Report Back from ASCO 2022: What’s the Latest in MBC Research?
Episode Notes
The record number of oncologists, scientists, patient advocates, and everyone in between were eager to attend the American Society of Clinical Oncology (ASCO) 2022 annual meeting and descended upon Chicago, Illinois early in the month of June to hear the latest research findings in cancer care. About 31,000 of them were able to rest from the Zoom fatigue and put their physical stamina to the test trekking the vast McCormick Place, sections of which were transformed into field hospital wards when the pandemic hit in 2020.
I have no doubt the by now you have heard that some of the research highlights presented this year are “practice-changing.” In fact, a plenary presentation for Destiny-Breast04 clinical trial received a rarely given standing ovation. In breast cancer, was is worthy of a standing ovation? What practice is it changing? We are eager to hear the answer to these questions and a lot more in the report back from ASCO
Just like the conference itself, the report back from ASCO has become an annual event and a tradition at SHARE. Shortly after the conference my co-producer of the Our MBC Life podcast Natalia Green and I welcomed Dr Niel Iyengar to SHARE to talk about the main highlights in Metastatic Breast Cancer from 2022 ASCO. We are thrilled to be able to bring it to you as a bonus podcast episode.
It would be negligent to not comment on the most thrilling event during this exhilarating conference, which was the reveal of the trastuzumab deruxtecan (Enhertu) data from the DESTINY-Breast04 trial in HER2-low metastatic breast cancer, presented by Dr. Shanu Modi of MSKCC. With a near doubling of median progression-free survival (mPFS) (5.1 to 9.9 months) in all patients, irrespective of hormone receptor (HR) status, it was clear that this was game changing data. The announcement elicited even more excitement as the overall survival (OS) and HR- cohort data was revealed. Median overall survival (mOS) in the overall Enhertu treated population was 23.4 months (compared to 16.8 months) and even more surprising was the 18.2-month OS in the HR-/HER2-low subgroup (previously defined as triple negative breast cancer, or TNBC) compared to the dismal 8.3 months with chemo. Not only will this data immediately impact the treatment paradigm, but it will also shake up how we segment breast cancer patients by defining a new sub-segment of HER2-low disease (which comprises ~50% of all breast cancers). This also raises the question, do we need better diagnostic tools to stratify these patients based on HER2 quantification? The answer is yes, as current immunohistochemistry (IHC) methods were shown to miss patients who could potentially benefit from Enhertu. Add Enhertu into into the toolbox along with PARP, HER2, CDK4/6 inhibitors, and checkpoint inhibitors, and the future is looking a bit brighter for all breast cancer patients. “It is no surprise that following the presentation the entire plenary hall erupted in a standing ovation to celebrate not the presenter, not the data itself, but the implications for individuals who suffer and will suffer from the crippling diagnosis of metastatic breast cancer,” as Karson Kump wrote in the Health Advances Blog
Subjects and Terms Included in This Episode
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In scientific literature and trial results announcements, a p value of less than 0.05 generally is set as a benchmark to determine whether findings are "statistically significant," but the lay people often make the mistake of conflating that number with clinical significance, P values don't tell anything about clinical benefit. They only show how likely results are to be true and not a play of chance. A p value of <0.05 does not necessarily indicate that a treatment is effective. It means that one illegitimate effect (false-positive result) is expected in every 20 comparisons.
Researchers can conduct a trial in 2,000 patients and identify a difference of a few days in survival. It might be statistically significant, but it's not clinically important. When you try to see this same small difference in the general patient population, the effect is smaller and the toxicity is higher.
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The Kaplan-Meier curve is and. what it is used for. It shows the probability that a subject will survive up to time t. The curve is constructed by plotting the survival function against time.
The curve displays both those participants who have had the event, and the duration on study of those who have not yet had the event. The x-axis shows time, and the y-axis shows the proportion of patients who have or have not had the event. So at x=0 (the start of the trial) and y is 100%. The curve is downward sloping.
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HR = hazard in treatment arm
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Hazard in control arm
In clinical research, hazard ratios are often used in clinical trials to measure survival at any point in time in a group of patients who have been given a specific treatment compared to a control group given another treatment or a placebo. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of greater than one or less than one means that survival was better in one of the groups.
What does a hazard ratio of 0.75 mean? Interpretation of a Hazard Ratio. HR (E vs C) = 0.75 for an overall survival end point. This means on average, under an exponential distribution, approximately • a 25% lower risk of death (25% as 1 − 0.75 = 0.25)
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Randomized controlled trials (RCT) are prospective studies that measure the effectiveness of a new intervention or treatment.
