FDA Grants Regular Approval to TRODELVY® for Advanced Triple Negative Breast Cancer

SUMMARY: The FDA on April 7, 2021, granted regular approval to TRODELVY® (Sacituzumab govitecan) for patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (mTNBC), who have received two or more prior systemic therapies, at least one of them for metastatic disease. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients and African American females. It is usually aggressive, and tumors tend to be high grade, and patients with TNBC are at a higher risk of both local and distant recurrence and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival of only 2-3 months.

TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.

The FDA granted accelerated approval to TRODELVY® in April 2020 based on Objective Response Rate of 33.3% and Duration of Response of 7.7 months in a Phase I/II study. The ASCENT trial served as a confirmatory analysis, expanding the previous TRODELVY® indication to include treatment in adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

The ASCENT study is an open-label, multicenter, active-controlled, randomized, confirmatory Phase III trial in which 529 patients with unresectable locally advanced or metastatic TNBC patients were enrolled. Eligible patients had relapsed/refractory disease and had received two or more prior systemic therapies (including a taxane), one of which could be in the neoadjuvant or adjuvant setting, if disease progression occurred within 12 months. Patients were randomly assigned 1:1 to receive TRODELVY® 10 mg/kg IV on days 1 and 8 of a 21-day cycle (N=267) or physician’s choice of single-agent chemotherapy (N= 262). The Primary endpoint was Progression Free Survival (PFS) in patients without brain metastases at baseline (N=468), as measured by a blinded Independent Centralized Review. Secondary endpoints included PFS for the total population (with and without brain metastases), Overall Survival (OS), Objective Response Rates (ORR) and Safety.

Among all randomly assigned patients (with and without brain metastases), the median PFS for patients receiving TRODELVY® was 4.8 months, compared with 1.7 months in those receiving chemotherapy (HR=0.43; P <0.0001). This represented a statistically significant and clinically meaningful 57% reduction in the risk of disease progression or death. The median OS was 11.8 months and 6.9 months respectively, in favor of TRODELVY® (HR= 0.51; P<0.0001), representing a 49% reduction in the risk of death. The most common adverse reactions in patients receiving TRODELVY® were fatigue, rash, decreased appetite, nausea, vomiting diarrhea, constipation, alopecia, anemia and abdominal pain.

It was concluded that ASCENT is the first Phase III study of an Antibody Drug Conjugate, with significant PFS and OS improvement over Standard-of-Care chemotherapy, in pretreated patients with metastatic Triple Negative Breast Cancer, fulfilling an unmet medical need.

ASCENT: A randomized phase III study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Bardia A, Tolaney SM, Loirat D, et al. ESMO Virtual Congress 2020. Abstract LBA17. Presented September 19, 2020.

Advances in Triple Negative Breast Cancer

Written by: Debra Patt, MD, PhD, MBA
Content Sponsored by: Bristol Myers Squibb
Dr. Patt is a paid consultant for BMS and was compensated for her contribution in drafting this article.

Metastatic triple negative breast cancer (TNBC) is a devastating disease, making up 15% of all cancers, and having a limited outcome with an overall survival average of around a year.1,2 It is a diagnosis of exclusion, as tumor cells do not express the targetable hormone receptors (estrogen or progesterone receptors) or HER2, thus treatment options have historically relied on systemic chemotherapy rather than targeted treatment.3 This aggressive subtype is often associated with an earlier age of onset and an aggressive clinical course. Ethnic disparities have been identified for triple negative disease, with the incidence highest among patients who have a non-Hispanic black ethnic background compared to other ethnic groups.1 Furthermore, African American women are more likely to develop metastases compared to women of other races. Metastatic progression for triple-negative disease is generally characterized by early relapse and predominantly visceral (including liver, pulmonary and central nervous system) metastases.3

Historically, advances in the treatment of triple negative breast cancer have been rare. Multiple immunotherapy options in combination with chemotherapy are now approved in metastatic TNBC for patients with PD-L1 positive, first-line disease, and today there is much excitement about further evidence supporting its use in the metastatic and early stage settings.4 However, no head-to-head data exists to identify the optimal chemotherapy partner for checkpoint inhibition and not all chemotherapy agents appear to provide similar efficacy based on current data, hence more investigations are needed.5,6 Furthermore, while the incidence of immune-related adverse events such as endocrinopathies are low, the permanence of these side effects, particularly in the early stage setting, is concerning to some and should be closely monitored.

