Tag: 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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

It is estimated that approximately 60% of metastatic breast cancers categorized as HER2-negative express low levels of HER2, defined as a score of 1+ on ImmunoHistoChemical (IHC) analysis or as an IHC score of 2+ and negative results on In Situ Hybridization (ISH). These HER2-low breast cancer tumors are treated as HER2-negative, as currently available HER2-directed therapies have resulted in poor outcomes. These patients have limited targeted treatment options and are often treated with single agent palliative chemotherapy following progression on first line chemotherapy.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life , thus minimizing systemic exposure. The potential activity of ENHERTU® in HER2-low breast cancer tumors is driven by the bystander antitumor effect, offered by the optimized ADC technology. Previously published Phase I and II trials have shown that ENHERTU® in heavily pretreated patients with HER2-low metastatic breast cancer resulted in an Overall Response Rate of 37%, and median Progression Free Survival ranging from 6.3 to 11.1 months.

DESTINY-Breast04 is a multicenter, randomized, open-label, Phase III trial, conducted to evaluate the efficacy and safety of ENHERTU® as compared with the physician’s choice of chemotherapy, in patients with HER2-low metastatic breast cancer. In this study, patients were randomly assigned in a 2:1 ratio to receive ENHERTU® 5.4 mg/kg IV every 3 weeks (N=373) or the physician’s choice of Capecitabine, Eribulin, Gemcitabine, Paclitaxel, or Nab-paclitaxel (N=184). Low expression of HER2 was defined as a score of 1+ on ImmunoHistoChemical (IHC) analysis or as an IHC score of 2+ and negative results on In Situ Hybridization (ISH). Randomization was stratified according to HER2-low status (IHC 1+ versus IHC 2+ and ISH-negative), the number of previous lines of chemotherapy for metastatic disease (one versus two), and Hormone Receptor (HR) status (positive versus negative) and if positive, previous CDK4/6 inhibitor therapy versus no CDK4/6 inhibitor therapy. IHC scores for HER2 expression were determined through central testing with the use of VENTANA HER2/neu investigational assay system, according to an algorithm adapted from the 2018 ASCO/CAP testing guidelines. Eligible patients must have received chemotherapy for metastatic disease or have had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with Hormone Receptor positive (HR-positive) disease must have received at least one line of endocrine therapy. Patients with treated, stable brain metastases were eligible. Patients were ineligible if they had a history of noninfectious interstitial lung disease treated with steroids or had suspected interstitial lung disease on imaging at screening. Both treatment groups were well balanced and approximately 89% in the ENHERTU® group and 90% in the chemotherapy group were HR-positive. The Primary end point was Progression Free Survival (PFS) among patients with HR-positive disease. Secondary end points included PFS among all patients, Overall Survival (OS) in the HR-positive cohort and among all patients, Objective Response Rate (ORR), Duration of Response, and efficacy in the HR-negative cohort. The median duration of follow up for survival was 18.4 months.

At the time of the primary efficacy analysis, the median PFS in the HR-positive cohort was 10.1 months in the ENHERTU® group and 5.4 months in the physician’s choice group (HR for disease progression or death=0.51; P<0.001). This benefit with ENHERTU® was seen consistently across all analyzed subgroups which included HER2 IHC 1+, HER2 IHC 2+ and ISH-negative, as well as those who had received previous treatment with CDK4/6 inhibitors. The median PFS among all patients was 9.9 months in the ENHERTU® group and 5.1 months in the physician’s choice group (HR for disease progression or death=0.50; P<0.001). The median PFS in the HR-negative cohort was 8.5 months in the ENHERTU® group and 2.9 months in the physician’s choice group (HR=0.46).

The median OS in the HR-positive cohort was 23.9 months in the ENHERTU® group and 17.5 months in the physician’s choice group (HR for death=0.64; P=0.003). The median OS among all patients was 23.4 months in the ENHERTU® group and 16.8 months in the physician’s choice group HR=0.64; P=0.001). The median OS in the HR-negative cohort was 18.2 months in the ENHERTU® group and 8.3 months in the physician’s choice group (HR=0.48).

