ASCO 2022: When The Dust Settles, What Are My Treatment Options For ER+/HER2- MBC?
This is part 2 of our 2-part series, we call ASCO 2022: When The Dust Settles. Our senior producer Victoria Goldberg is joined by the co-host , Kate Pfitzer and the friends of this podcast, three prominent clinicians and thought leaders in the field of breast cancer, Doctors Stephanie Graff, Sara Hurvitz, and Kevin Kalinsky. We’ve seen a lot of interesting data come out of 2022 ASCO in the metastatic hormone receptor-positive setting and are very eager to discuss survival data from PALOMA-2 and MONARH-3, the emergence of oral SERDs from the EMERALD trial, and the data from a small but very interesting phase 2 MAINTAIN trial. In the next hour you will get a lot of information and some of it might be somewhat complex. So in order to make it a little less overwhelming, here is a list of questions we will attempt to answer in this episode
What does the new survival data from mean PALOMA-2 and MONARCH-3 trials mean for the clinicians in how they view the 3 CDK4/6 inhibitors and the impact for patients in how the treatments are selected for them?
We have a definitive answer to what is to be used in the first-line setting. It is one of the 3 FDA approved cdk4/6 inhibitors in combination with hormonal therapy, but what about the second-line setting. Should CDK4/6 inhibition continue after the disease progression? Will the data from the MAINTAIN trial help us answer this question?
What are the strategies for a patient who progresses after a CDK4/6 inhibitor. At what point should a patient be tested for acquiring ESR1 or PI3 kinase mutations? What is the role of chemotherapies and the newly approved antibody drug conjugates?
SERDs [selective estrogen receptor degraders], and especially oral SERDs are exciting new therapies. There has been so much hope placed in these agents. We’ve been waiting for better endocrine therapies and the opportunity to have an oral agent instead of the intermuscular fulvestrant [Faslodex]. And so We’ve been eagerly awaiting data from the EMERALD trial , which had compared the oral agent ela’cestrant with endocrine therapy of physician’s choice. Based on the results from this and other trials, what does the future look like for this class of drugs
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313476/
Key Questions Answered [from the transcript]
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The approval of Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors changed the treatment landscape for patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Currently approved agents include palbociclib (palbo), ribociclib(Ribociclib) and abemaciclib (abema) which are all approved for concurrent use with hormonal therapy based on the randomized phase III trials PALOMA, MONALEESA and MONARCH studies respectively. These agents have significantly improved progression free survival when combined with anti-estrogen therapy compared to monotherapy with anti-estrogen therapy. Some agents have also shown statistically significant improvement in overall survival in the metastatic setting.
Cyclins and CDKs are essential in regulating the progression through the distinct phases of the cell cycle, G1, S, G2 and M phases and hence play an important role in regulating cell cycle transitions. CDKs are serine/threonine kinases which are regulated by their interactions with cyclins and CDK inhibitors. CDK activity is often dysregulated in cancer cells and hence they are an attractive target for anti-cancer therapy. In human cells, there are 20 CDKs and 29 cyclins
The CDK 4/6 inhibitors fall into two broad categories based on their toxicity profile and the dose –delivery schedules. Palbociclib and ribociclib both have >24-hour half-lives and are dosed daily. Abemaciclib has a shorter half-life and is dosed twice daily. Due to their myelosuppressive effects, Palbociclib and ribociclib are dosed daily for 21 days followed by a one- week break to enable neutrophil count recovery in patients. Abemaciclib is dosed continuously without a break and is associated with lower incidence and less severe bone marrow suppression compared to the other agents
Even though all three drugs have a similar mechanism of action, they have varying side effect profiles. The differential targets of these drugs, especially the relative potency of CDK4 vs CDK6 and are most likely responsible for the different dose limiting toxicities (45). Some of the pertinent side effects for each of the drugs are as follows: Neutropenia, leukopenia and fatigue for palbociclib; neutropenia, increased creatinine, hyponatremia, QTc prolongation for ribociclib; diarrhea and fatigue for abemaciclib.