Germline BRCA mutations occur in approximately 10–30% of TNBC cases.7 In previously treated metastatic disease, the use of poly (ADP-ribose) polymerase (PARP) inhibitors in germline BRCA mutation positive patients has also shown improvements in survival, with the main reported side effects being hematologic, fatigue and diarrhea.3,8 In heavily pretreated metastatic TNBC patients, the use of antibody-drug conjugates has also resulted in anti-cancer effects.9

While advances in the aggressive and difficult-to-treat triple negative breast cancer subset are promising, all of these recent advances leave us with new treatment options but also unanswered questions. Our knowledge is limited and certainly will improve over time as we understand better predictors of outcome like PD-L1 expression, tumor infiltrating lymphocytes, and other factors as well as the importance of chemotherapy backbone choice. Other agents are now available for previously treated metastatic TNBC patients and further studies will be needed to assess the efficacy of these agents in earlier lines of therapy. Additionally, long-term follow up of studies will also be important to truly understand the impact of these new targeted approaches and the impact of drug tolerability on efficacy and patient quality of life.

References
1. DeSantis CE, Fedewa SA, Sauer AG, Kramer JL, Smith RA, Jemal A. CA Cancer J Clin. 2016;66:31-42.
2. Marra A, Viale G, Curigliano G. BMC Medicine. 2019;17:90-99.
3. Bergin ART, and Loi S. F1000Research. 2019;8: F1000 Faculty Rev-1342. Published online 2019 Aug 2.
4. Simmons CE, Brezden-Masley C, McCarthy J, McLeod D, Joy AA. Ther Adv Med Oncol. 2020;12:1-15.
5. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, et al. DOI: 10.1200/JCO.2020.38.15_suppl.1000 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1000-1000.
6. Miles D, Gligorov J, Andre F, Cameron D, Schneeweiss A, et al. Annals of Oncology. 2020;31 (suppl 4):S1142-S1215. 10.1016/annonc/annonc325.
7. Vagia E, Mahalingam D, Cristofanilli M. Cancers (Basel). 2020 Apr;12:916-941.
8. Madariaga A, Bowering V, Ahrari S, Oza AM, and Lheureux S. Int J Gynecol Cancer. 2020; 30:903-915.
9. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, et al. N Engl J Med. 2019;380:741-751.

Sugar-Sweetened Beverages May Increase Breast Cancer Mortality

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. It is estimated that more than 3.5 million breast cancer survivors are alive in the US. Understanding risk factors and modifying lifestyle behaviors can impact outcomes in this patient group.

Consumption of sugar-sweetened beverages has significantly increased over the past 3 decades worldwide, increasing the risk of obesity, hypertension and Type 2 diabetes, and in turn impacting cardiometabolic health. It is estimated that among all worldwide yearly deaths from diabetes and cardiovascular diseases, over 178,000 were attributable to sugar-sweetened beverages consumption.

More recently published large prospective French study (BMJ 2019;366:l2408) concluded that consumption of sugary drinks was positively associated with the risk of overall cancer and breast cancer. It has been hypothesized that sugar-sweetened beverages contain large quantities of sucrose and fructose which promote visceral adiposity, which can boost tumorigenesis through alterations in adipokine secretion and cell signaling pathways, independent of body weight. Further, long term consumption of sugary drinks result in high glycemic index or glycemic load, with chronically high blood glucose, and therefore chronically elevated insulin concentration. Insulin increases bioactive IGF-1, as well as proinflammatory markers, such as C reactive protein, and systemic inflammation is thought to promote cancer development by inhibiting apoptosis and stimulating cell proliferation, thereby increasing the risk of several cancers, including breast, liver, pancreas, endometrium, colorectal and bladder. Even though there is growing evidence of an association between sugar-sweetened beverages and increased risk of mortality in various populations, the effect of sugary drinks on mortality among breast cancer patients is unknown.

The researchers in this Western New York Exposures and Breast Cancer (WEB) Study assessed the relationship between sugar-sweetened soda and both all-cause and breast cancer mortality among 927 women between ages 35 to 79, who had been diagnosed with breast cancer. In this study, a food frequency questionnaire was used to assess frequency of sugar-sweetened soda consumption in the 12 to 24 months prior to diagnosis of breast cancer. Breast cancer cases were followed for a median of 18.7 years, with ascertainment of vital status via the National Death Index (NDI). This study focused on sugar-sweetened soda, as they are sugar loaded and add extra calories to the diet with no nutritional benefit.