The ORR in the HR-positive group was 52.6% in the ENHERTU® group and 16.3% in the physician’s choice group, and the median duration of response was 10.7 months in the ENHERTU® group and 6.8 months in the physician’s choice group. The ORR among all patients was 52.3% in the ENHERTU® group and 16.3% in the physician’s choice group. Among HR-negative cohort, the ORRs were 50% and 16.7% respectively.

Grade 3 or higher adverse events occurred in 53% of the patients who received ENHERTU® and 67.4% of those who received the physician’s choice of chemotherapy. Adjudicated, drug-related Interstitial Lung Disease or pneumonitis occurred in 12.1% of the patients who received ENHERTU®.

The authors concluded that this is the first Phase III, practice-changing trial of a HER2-directed therapy in patients with HER2-low metastatic breast cancer, to show a statistically significant and clinically meaningful benefit in PFS and OS, compared to standard chemotherapy, regardless of Hormone Receptor status, with a generally manageable safety profile. The authors added that the strong efficacy of ENHERTU® in this HER2-low patient population, with approximately 50% lower risk of disease progression and 36% lower risk of death with ENHERTU® compared to standard chemotherapy, supports the need to reclassify HER2-low as a new targetable category of metastatic breast cancer.

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. Modi S, Jacot W, Yamashita T, et al. for the DESTINY-Breast04 Trial Investigators. N Engl J Med 2022; 387:9-20.

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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy.

Cyclin Dependent Kinases (CDK) 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. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) 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 and associated with increased expression of CDK4. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest.

MAINTAIN trial is an investigator-initiated, multicenter, Phase II, double-blind, placebo-controlled, prospective randomized study, conducted to evaluate the efficacy of Fulvestrant or Exemestane with or without KISQALI®, in patients with HR+/HER2-negative metastatic breast cancer, who had previously progressed on any CDK 4/6 inhibitor plus any endocrine therapy. In this study, 119 evaluable patients were randomized 1:1 to receive either KISQALI® 600mg orally once daily given 3 weeks on and 1 week off plus switch endocrine therapy (N= 60) or placebo plus switch endocrine therapy (N=59). Patients treated with prior Fulvestrant received Exemestane as endocrine therapy in the randomization, whereas if prior Exemestane was endocrine therapy, patients received Fulvestrant. If patients received neither as prior endocrine therapy, Fulvestrant or Exemestane was given per investigator discretion, although Fulvestrant was encouraged. Ultimately, 83% of patients received Fulvestrant and 17% received Exemestane. Eligible patients were postmenopausal, had HR+/HER2- negative metastatic breast cancer and had progressed on prior endocrine therapy and any CDK4/6 inhibitor. With regards to prior CDK 4/6 inhibitor treatment, 84% received IBRANCE® (Palbociclib), 11% received KISQALI®, 2% received VERZENIO® (Abemaciclib) and 3% received IBRANCE® and another CDK 4/6 inhibitor. The median duration of treatment with the prior CDK4/6 inhibitor was 15.5 months in the KISQALI® group and 17 months in the placebo group. Approximately 60% of patients had visceral metastasis, 45% had de novo metastasis at diagnosis, 18% had bone-only disease, 18% had received 2 or more prior endocrine therapies for metastatic disease, and 9% had received chemotherapy. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Response Rate (ORR), Clinical Benefit Rate, safety, and tumor and blood biomarkers. The median follow up was 18.2 months.

There was a statistically significant PFS improvement for patients randomized to KISQALI® plus endocrine therapy and the median PFS for patients in the KISQALI® plus endocrine therapy was 5.33 months, compared with 2.76 months for patients receiving placebo and endocrine therapy (HR=0.56;; P=0.004). At 12 months, the PFS rates were 24.6% in the KISQALI® group versus 7.4% in the placebo group. Similar results were noted in the subset of patients treated with Fulvestrant and KISQALI®, and the median PFS for those randomized to KISQALI® was 5.29 months versus 2.76 months in the placebo group (HR=0.59; P=0.02). The PFS benefit was more evident in KISQALI® group compared to the placebo group, especially among those who received a shorter duration of therapy with a prior CDK4/6 inhibitor (HR=0.36) and among those over age 65 years (HR=0.31). The Overall Response Rate in the KISQALI® group was 20%, compared to 11% in the placebo group, and the median Duration of Response was 18.8 months in those treated with KISQALI® and endocrine therapy, compared with 14.8 months for those treated with placebo plus endocrine therapy. There was also a significant improvement in the Clinical Benefit Rate (CBR), defined as patients who achieved Complete Response, Partial Response, or stable disease lasting at least 24 weeks. The CBR was significantly improved in the KISQALI® group, compared with the placebo group, and was 43% versus 25%, respectively (P=0.06). The most common adverse event in the KISQALI® group was neutropenia at 72%, compared to 15% in the placebo group.