From Transcript
Sara Hurvitz: there are a lot of theories as to why the two drugs, ribociclib and abemociclib, demonstrated significant overall survival benefits in multiple trials.
Ribociclib has been associated with overall survival benefits in three trials. Abemaciclib demonstrated overall survival benefit in the MONARCH-2 study. And they're getting very close to showing survival benefit in MONARCH-3 that was presented at ESMO a few months ago.
A lot of people are saying, Well, it's the study design. They enrolled patients. who weren't likely to show benefit, they also lost a lot of patients to the follow up, so there's a lot of missing data for patients who didn't have survival , but, I'm beginning to wonder whether or not it has to do with the drug itself. It’s a different drug. It's very well tolerated. Probably the best tolerated of all three cdk4/6 inhibitors, but it's not as potent, it doesn't spend as much time inhibiting the cyclin dependent kinases, as the other drugs do. and it may just not be the best drug of the three. And if you look at the early stage setting, palbociclib was tested in patients with non-metastatic breast cancer in two clinical trials and failed to demonstrate any benefit by adding the palbo to endocrine therapy and early stage disease.
On the other hand, abema did show benefit. So we're getting a number of trials now, PALOMA-2, PALOMA-3 with no significant survival benefit. , and PALLAS and PENELOPE-B showing no significant benefit at all with palbo in the early stage setting. And this is beginning to distinguish palbo.
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From the Transcript
Stephanie Graff
1.. PALOMA-2 failed to show an overall survival advantage of adding palbo to Letrozole for metastatic ER-positive breast cancer. The primary endpoint of the study was median progression-free survival, the co-end point was overall survival. Overall survival was not met. I consider this a negative study.
2. If you are currently living with metastatic breast cancer and have been on palbocyclib for more than a minute, keep taking it. Do not freak out. It's okay.
3. When you look at palbociclib, ribociclib, and abemaciclib across trials, they all had very similar median progression free survivals. Which tells us that they're all active drugs in a hormone receptor positive metastatic breast cancer. I am so thankful for palbo because we had it first. We had it for years before we had the others. It has maybe a little bit better, maybe a little bit different side effect profile than the others.
For lots of patients the out of pocket cost is favorable for palbociclib compared to the others. And if for no other reason than that, it was the trailblazing compound that is really important and deserves to be celebrated. That deserves a standing ovation. But I can't in the same breath say that they all showed similar median progression-free survivals. So they're all the same and they didn't all show overall survival, so it's okay. You can't cross trial compare to say they're the same and then not cross trial compare to say that they're different. You can't look at the median progression-free survival being the same and say they're all the same and then look at the side effects and say they're all different, so they're all different. We can't do that. That's not how science works. We know that abemaciclib causes diarrhea and ribociclib prolongs the QT interval. We know that abemaciclib Improves overall survival, adjuvant and metastatic
Ribociclib is positive in the metastatic setting and positive in adjuvant setting. Palbo is negative in the adjuvant setting and negative in the metastatic setting and doesn't affect QT interval or diarrhea to the degree that the other two drugs do. We have to accept that there's a chance that these drugs just interact with their targets differently,
4. But back to the people who are currently taking it today, there's a lot different about these trials. There are differences in compliance with the medicine. There are differences in dose modification. There are differences in the type of patients, like how many lines of prior therapy, how recently they had had endocrine therapy, what timeframe in pandemic life and CDK 4/6 inhibitor life, fulvestrant versus aromatase inhibitor versus tamoxifen , there are so many differences that if you are on a medicine and it is controlling your cancer and it is working for you and you are tolerating it, do not stop it because all you're gonna do is build resistance to the medicine you stopped. And we know from the MAINTAIN trial, which I'm sure you're getting ready to talk about.