Consumption of sugar-sweetened soda five times or more per week was noted to result in a 62% higher likelihood of dying from any cause and 85% more likely to die from breast cancer specifically, compared to women who never or rarely consumed sugar-sweetened soda. The risk of mortality was similarly increased among ER-positive, but not ER-negative patients, among women with BMI above the median, but not below the median. The risk of total mortality was higher in premenopausal women but not post-menopausal women.

It was concluded from this study that a higher frequency of sugar-sweetened soda consumption was associated with increased risk of total and breast cancer mortality among breast cancer patients, supporting existing guidelines on reducing consumption of sugar-sweetened beverages, including for women with a diagnosis of breast cancer. The authors added that this study provides evidence that diet may impact longevity of women after breast cancer.

Study Finds Regularly Drinking Sugar-Sweetened Soda May Increase Total and Breast Cancer Mortality. Koyratty N, McCann SE, Millen AE, et al. Cancer Epidemiol Biomarkers Prev March 2 2021 DOI: https://doi.org/10.1158/1055-9965.EPI-20-1242.

MARGENZA® Superior to Trastuzumab in Heavily Pretreated HER2-Positive Breast cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2 oncoprotein is also expressed by tumor cells in GastroEsophageal and other solid tumors.

HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (Ado-Trastuzumab Emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.MOA-of-MARGENZA

MARGENZA® (Margetuximab-cmkb) is an Fc-engineered, monoclonal antibody that binds to the HER2 oncoprotein with high specificity and affinity and inhibits tumor cell proliferation and survival, by mediating Antibody-Dependent Cellular Cytotoxicity (ADCC). It is postulated that the Fab portion of MARGENZA® has the same specificity and affinity to HER2 oncoprotein as Trastuzumab, with similar ability to disrupt signaling. However, the modified Fc region of MARGENZA®, which binds to Fc receptor expressing cells such as immune cells, has increased affinity for activating Fc receptor FCGR3A (CD16A) and decreased affinity for inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater ADCC and Natural Killer cell activation. Approximately 85% of individuals are CD16A-158F allele carriers.

The SOPHIA study is a randomized, multicenter, open-label, Phase III clinical trial, in which MARGENZA® plus chemotherapy was compared to Trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer, who have previously been treated with anti-HER2-targeted therapies. This study enrolled 536 patients who were randomized 1:1 to receive either MARGENZA® 15 mg/kg IV every three weeks (N=266) or Trastuzumab 6 mg/kg (8 mg/kg loading dose) IV every three weeks (N=270), in combination with Capecitabine, Eribulin, Gemcitabine or Vinorelbine, given at the standard doses. The median age was 56 years, all study patients had previously received Trastuzumab, all but one patient had previously received PERJETA® (Pertuzumab), and 91% of patients had previously received KADCYLA®. Patients were stratified by choice of chemotherapy, number of lines of therapy in the metastatic setting and number of metastatic sites. The dual Primary endpoints of the study were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Additional efficacy outcome measures included Objective Response Rate (ORR) and Duration of Response (DOR) assessed by BICR.

This study demonstrated a statistically significant 24% reduction in the risk of disease progression or death with MARGENZA® plus chemotherapy compared with Trastuzumab plus chemotherapy (HR= 0.76; P=0.03), with a median PFS of 5.8 months versus 4.9 months respectively. Treatment benefit was more pronounced in patients with CD16A genotypes containing a 158F allele (median PFS 6.9 versus 5.1 months, HR=0.68; P=0.005). The ORR for MARGENZA® plus chemotherapy was 22%, with a median Duration of Response of 6.1 months, compared to an ORR of 16% and median Duration of Response of 6.0 months for Trastuzumab plus chemotherapy. After the second planned interim analysis, the median OS was 21.6 months with MARGENZA® versus 19.8 months with Trastuzumab (HR= 0.89; P=0.33) and the ORR was 25% versus 14% respectively (P<0.001). The final Overall Survival (OS) analysis is expected in the second half of 2021. Safety was comparable in treatment groups, although the incidence of infusion-related reactions, mostly in cycle 1, was higher with MARGENZA® (13.3% versus 3.4%).

It was concluded that MARGENZA® in combination with chemotherapy significantly improved PFS, compared to Trastuzumab plus chemotherapy, in pretreated patients with HER2 positive metastatic breast cancer. MARGENZA® along with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies.