A study design that randomly assigns participants into an experimental group or a control group. As the study is conducted, the only expected difference between the control and experimental groups in a randomized controlled trial (RCT) is the outcome variable being studied.
Advantages
Good randomization will "wash out" any population bias
Easier to blind/mask than observational studies
Results can be analyzed with well known statistical tools
Populations of participating individuals are clearly identified
Disadvantages
Expensive in terms of time and money
Volunteer biases: the population that participates may not be representative of the whole
Loss to follow-up attributed to treatment
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In a randomized trial some study participants will be assigned to a “control arm” or “control group” in the study.
Those who are in the control arm will not receive the new treatment that is under study, to provide a comparison to see how the innovation compares against an old treatment. Members of the control group in MBC trial will receive the standard of care treatment and never placebo alone.
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An arm type in which a group of participants receives the intervention/treatment that is the focus of the clinical trial.
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Overall survival refers to the fact that a patient has not died from any cause. Thus, in a clinical trial the measure of overall survival would compare the number of patients who had died and the number who had not died.
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Progression free survival refers to survival without progression of the disease. In a clinical trial a measure of progression free survival would compare the number of patients whose disease had progressed (got worse) with the number whose disease had had not progressed.
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Clinical trial endpoints can be classified as primary or secondary. The primary endpoint is the most important outcome and is used to assess the primary objective of a trial.
Primary endpoints measure outcomes that will answer the primary or most important question being asked by a trial, such as whether a new treatment is better at preventing disease-related death than the standard therapy33.
Secondary endpoints answer other relevant questions about the same study; for example, whether there is also a reduction in disease measures other than death or outcomes rated by patients such as quality of life
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Antibody–drug conjugates (ADCs is anew class of anticancer agents, capable of exploiting the specificity of monoclonal antibodies toward cellular-antigens for a targeted release of potent cytotoxic drugs, with a potential increased activity and reduced toxicity compared with traditional chemotherapies.
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A type of protein that is made in the laboratory and can bind to certain targets in the body, such as antigens on the surface of cancer cells. There are many kinds of monoclonal antibodies, and each monoclonal antibody is made so that it binds to only one antigen. Monoclonal antibodies are being used in the treatment of breast cancer. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells.
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A substance that kills cells, including cancer cells. These agents may stop cancer cells from dividing and growing and may cause tumors to shrink in size.
Chemotherapy drugs are made to kill all the cells that are growing fast—even normal cells. However, not all drugs that treat cancer are cytotoxic. New treatments like targeted therapies and immunotherapies are not cytotoxic. Instead, they work by getting in the way of a cancer cell's growth.
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Antibody drug conjugates (ADCs) employ the exquisite specificity of tumour-specific monoclonal antibodies (mAb) for the targeted delivery of highly potent cytotoxic drugs to the tumour site. The chemistry of the linker, which connects the drug to the mAb, determines how and when the drug is released from the mAb. This, as well as the chemistry of the drug, can dictate whether the drug can diffuse into surrounding cells, resulting in ‘bystander killing’. Initially, any bystander killing mechanism of action of an ADC was understood to involve an essential sequence of steps beginning with surface antigen targeting, internalisation, intracellular linker cleavage, drug release, and diffusion of drug away from the targeted cell. However, recent studies indicate that, depending on the linker and drug combination, this mechanism may not be essential and ADCs can be cleaved extracellularly or via other mechanisms.
Novel Therapies Mentioned in the Episode
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Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
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Sacituzumab govitecan-hziy is an antibody–drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.
More on CDK4/6 inhibitors
The MANTAIN study gave us a first legistimate answer to the question that everyone has been asking - “Is there a difference in the 3 cdk4/6 inhibition therapies? Should they be sequenced?” Considering the data from the MAINTAIN trial when patients received ribociclib with a new endocrine therapy partner after progression under any CDK4/6 inhibitor administered together with endocrine therapy, the answer seems to be yes, and patients should be offered ribociclib after progressing on a different cdk4/6 inhibitor, like ibrance for example.
This ASCO heard a presentation of the long awaited survival data on palbociclib, more commonly known as ibrance, to an AI in the first-line treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. The era of CDK4/6 inhibitors began at ASCO 7 years ago with the presentation of the primary endpoint, PFS from the same PALOMA-2 study. It confirmed efficacy of palbociclib, and almost doubled progression-free survival by addition of palbociclib to mono endocrine therapy letrazoole versus endocrine therapy alone (24.8 versus 14.5 months). Both the data from the MONALEESA-2 study (25.3 months) and the data from the MONARCH 3 study (28.8 months) confirmed the clear advantage in PFS with the addition of CDK4/6 inhibitors in HR-positive breast cancer in the metastatic setting. This therapy is now the standard of care in metastatic HR-positive HER2-negative breast cancer.