It was concluded from this randomized, placebo-controlled trial that, treatment with KISQALI® and an alternate endocrine therapy, after progression on a prior CDK4/6 inhibitor, showed a 43% reduction in the risk of progression or death, compared with placebo and endocrine therapy, in patients with HR+/HER2-negative metastatic breast cancer.

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. Kalinsky K, Accordino MK, Chiuzan C, et al. J Clin Oncol 40, 2022 (suppl 17; abstr LBA1004). DOI: 10.1200/JCO.2022.40.17_suppl.LBA1004.

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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.

TRODELVY® (Sacituzumab govitecan) 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.

TRODELVY® was approved by the FDA in 2021 for patients with unresectable, locally advanced or metastatic Triple Negative Breast Cancer, who have received two or more prior systemic therapies, at least one of them for metastatic disease. In the IMMU-132 Phase I/II study, the Hormone Receptor positive (HR+)/HER2-negative cohort of patients with metastatic breast cancer patients had an Objective Response Rate (ORR) of 31.5%, median Progression Free Survival (PFS) of 5.5 months and median Overall Survival (OS) of 12 months, with manageable toxicities, when treated with TRODELVY®.

TROPiCS-02 is a global, open-label, randomized, Phase III study, conducted to confirm the benefit of TRODELVY® in HR+/HER2- negative advanced breast cancer. In this study, 543 patients with HR+/HER2-negative, unresectable, locally advanced or metastatic breast cancer, were randomly assigned 1:1 to receive TRODELVY® 10 mg/kg IV on D1 and 8, every 21 days (N=272), or treatment of physician’s choice, which included single agent treatment with either Capecitabine, Eribulin, Vinorelbine, or Gemcitabine (N=271). Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced. Eligible patients had 3 median prior chemotherapy regimens for metastatic breast cancer, and one prior therapy for metastatic breast cancer was allowed if disease progressed in 12 months or less after neoadjuvant chemotherapy. Patients were required to have received endocrine therapy, a CDK4/6 inhibitor and at least one prior therapy with a Taxane in any setting. Majority of patients had visceral metastases (95%), 86% had prior endocrine therapy for metastatic breast cancer for at least 6 months, and 60% and 38% received prior CDK4/6 inhibitors for 12 months or less, and for more than 12 months, respectively. The Primary endpoint was Progression Free Survival (PFS) by blinded Independent Central Review (final analysis) and key Secondary endpoint was Overall Survival (OS) at the first planned interim analysis.

The median Progression Free Survival was 5.5 months with TRODELVY® versus 4 months with standard chemotherapy (HR=0.66; P=0.0003), representing a 34% improvement in PFS with TRODELVY®. This benefit was seen across all treatment subgroups including those who were 65 years or older, those who were heavily pretreated, as well as those with visceral metastases. The Objective Response Rate (ORR) was 21% with TRODELVY® versus 14% with standard chemotherapy. The Clinical Benefit Rate was also higher with TRODELVY® versus standard chemotherapy (34% versus 22%) and median duration of response was 7.4 months and 5.6 months respectively. Overall Survival data were immature, but there was a numerical, non-significant improvement in the median Overall Survival noted in the TRODELVY® group, compared to the standard chemotherapy group (13.9 months versus 12.3 months; HR=0.84; P=0.14), respectively. Treatment with TRODELVY® also resulted in an overall health-related Quality of Life benefit over chemotherapy, with delayed deterioration in fatigue and global health status/ Quality of Life scales, according to the researchers. Grade 3 or more adverse events were observed in 74% of patients receiving TRODELVY® and in 60% of those receiving chemotherapy, and the most common toxicities associated with TRODELVY® were diarrhea and neutropenia.