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. Rugo HS, Im SA, Cardoso F, et al. for the SOPHIA Study Group. JAMA Oncol. Published online January 22, 2021. doi:10.1001/jamaoncol.2020.7932

Key Breast Cancer Risk Genes Identified from Two Large Studies

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence.

Genetic testing for cancer susceptibility with multigene testing panels is now becoming widely available and affordable. Identification of pathogenic variants in predisposition genes such as BRCA1 and BRCA2 among carriers has provided benefit through early intervention. However, the evidence of an association with cancer is often weak for many other genes on multigene testing panels, and estimates of the cancer risks associated with such variants are often not available. Further, estimates of the prevalence of pathogenic variants in predisposition genes in the general population are lacking.

Two large breast cancer case-control studies analyzed the associations between a number of commonly accepted cancer susceptibility genes and breast cancer risk.

The multinational study by Dorling et al. used a panel of 34 commonly accepted cancer susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls (unaffected woman) from 25 countries participating in the Breast Cancer Association Consortium. The authors estimated odds ratios for breast cancer overall and tumor subtypes and evaluated missense-variant associations and classification of pathogenicity. The researchers found strong evidence of an association with breast cancer risk for Protein-Truncating Variants (genetic variants) caused by frameshift mutations in 9 genes, with a significant risk for breast cancer and P value of less than 0.0001 for 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2 – Odds Ratios ranging from 2.1 for ATM to 10.6 for BRCA1), and a P value of less than 0.05 for the other 4 genes (BARD1, RAD51C, RAD51D, and TP53 – Odds Ratio ranging from 1.8 for RAD51D to 3.06 for TP53). Further, it was noted that for the genetic variants in most of these genes, the Odds Ratio differed according to breast cancer subtype. Protein-Truncating Variants in ATM and CHEK2 were more strongly associated with ER-positive disease than with ER-negative disease, whereas genetic variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D were more strongly associated with ER-negative disease than with ER-positive disease. It was also found that rare missense variants in CHEK2 overall, as well as variants in specific domains in ATM, were associated with moderate breast cancer risk. The researchers also noted that none of the other 25 genes in the panel were informative for the prediction of breast cancer risk. This study places Protein-Truncating Variants in BRCA1, BRCA2, and PALB2 in the high-risk category and Protein-Truncating Variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D in the moderate-risk category.

The US study by Hu et al. used a panel of 28 cancer predisposition genes to perform sequencing on samples from 32,247 women with breast cancer and 32,544 controls (unaffected women) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. The researchers assessed the associations between pathogenic variants in each gene and the risk of breast cancer.
The researchers noted that pathogenic variants in 12 established breast cancer predisposition genes were detected in 5% of breast cancer patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with Odds Ratios of 7.62 and 5.23 respectively and pathogenic variants in PALB2 were associated with a moderate risk (Odds Ratio 3.83). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of ER-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of ER-positive breast cancer. Pathogenic variants in the other 16 candidate breast cancer predisposition genes were not associated with an increased risk of breast cancer.

Taken together, the results from these two large case-control studies suggested that variants in 8 genes – BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2, had a significant association with breast cancer risk and majority of the other genes tested did not have a significant association with disease. Further, the distribution of mutations among women with breast cancer was different from the distribution among controls (unaffected women). Among breast cancer patients, the majority of mutations were in BRCA1, BRCA2, and PALB2, and among controls, the majority of mutations were in CHEK2 and ATM.

It can be concluded that, these two studies define the genes that are of utmost clinical value for inclusion on sequencing panels, for the prediction of breast cancer risk, and provides estimates of the prevalence of the pathogenic variants in the unaffected population. The authors added that these estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.

Breast Cancer Risk Genes – Association Analysis in More than 113,000 Women. Breast Cancer Association Consortium; Dorling L, Carvalho S, Allen J, et al. N Engl J Med 2021;384:428-439.

A Population-Based Study of Genes Previously Implicated in Breast Cancer. Hu C, Hart SN, Gnanaolivu R, et al. N Engl J Med 2021;384:440-451.

Real-World Data: Surgery Improves Survival in Treatment Responsive Metastatic Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene and about 50% of HER2-positive breast cancers are Hormone Receptor positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. Not all HER2-positive, Hormone Receptor positive metastatic breast cancer patients, are candidates for chemotherapy. These patients however may benefit from anti-HER2 targeted therapy given along with endocrine therapy.