5. Final point is for me, at the end of the day when I sit down in a clinic to talk about this for patients They're gonna look at me and say, Doc, which one would you take? Which one would you give your sister?Which one would you give your mother? And I can't explain why PALOMA-2 being negative isn't a huge deal because it matters. And to try to nuance that for 45 minutes, one on one with a patient isn't right for the patient and isn't right for me sleeping at night. Yeah. So it's gonna change It's gonna change my prescribing habit.
I previously used a lot of palbocyclib honestly, transparently because of insurance, red tape, a lot of the times palbo was the simplest one to get., and now I'm not.
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From the transcript
Stephanie Graff
So for a patient that has a baseline prolonged QT interval, for a patient who had terrible diarrhea with their adjuvant chemotherapy and says never again, for a patient who's on three or four or seven medicines for depression, anxiety, bipolar, et cetera, who I can't add ribociclib because of the drug drug interactions.
These are real things that happen in oncology clinic I have palbo in my pocket for a patient I start on abemaciclib and who poops for two weeks straight and comes in and says, We are not talking about dose reductions. We're talking about a new medicine for me, Dr. Graff. I will say, okay.
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Sara Hurvitz [from the transcript]
No, because the vast majority of patients do experience disease progression at some point.
I have a patient who's been on palbo for over 12 years. she was on the trio-18 study for the first trial that evaluated this combination, but we don't have evidence that she's cured or that a patient's cured by this and the majority of patients aren't having complete responses, you can still see some level of evidence of the disease.
So until we have better evidence, suggesting that you can distinguish those patients who will have a long term durable remission, I think you have to continue them on therapy unless they are not tolerating it for some reason. Now, in HER2-positive disease, there are patients who have complete responses.
You can't see any cancer whatsoever on imaging. , there was a patient. Dr. Slaman’s trial back in the nineties, one of the earliest trials of Trastuzumab, , who did probably achieve a curewith HER two positive disease. But the pace of disease and the biology of the disease are very different when the tumor is HER2-positive.
With ER-positive disease, it can become indolent and be quiet or dormant for many years before coming back. So stopping therapy early may actually impair a patient's long-term survival. We just don't know. So if a patient is tolerating things well, I would be reluctant to just take them off of therapy.
Glossary
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Used to block the activity of an enzyme called aromatase, which the body uses to make estrogen in the ovaries and in other tissues. Aromatase inhibitors are used primarily in postmenopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively. However, these drugs can be used in premenopausal women if they are given together with a drug that suppresses ovarian function.
Examples of aromatase inhibitors approved by the FDA are anastrozole (Arimidex) and letrozole (Femara), both of which temporarily inactivate aromatase, and exemestane (Aromasin), which permanently inactivates aromatase.
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QT interval prolongation is an abnormality of the electrical activity of the heart, which places individuals at risk for life-threatening ventricular arrhythmias, including torsade de pointes (TdP) and sudden cardiac death.
Women with mBC may take medications that can increase the risk of drug-induced toxicities, including prolongation of cardiac repolarization (prolongation of QT interval).
Corrected QT (QTc) prolongation, a toxicity associated with many cancer treatments, can lead to potentially life-threatening ventricular arrhythmias. As such, it is important to identify patients at risk for QTc prolongation due to comorbid conditions, concomitant medications, or electrolyte abnormalities.eal-world data show that a large proportion of patients with HR+/HER2‒ mBC, specifically older women, have risk factors for QTc prolongation. Knowledge of the real-world propensity for QTc prolongation and common risk factors in women with HR+/HER2‒ mBC are of significant interest when assessing the benefit/risk profile of treatment options. Assessing QTc prolongation risk when making treatment choices as part of individualized care for women with mBC is becoming even more critical with the increase in treatment options.