Positive OS data are already available for the MONALEESA-2 in postmenopausal women, as well as the MONALEESA-7 in premenopausal women and the MONALEESA-3 in combination with fulvestrant. In the second-line setting MONARCH 2 also reported positive OS data, while MONARCH 3 results on OS are still pending. Although CDK4/6 inhibitors as class improved overall survival (OS) of HR+/HER2– metastatic breast cancer patients, in the PALOMA-2 study, after 7.5 years of follow-up, results did not reach key secondary endpoint – OS and failed to show the overall survival benefit.There could be few reasons for this finding. One of the reasons could be significant dropout from the study, as even one third of patients were missing survival data – 13% of patients in the palbociclib arm and 21% in the placebo arm. The OS analysis was adjusted by exclusion of the patients missing survival data, which most most likely has provoked some bias. Further on, the PALOMA-2 study has included quite diverse patient population. 20% of the patients on the trial were less than 12 months out after they were treated for early stage diagnosis before they progressed to stage 4 that might indicate extremely aggressive and difficult to treat type of breast cancer. When the OS was analyzed solely in the subgroup of patients with disease free interval longer than 12 months, OS in the palbociclib group was 64 months compared to 44.6 months in the placebo group, which is comparable to the OS data from the MONALEESA-2 study, which confirmed significant OS prolongation by addition of CDK4/6 inhibitor ribociclib to the aromatase inhibitor. Two essential questions now arise for clinical practice: (1) How should the doctors deal with the patients who are currently on palbociclib? (2) Which of the 3 available CDK4/6 inhibitors should be offered to new patients?
To answer the first question: There is currently no data that indicates patients on palbociclib should be switched to another CDK inhibitor. If the patient tolerates the drug well, she should continue treatment (never change a winning team).
Concerning the second question: The already positive OS data on ribociclib and the OS data from the PALOMA-2 data now presented at ASCO must be taken into account in everyday clinical practice.Ribociclib resulted in the strongest OS data available so far, which is a fact that cannot be neglected. PALOMA-2 OS data of over 50 months for everyone and over 60 months in clearly endocrine-sensitive patients, positions palbociclib as full-fledged CDK4/6 inhibitor in the first-line treatment of endocrine-sensitive postmenopausal population, especially due its favorable toxicity profile, which makes it the optimal choice in old and fragile patients with lots of comorbidities.
Abstracts Presented at ASCO and Mentioned in the Episode
DESTINY-Breast 04 LBA3 Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): A randomized, phase 3 study (NCT03734029)
Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): Safety follow-up of the randomized, phase 3 study DESTINY-Breast03.(NCT03529110)
LBA1001 Primary results from TROPiCS-02: A randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor–positive/HER2-negative (HR+/HER2-) advanced breast cancer
LBA1003 Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2.
A 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 (MBC): MAINTAIN trial.
NRG-BR002: A phase IIR/III trial of standard of care systemic therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) for newly oligometastatic breast cancer (NCT02364557)
Meet the Guest of this Episode
Neil Iyengar, MD
Associate Attending Physician,Breast Medicine ServiceMemorial Sloan Kettering Cancer Center
New York, New YorkAssociate Attending Physician, Rockefeller University Center for Clinical and Translational Science and Weill Cornell Medicine, New York.
Research area - developing a personalized intervention platform which matches patients to relevant lifestyle modifications to reduce breast cancer risk.
Dr. Neil Iyengar is a board-certified Medical Oncologist and clinical-translational researcher at Memorial Sloan Kettering Cancer Center (MSKCC) where he specializes in the care of patients with breast cancer. Dr. Iyengar received his undergraduate and medical degrees from the University of Illinois at Chicago and completed residency training in Internal Medicine at the University of Chicago Medical Center followed by fellowship in medical oncology and hematology at MSKCC.
Dr. Iyengar’s research program investigates interventions to improve metabolic health as a strategy to reduce breast cancer risk and mortality. His group is testing the anti-cancer effects of structured exercise and nutritional interventions in people at high risk or diagnosed with breast cancer. Dr. Iyengar also leads the Healthy Living Program, a novel cancer care model that aims to translate research findings from lifestyle intervention trials into clinical practice during and after cancer therapy. His work has been recognized and awarded by several organizations, including research grants from the National Cancer Institute, American Cancer Society, the Breast Cancer Research Foundation, Conquer Cancer the ASCO Foundation, and others.
Twitter: @Neil_Iyengar