Approximately 6% of newly diagnosed breast cancer patients present with Stage IV disease. Systemic therapy has been the cornerstone of treatment for patients with metastatic breast cancer. Breast surgery is often not a consideration for patients with metastatic breast cancer. However, breast surgery can be offered for palliation of symptoms, taking into consideration the risks and benefits of such intervention, in a patient with an ulcerated, bleeding, or a fungating tumor mass, that cannot be controlled with systemic therapy.

Surgical resection of metastatic disease is not a new concept. Previously published results from randomized controlled trials among patients with metastatic breast cancer concluded that there was no survival advantage with surgical intervention. However these results have been questioned because of the small number of participants, and did not take into account either the Hormone Receptor, HER-2 status or the sequence of chemotherapy in relation to the surgical intervention. It therefore remains unclear whether surgery, in addition to systemic treatments and radiation therapy, improves survival for certain patients with metastatic breast cancer.

The authors in this real-world study identified 12,838 patients with HER-2 overexpressing and Hormone Receptor positive, Stage IV breast cancer, from the NCI database. They then studied patients who had either systemic therapy alone, systemic therapy and surgery, or had systemic therapy, surgery and radiation, and evaluated whether certain biologic subtypes and timing of chemotherapy were associated with survival advantages. Specifically, they evaluated whether the Hormone Receptor status had an influence on surgical benefit, in these treatment-responsive breast cancer patients, understanding that triple negative breast cancers are not very responsive to treatment. The researchers excluded patients who died within six months of their diagnoses, in order to ensure that only treatment-responsive cancers were being studied. The goal of this study was to understand if surgery made a difference in metastatic breast cancers that were responsive to treatment.

The researchers noted that patients with a surgical intervention tended to have a longer survival, compared to patients with other treatment plans. Patients whose cancers were HER2-positive saw prolonged survival, especially when their treatment plan included surgery. Further, in addition to the benefit of surgery among treatment-responsive metastatic breast cancer patients, the authors noted that systemic therapy before surgery (preoperative systemic therapy which included chemotherapy and targeted therapies) had the greatest survival advantage in patients with positive HER-2 and Estrogen and Progesterone Receptor status.

It was concluded from this study that patients with Stage IV breast cancer responsive to systemic therapy may be able to benefit from the addition of surgery, regardless of their biologic subtype. The authors added that clinicians should evaluate real-world evidence, including this study, when choosing the optimal treatment for their patients with metastatic breast cancer, as it may be difficult to conduct randomized clinical trials in this patient population.

ASO Author Reflections: Surgery Offers Survival Advantage in Treatment-Responsive Metastatic Breast Cancer. Stahl K, Dodge D, and Shen C. Annals of Surgical Oncology, 2020; DOI: 10.1245/s10434-020-09286-9

Adjuvant VERZENIO® with Endocrine Therapy in High Risk Early Stage Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-ABEMACICLIB-A-CDK4-and-CDK6-Inhibitor

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

VERZENIO® is presently approved by the FDA as monotherapy as well as in combination with endocrine therapy for patients with HR-positive, HER2- negative advanced breast cancer. The addition of VERZENIO® to FASLODEX® resulted in a statistically significant improvement in Overall Survival among patients with HR-positive, HER2-negative advanced breast cancer, who had progressed on prior endocrine therapy. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk early breast cancer.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5 to 10 years of physicians choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease Free Survival (IDFS), and Secondary end points included distant Relapse Free Survival, Overall Survival, and safety. At a preplanned interim analysis, the addition of VERZENIO® to endocrine therapy resulted in a 25% reduction in the risk of developing a Invasive Disease Free Survival (IDFS) event, relative to endocrine therapy alone. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and Overall Survival. The current study describes outcomes following an extended follow up of this trial, with a median follow up time of 19 months.

At the time of this primary outcome analysis, 1,437 patients (25.5%) had completed the two-year treatment period and 3,281 patients (58.2%) were in the two-year treatment period. The combination of VERZENIO® plus endocrine therapy continued to demonstrate superior Invasive Disease Free Survival (IDFS) compared to endocrine therapy alone, with a 28.7% reduction in the risk of developing invasive disease (P=0.0009; HR=0.713). The 2-year IDFS in the combination group was 92.3% and 89.3% in the endocrine therapy alone treatment group. This IDFS benefit with VERZENIO® was consistently noted in all prespecified subgroups. Further, there was an improvement in the 2-year distant Relapse Free Survival rate among patients who received the combination treatment compared with those who received endocrine therapy alone (93.8% versus 90.8%, respectively). Overall Survival data was immature at the time of analysis.