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Cyclins and CDKs are essential in regulating the progression through the distinct phases of the cell cycle, G1, S, G2 and M phases and hence play an important role in regulating cell cycle transitions. CDKs are serine/threonine kinases which are regulated by their interactions with cyclins and CDK inhibitors. CDK activity is often dysregulated in cancer cells and hence they are an attractive target for anti-cancer therapy. In human cells, there are 20 CDKs and 29 cyclins (8). CDK1, CDK2, CDK3, CDK4, CDK6, and CDK7 directly regulate cell-cycle transitions and cell division, whereas CDK 7–11 mediate cell-cycle associated gene transcription
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Hormone therapy (also called hormonal therapy, hormone treatment, or endocrine therapy) slows or stops the growth of hormone-sensitive tumors by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells. Tumors that are hormone insensitive do not have hormone receptors and do not respond to hormone therapy.
Hormone therapy for breast cancer should not be confused with menopausal hormone therapy (MHT)—treatment with estrogen alone or in combination with progesterone to help relieve symptoms of menopause. These two types of therapy produce opposite effects: hormone therapy for breast cancer blocks the growth of HR-positive breast cancer, whereas MHT can stimulate the growth of HR-positive breast cancer. For this reason, when a woman taking MHT is diagnosed with HR-positive breast cancer she is usually asked to stop that therapy.
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(my-TOH-sis) The process by which a single parent cell divides to make two new daughter cells. Each daughter cell receives a complete set of chromosomes from the parent cell.
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Oral selective estrogen receptor degraders (SERDs) are a developing group of medications for estrogen receptor-positive breast cancer.
The only SERD that’s FDA approved is an injection called fulvestrant (Faslodex). Many oral SERDs are being studied in clinical trials, but none of them are FDA approved yet.
Elacestrant is an oral SERD that’s pending FDA approval. It helped improve the time without seeing cancer growth in certain people with advanced breast cancer in clinical trials.
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The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. In a clinical trial, measuring the overall survival is one way to see how well a new treatment works. Also called OS.
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The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works. Also called PFS
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Drugs, such as fulvestrant (Faslodex), work in a somewhat different way to block estrogen’s effects. Like SERMs, fulvestrant binds to the estrogen receptor and functions as an estrogen blocker. However, unlike SERMs, fulvestrant does not mimic estrogen. For this reason, it is called a pure antiestrogen. In addition, when fulvestrant binds to the estrogen receptor, the receptor is targeted for destruction.
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Bind to estrogen receptors, preventing estrogen from binding. Examples of SERMs approved by the FDA for treatment of breast cancer are tamoxifen (Nolvadex) and toremifene (Fareston).
Because they bind to estrogen receptors, SERMs can potentially not only block estrogen activity (by preventing estrogen from binding to its receptor) but also mimic the effects of estrogen, depending on where they are expressed in the body. For example, tamoxifen blocks the effects of estrogen in breast tisue but acts like estrogen in the uterus and bone.
Hormone Therapy Fact Sheet
Novel Therapies Mentioned in the Episode
Trastuzumab Deruxtecan (Enhertu or TdxD)
Elacestrant (oral selective estrogen receptor degrader)
Sacituzumab Govitecan (Trodelvy)
CDK4/6 inhibitors - palbociclib [Ibrance], ribociclib [Kisqali] , and abemaciclib [Verzenio]
Venetoclax - potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior endocrine therapy (VERONICA trial)
Avelumab
Clinical Trials Mentioned in this Episode
MAINTAIN - randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer [NCT02632045]
EMERALD - randomized phase III trial of elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer[]NCT03778931
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) [NCT03701334]
PACE - a multicenter phase II trial randomizing pts 1:2:1 to Arm A: fulvestrant alone (with option for palbociclib monotherapy crossover at time of progression);Arm B: fulvestrant and palbociclib; or Arm C: fulvestrant, palbociclib, and avelumab.[NCT03147287]
PALLAS - randomised open-label phase III study of Palbociclib with adjuvant endocrine therapy in early breast cancer
PENELOPE-B - double-blind, placebo‐controlled, phase III study in women with hormone receptor–positive, human epidermal growth factor receptor 2–negative primary breast cancer without a pathological complete response after taxane‐containing NACT and at high risk of relapse [NCT01864746]
VERONICA - randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC) [NCT03584009]
postMONARCH - phase 3 study of abemaciclib plus fulvestrant versus placebo plus fulvestrant in patients with HR+, HER2-, metastatic breast cancer following progression on a CDK4 & 6 inhibitor and endocrine therapy [NCT05169567]
Overview of the clinical trials for the approved CDK4/6 inhibitors in the metastatic setting.