It was concluded from this landmark analysis that treatment with TRODELVY® resulted in a statistically significant and clinically meaningful improvement in Progression Free Survival, compared to standard chemotherapy, in heavily pre-treated patients with HR+/HER2-negative, endocrine-resistant, unresectable, locally advanced or metastatic breast cancer, and should therefore be considered as a new treatment option for this patient population.

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. Rugo HS, Bardia A, Marmé F, et al. J Clin Oncol 40, 2022 (suppl 17; abstr LBA1001)

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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

Patient undergoing breast conserving surgery, often receive adjuvant breast radiation therapy to reduce the risk of local recurrence. Radiation therapy however is inconvenient, expensive and is associated with acute and late toxicities. Previously published study by Kunkler IH, et al. (Lancet Oncol. 2015;16:266-273) concluded that radiotherapy could be avoided in a subset of elderly patients with low risk breast cancer following breast conserving surgery.

Conventional clinical pathological factors have limited ability to identify breast cancer patients with low risk disease, who could avoid radiation therapy. Molecular defined intrinsic subtypes of breast cancer can provide additional prognostic information. Breast cancer is heterogeneous malignancy and using global gene expression analyses, 5 breast cancer intrinsic subtypes have been established. They include Luminal A, Luminal B, HER2-enriched, Basal-like, and Normal breast-like group. Luminal A breast cancer patients have the lowest risk of recurrence. In a retrospective analysis of women over age 60 years, with Luminal A, Grade 1-2, T1N0 breast cancer, treated with breast conserving surgery and endocrine therapy alone, the local recurrence rate was low (JCO 2015; 33:2035). However, the utility of combining molecular subtype (Luminal A subtype) with clinical pathological factors, to guide radiotherapy decision-making, has not been prospectively evaluated.

LUMINA is a prospective multicenter single-arm, cohort study, in which 501 women, 55 years and older, who had undergone breast conserving surgery for breast cancer, were enrolled. Eligible patients had invasive ductal T1N0, Grade 1-2, Luminal A breast cancer, had undergone breast conserving surgery, with excision margins of at least 1 mm and sentinel lymph node biopsy, omitted radiotherapy, and had received adjuvant endocrine therapy for at least 5 years. Luminal A subtype was defined as ER 1% or more, PR more than 20%, HER2 negative and Ki67 13.25% or less. Ki67 immunohistochemistry was performed centrally in one of three Canadian laboratories using International Ki67 Working Group methods. The median patient age was 67 years, 66% had Grade 1 tumors, 88% of patients were less than 75 years, and the median tumor size was 1.1 cm. Patients were followed every six months for the first two years and then yearly. The Primary outcome was local recurrence defined as time from enrollment to any invasive or non-invasive cancer in the ipsilateral breast. Secondary endpoints included contralateral breast cancer, Relapse Free Survival (RFS) based on any recurrence, Disease Free Survival, and Overall Survival.

At a median follow up of 5 years, the local recurrence rate was 2.3% and the rate of contralateral breast cancer was 1.9%. The 5-year Relapse Free Survival, Disease Free Survival and Survival rate was 97.3%, 89.9% and 97.2% respectively.

The authors concluded that among women 55 years of age and over, with low grade Luminal A breast cancer, omission of radiation therapy following breast conserving surgery and treatment with endocrine therapy alone for 5 years or more, resulted in very low rates of local recurrence at 5 years. The researchers added that approximately 30,000-40,000 women per year in North America, predominantly in the US, could avoid the morbidity, expense, and inconvenience of radiotherapy.

LUMINA: A prospective trial omitting radiotherapy (RT) following breast conserving surgery (BCS) in T1N0 luminal A breast cancer (BC). Whelan TJ, Smith S, Nielsen TO, et al. J Clin Oncol. 2022;40(suppl 17):LBA501. doi:10.1200/JCO.2022.40.17_suppl.LBA501