The researchers also evaluated outcomes among 2,498 patients with centrally assessed high tumor Ki-67 status. Among patients in this cohort, those who received the combination treatment had a 30.9% decreased risk of invasive disease compared with those who received endocrine therapy alone (P=0.01; HR=0.691) and the 2-year IDFS rates in the combination group and the endocrine therapy alone group were 91.6% and 87.1%, respectively. There were no new safety signals observed with VERZENIO®.

It was concluded that at the time of this primary outcome analysis, VERZENIO® combined with endocrine therapy continued to demonstrate a clinically meaningful improvement in Invasive Disease Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer.

Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. O’Shaughnessy JA, Johnston S, Harbeck N, et al. Presented at the 2020 San Antonio Breast Cancer Symposium, December 8-11. Abstract. GS1-01.

Chemotherapy Can Be Spared in Majority of Postmenopausal Women with Node Positive Early Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer were diagnosed in 2020 and about 42,170 women died of the disease. Approximately 25% of patients with Hormone Receptor (HR)-positive, HER2-negative early breast cancer have metastatic lymph node involvement and two third of these patients are postmenopausal. Majority of these patients currently receive chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for early stage, HR-positive, HER-negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.

In the ground-breaking TAILORx (Trial Assigning Individualized Options for Treatment) study which enrolled 10,273 patients with HR-positive, HER2-negative, axillary node-negative breast cancer, patients were divided into three groups based on their Recurrence Score. Patient with Intermediate Recurrence Score of 11-25 were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. There was no benefit noted from adding chemotherapy to endocrine therapy, for women older than 50 years in this Intermediate RS group, suggesting that a significant percentage of women with node-negative breast cancer do not achieve substantial benefit from chemotherapy. Whether the results of TAILORx can be extrapolated to women with node-positive breast cancer has remained unclear. It is estimated that approximately 85% of women with node-positive disease have Recurrence Score results of 0-25.

The RxPONDER trial was designed to determine the benefit of chemotherapy, in patients who had a Recurrence Score of 0-25. This trial did not include pre and postmenopausal women with Recurrence Score results 26-100 based on previously published studies suggesting that this patient group benefited from chemotherapy. SWOG S1007 (RxPONDER) is an multicenter, international, prospective, randomized, Phase III trial, in which patients with HR-positive, HER2-negative breast cancer with 1-3 positive axillary lymph nodes were included, to determine which patients would benefit from chemotherapy and which patients could safely avoid it. In this study, a total of 5083 HR-positive, HER2-negative breast cancer patients with 1-3 positive lymph nodes and Oncotype DX Recurrence Score of less than 25 were randomly assigned 1:1 to receive chemotherapy plus endocrine therapy or endocrine therapy alone. Approximately two-thirds of patients were postmenopausal and one-third were premenopausal and had no contraindications to taxane and/or anthracycline based chemotherapy. Patients were stratified by Recurrence Score (0-13 versus 14-25), menopausal status, and axillary nodal dissection versus sentinel node biopsy. The Primary endpoint was Invasive Disease Free Survival (IDFS), defined as local, regional, or distant recurrence, any second invasive cancer, or death from any cause, and whether the effect depended on the Recurrence Score. Secondary endpoints included Overall Survival (OS).

At a median follow up of 5.1 years, there was no association noted between Recurrence Score (RS) values and chemotherapy benefit for the entire study population (P=0.30). However, a prespecified analysis did show a significant association between chemotherapy benefit and menopausal status. Premenopausal women (N=1665) with an RS between 0 and 25 had an IDFS benefit with the addition of chemotherapy to endocrine therapy compared with endocrine therapy alone (94.2% versus 89%, HR=0.54; P=0.0004). This absolute 5.2% benefit in the premenopausal subset was highly significant. The relative risk reduction with the addition of chemotherapy to endocrine therapy for the two RS risk groups 0-13 and 14-25 was consistent in the premenopausal population, with an overall Hazard Ratio of 0.54. The absolute benefit was numerically higher in those with RS 14-25. Consistent benefit was again noted regardless of number of involved lymph nodes, although there was slight variation in the absolute benefit. Postmenopausal women (N=3350) did not benefit with the addition of chemotherapy to endocrine therapy when compared endocrine therapy alone, regardless of Recurrence Score (91.9% versus 91.6%, HR=0.97; P=0.82). Chemotherapy also improved Overall Survival in the premenopausal cohort, although the follow up is limited.