Clinical Activity of the CDK4/6 inhibitors in different clinical settings.
Want More?
If you have not done so already, listen to our past interviews with the guests of this episode as well as ASCO 2022-related content.
Meet the Guests of this Episode
Sara Hurvitz, MD, FACP
Dr. Hurvitz is an associate professor at the David Geffen School of Medicine at UCLA; medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit; co-director of the Santa Monica-UCLA Outpatient Oncology Practices; and director of the Breast Cancer Clinical Trials Program at UCLA. She is also a member of the American Society of Clinical Oncology and the American Association of Cancer Research, and is a fellow of the American College of Physicians.
Dr. Sara Hurvitz is a medical oncologist who specializes in the treatment of women with breast cancer, and is involved in designing, implementing and leading national and international clinical trials to test new targeted therapies. She is board certified in internal medicine and medical oncology.
Dr. Hurvitz maintains a robust clinical and translational research portfolio, for which she has won numerous awards over the years, including the Marni Levine Memorial Breast Cancer Research Award in years between 2008 and 2015. She currently leads the Translation Oncology Research Laboratory at UCLA in the preclinical evaluation of novel breast cancer targets.
Dr. Hurvitz earned her medical degree from the University of Southern California School of Medicine. She then completed her internal medicine residency at UCLA, serving as chief resident, followed by her hematology/oncology fellowship at UCLA.
Kevin Kalinsky, MD, MS
Dr. Kalinsky is an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. He serves as the director of the Glenn Family Breast Center at Winship where he is tasked with fulfilling the vision to improve breast cancer outcomes by aligning research and education with cancer treatment and prevention. Dr. Kalinsky received his medical degree from the Medical University of South Carolina and a Masters in Biostatistics, Patient Oriented Research Track from Columbia University Mailman School of Public Health. His training included a Residency and Medical Oncology Fellowship at Tufts-New England Medical Center, Breast Cancer Research Fellowship at Massachusetts General Hospital, and Breast Cancer Advanced Oncology Fellowship at Memorial Sloan-Kettering Cancer Center. Dr. Kalinsky's research involves the development of early-phase clinical trials to assess novel therapeutics in breast cancer based on tumor genomics. He has received the NCI Cancer Clinical Investigator Team Leadership Award, Physician of Impact Award by Komen Greater NYC, Ewig Clinical Scholar Teaching Award, and SWOG Career Engagement Award.
Stephanie Lynn Graff, MD, FACP
Dr. Graff is the Director of Breast Oncology at Lifespan Cancer Institute at the Legorreta Cancer Center at Brown University in Providence, Rhode Island.
Dr. Graff serves as co-lead of the Breast Cancer Translational Research Disease Working Group at Brown University and is an Assistant Professor of Medicine at the Warren-Alpert School of Medicine. In Dr. Graff is a medical advisor to the Dr. Susan Love Foundation for Breast Cancer Research.
Dr. Graff is board certified in Medical Oncology, Hematology, and Internal Medicine; and completed a breast oncology sub-fellowship at the University of Kansas. Dr. Graff is a PI on numerous clinical trials in addition to her work in translational research, genomics, and gender bias.
She is an award-winning writer, social media influencer, and sought-after public speaker. Dr. Graff has received the Frist Humanitarian Award for her work in the community and the Benjamin L. Sapers Memorial Award for her “passion for pedagogy, academic rigor, empathy and humanism, with profound feeling for the person as patient.”
Ultimately, Dr. Graff is passionate about connecting with her patients to provide personalized, comprehensive oncology care, advancing breast cancer research, and breast cancer prevention.
