaciclib with endocrine therapy for high-risk early breast cancer. So, for full disclosure here. So actually, together with Dr. Schapira, we are both on the editorial board of the Journal of Clinical Oncology. And so, the FDA has on a routine basis, published their approval summaries, highlighting, explaining their rationale going above and beyond what you can see on the package insert. And there has been so much noise and so much, so many questions about the approval for abemaciclib that I think those of us in the JCO knew that this was going to be a highly well-read and highly cited and receive with great interest by the public. So, the JCO invited our FDA colleagues to publish their approval summary in the JCO, and I'm so glad that they did, and I really recommend that all of you read it. It's very well written.
So, the only drug that we can use in the adjuvant setting at this point is abemaciclib; it’s the only one that has FDA approval is the only one that would be reimbursed by insurance.
The monarchE was a study for patients with ER-positive, HER2-negative, node-positive breast cancer. There are no patients with node-negative disease, and there were two separate cohorts. One was a cohort with a high anatomic risk, which implies at least four positive lymph nodes, or 1-3 positive lymph nodes, N1 disease, if they had high grades or T2 lesion. So T2 N1 or N1 with high grade or N2 disease with more than four positive nodes. That was cohort one, and that's the majority of patients.
There was a second cohort, Cohort 2, of patients with 1-3 positive lymph nodes and a high KI67. And where does KI67 come from? KI67 is another way to assess proliferation — another way to assess grades and correlates well with grade, and it gives a prognostic marker. Again, going along with high proliferative high-grade tumors more likely to have a higher risk of recurrence as a prognostic marker. What we did not know and have questions is whether this can also be predictive of a differential benefit; whether high-grade tumors differentially benefit from specific therapies the same way that HER2-positive status predicts for clinical benefits from anti-HER2 therapies while in HER2-negative disease, you don't see a clinical benefit. The question here becomes whether KI67 is a predictive marker or is it simply a prognostic marker — the higher your risk of recurrence, the more likely you're going to see an absolute benefit from an intervention. But the Cohort 2, with smaller anatomic risk and higher KI67 contributed to only a small number of events. It was late in being introduced and a lower number of patients on that arm.
When the data was published initially, the first interim analysis, which is the one that was reported, was initially published in the JCO in 2020, so about a year and a half ago, the study maps the primary objective in the what's called the ITT — the intent to treat population that included patients with both cohorts 1 and 2, and there was an improvement in invasive disease-free survival. But the FDA and they go very nicely to explain their rationale, there was only a small number of patients. Only 12 percent (12.5%) of patients completed adjuvant therapy at the time of the interim analysis that led to the release of the data. Only one eighth or 12 percent of the patients had completed two years of adjuvant treatment. And then, in the next analysis, with the overall survival in the first interim analysis for overall survival, 72 percent of patients have completed two years of therapy. So essentially, a lot of the data we did not have actually all patients completing their treatments.
One of the concerns that was ultimately raised by the FDA is that in the invasive disease-free survival data that have been released thus far, you do see a non-statistical numerical increase in events, in survival events, on the abemaciclib group. So, it appears that it crossed the unit, the confidence interval passes one, but ultimately it appears that there could be a deleterious survival benefit for patients treated with abemaciclib, a drug that is associated with toxicity. And this ultimately led the FDA on the basis of a pre-planned analysis to give a label indication exclusively to patients was a combination of factors. So essentially, it is the population in cohort 1 that has a high anatomic risk, but also a group of patients that have a high biologic risk with a high KI67. So, because of the current concerns about a potential worse overall survival for patients were treated with abemaciclib, and whether this has anything to do with toxicities, we do not know yet. So, I think that explains why the FDA took a more conservative approach in their label indication. And in fact, I actually commend what the FDA did.
And it is even possible that if, ultimately, if the overall survival data on maturity turn out to be unfavorable for the ITT population or the indicated population, then that would be a signal for a potential detriment for this curable population and may warrant a withdrawal of the current approval.
And I actually was impressed that the FDA made that statement because, again, it goes back to what I mentioned before with the challenge that we as individuals, humans, physicians, patients have with taking something away because, in this case, an approval has been given. It is our hope; we want to give treatments to patients because it is going to improve outcomes, and we were so hopeful, based on the metastatic data, that we would see similar impact in patients with early-stage disease and the data from various clinical trials are contradictory or conflicting at this point. And what the FDA is saying here, we see enough today to release the drug for a very high-risk population. But we need to be aware that further follow-up things may change, and we may need to be prepared to withdraw that approval. It goes back to what I mentioned earlier, the endowment effect. It's very difficult to take something away, but sometimes that may be what we need to do. I hope it doesn't happen, but I think we need to keep our eyes open.
Schapira: Well, Antonio, this has been a fascinating conversation on both topics, and I certainly know that I've learned a lot from you, and I'm sure our listeners have as well. So, I would like to thank you and for your time and your wisdom, as always.
Wolff: So kind of you. It was a treat to be here today. Thank you.
Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE)
Tamoxifen for early breast cancer: an overview of the randomised trials
Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03)
Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer—The Penelope-B Trial
Verzenio® (abemaciclib) Significantly Reduced the Risk of Cancer Returning in People with High Risk HR+, HER2- Early Breast Cancer
Pfizer Provides Update on Phase 3 PALLAS Trial of IBRANCE® (palbociclib) Plus Endocrine Therapy in HR+, HER2- Early Breast Cancer
NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC)
FDA Approval Summary: Abemaciclib With Endocrine Therapy for High-Risk Early Breast Cancer
Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study
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Cite this: DCIS and Low-Risk, Early-Stage Breast Cancer Part 2 - Medscape - Mar 31, 2022.