It was concluded from this practice-changing outcomes that postmenopausal women with HR-positive, HER2-negative breast cancer with 1-3 positive nodes and Oncotype DX Recurrence Score of 25 or less can safely avoid receiving adjuvant chemotherapy, whereas premenopausal patients with 1-3 positive nodes and a Recurrence Score of 25 or less should consider adjuvant chemotherapy. The authors added that these finding demonstrate that the great majority of postmenopausal women can be spared unnecessary chemotherapy and receive only endocrine therapy.

First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy ± chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence scores ≤ 25: SWOG S1007 (RxPONDER). Kalinsky K, Barlow WE, Meric-Bernstam F, et al. 2020 San Antonio Breast Cancer Symposium. Presented December 10, 2020. Abstract GS3-00.

FDA Approves MARGENZA® for HER2 Positive Metastatic Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2 oncoprotein is also expressed by tumor cells in gastroesophageal and other solid tumors.

HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (Ado-Trastuzumab Emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.MOA-of-MARGENZA

MARGENZA® (Margetuximab-cmkb) is an Fc-engineered, monoclonal antibody that binds to the HER2 oncoprotein with high specificity and affinity and inhibits tumor cell proliferation, and survival by mediating Antibody-Dependent Cellular Cytotoxicity (ADCC). It is postulated that the Fab portion of MARGENZA® has the same specificity and affinity to HER2 oncoprotein as Trastuzumab, with similar ability to disrupt signaling. However, the modified Fc region of MARGENZA® which binds Fc receptor expressing cells such as immune cells, has increased affinity for activating Fc receptor FCGR3A (CD16A) and decreases affinity for inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater ADCC and Natural Killer cell activation.

The SOPHIA study is a randomized, multicenter, open-label Phase III clinical trial, in which MARGENZA® plus chemotherapy was compared to Trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer, who have previously been treated with anti-HER2-targeted therapies. This study enrolled 536 patients who were randomized 1:1 to receive either MARGENZA® 15 mg/kg IV every three weeks (N=266) or Trastuzumab 6 mg/kg (or 8 mg/kg for loading dose) IV every three weeks (N=270), in combination with either Capecitabine, Eribulin, Gemcitabine or Vinorelbine, given at the standard doses. All study patients had previously received Trastuzumab, all but one patient had previously received PERJETA® (Pertuzumab), and 91% of patients had previously received KADCYLA®. Patients were stratified by choice of chemotherapy, number of lines of therapy in the metastatic setting and number of metastatic sites. The dual Primary endpoints of the study were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Additional efficacy outcome measures included Objective Response Rate (ORR) and Duration of Response (DOR) assessed by BICR.

This study demonstrated a statistically significant 24% reduction in the risk of disease progression or death with MARGENZA® plus chemotherapy compared with Trastuzumab plus chemotherapy (HR= 0.76; P=0.033), with a median PFS of 5.8 months versus 4.9 months respectively. Treatment benefit was more pronounced in patients with CD16A genotypes containing a 158F allele (median PFS 6.9 versus 5.1 months, HR=0.68; P=0.005). The ORR for MARGENZA® plus chemotherapy was 22%, with a median Duration of Response of 6.1 months, compared to an ORR of 16% and median Duration of Response of 6.0 months for Trastuzumab plus chemotherapy. The final Overall Survival (OS) analysis is expected in the second half of 2021. The most common adverse drug reactions occurring in more than 10% of patients receiving MARGENZA® plus chemotherapy included fatigue/asthenia, nausea, diarrhea, vomiting, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain.

It was concluded that MARGENZA® in combination with chemotherapy significantly improved PFS, compared to Trastuzumab plus chemotherapy, in pretreated patients with HER2 positive metastatic breast cancer. MARGENZA® along with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies.

SOPHIA primary analysis: A phase 3 study of margetuximab + chemotherapy (C) versus trastuzumab + C in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies. Rugo HS, Im SA, Shaw Wright GL, et al. J Clin Oncol 37, 2019 (suppl; abstr 1000)