Tag: Breast Cancer

Duration of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer

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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.

Luminal breast cancer is the most prevalent molecular subtype in postmenopausal females, accounting for over 70%. Despite substantial improvements in adjuvant therapies, the risk of disease recurrence continues indefinitely, with more than half the recurrences occurring after the first 5 years following diagnosis. Following initial adjuvant endocrine therapy with Tamoxifen for 5 years, the addition of extended adjuvant therapy has resulted in 40% longer Disease Free Survival (DFS), when compared to placebo or no extended therapy. However the benefit of extending adjuvant Aromatase Inhibitor therapy for 5 years beyond the initial 5-year duration regimen is less well established. Further, the most effective duration of such extended adjuvant endocrine therapy remains unclear. Added to this dilemma are the side effects associated with Aromatase Inhibitor therapy including hot flushes, arthralgia, and bone pain, as well as treatment-induced osteoporosis, which can have a significant impact on patient’s quality of life. Researchers in the Secondary Adjuvant Long-Term Study with Arimidex [Anastrozole] (SALSA) prospectively investigated whether an additional 2 years or 5 years of Anastrozole therapy would result in better outcomes, following the initial 5 years of endocrine therapy, in postmenopausal women with Hormone Receptor-positive breast cancer.

The authors conducted a prospective, multicenter, randomized, Phase III trial, which included 3,470 eligible postmenopausal women with Stages I, II or III early stage breast cancer with no evidence of recurrence. Enrolled patients had invasive Hormone Receptor-positive breast cancer, and had received 5 years (plus or minus 12 months) of adjuvant endocrine therapy with Tamoxifen, Aromatase Inhibitors, or both sequentially, up until 12 months before randomization. Patients were randomly assigned 1:1 to receive Anastrozole 1 mg, orally daily, for either 2 additional years for a total of 7 years (N=1732) or 5 additional years for a total of 10 years (N=1738). The two treatment groups were well balanced. The median age at the time of randomization was 64 years, 72% of patients had tumors that were smaller than 2 cm, 66% had node-negative disease, and 19% had high-grade tumors. Stratification criteria included pathological tumor stage, pathological node stage, primary adjuvant endocrine therapy and adjuvant chemotherapy.

The primary analysis included all the patients who were still participating in the study (N=3208), including 1,603 in the 2-year group versus 1,605 in the 5-year group. In the primary analysis population of 3208 patients, 51% had received Tamoxifen alone for the initial 5 years, 7.3% had received an Aromatase Inhibitor alone, and 41.7% had received an Aromatase Inhibitor in combination with Tamoxifen. The Primary end point was Disease Free Survival (DFS). Secondary end points were Overall Survival (OS), contralateral breast cancer, second primary cancer, and clinical bone fracture. The median follow-up after randomization was 118 months.

The researchers observed no difference in DFS with 2 versus 5 additional years of adjuvant endocrine therapy with Anastrozole. The DFS 10 years since randomization was 73.6% in the 2-year group versus 73.9% in the 5-year group (HR=0.99; P=0.90). Contralateral breast cancer occurred in 2.2% versus 2.1% of patients (HR= 1.15), and local recurrence occurred in 3% versus 2.4% in the 2 year and 5 year groups, respectively. There was no difference noted for Overall Survival at 8 years between the two treatment groups (87.5% in the 2-year group and 87.3% in the 5-year group, HR for death from any cause=1.02). The risk of clinical bone fracture however was higher in the 5-year group than in the 2-year group (HR=1.35).

It was concluded from this study that in postmenopausal women with Hormone Receptor positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending endocrine therapy with an Aromatase Inhibitor by an additional 5 years provided no benefit over a 2-year extension, but was associated with a greater risk of bone fracture.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. Gnant M, Fitzal F, Rinnerthaler G, et al. N Engl J Med 2021; 385:395-405.

Genetic Testing in Older Women with Breast Cancer

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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. There are 12 established breast cancer predisposition genes implicated among breast cancer cases, unselected for family history or young age at breast cancer diagnosis. Only loss-of-function through protein truncation and missense variants labeled as pathogenic, are classified as Pathogenic Variants-PV in the ClinVar database. They include ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53. Among these genes, BRCA1, BRCA2, and PALB2 are high risk genes, whereas the other genes are considered moderate risk. Identifying high risk genes in women with breast cancer is relevant both for prevention and treatment. Breast cancer prevention opportunities include contralateral prophylactic mastectomy or surveillance with MRI of the breast, prophylactic salpingo-oophorectomy for BRCA mutation carriers, avoidance of radiation in TP53 mutation carriers, and genetic testing for family members. PARP inhibitor LYNPARZA® (Olaparib) is indicated for the treatment of patients with deleterious or suspected deleterious germline BRCA1/2 mutated, HER2-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Younger age at diagnosis, strong family history of breast and/or ovarian cancer, Ashkenazi Jewish ancestry, or Triple Negative Breast Cancer (TNBC), are all associated with hereditary breast cancer and approximately 10% of these patients carry a Pathogenic Variant in a breast cancer predisposition gene.

According to the NCCN guidelines, hereditary cancer testing for women with breast cancer diagnosed at age greater than 65 years, without specific risk factors such as Ashkenazi Jewish ancestry or family history of cancer, has limited clinical utility as these women have less than 2.5% chance of having a Pathogenic Variant in a high risk gene. However, few studies have specifically evaluated breast cancer predisposition genes in women over age 65 years.

The authors conducted this study to determine the prevalence of Pathogenic Variants in established breast cancer predisposition genes, and to estimate remaining lifetime risks of breast cancer associated with Pathogenic Variants, among women over age 65 years in the general population. A total of 26,707 women over age 65 years from population-based studies (N=13,762, 51.5% with breast cancer and N=12,945, 48.5% age and study matched unaffected women controls) were tested for Pathogenic Variants in germline breast cancer predisposition gene. The researchers then assessed the frequencies of Pathogenic Variants and associations between Pathogenic Variants in each gene and breast cancer, and estimated the remaining lifetime breast cancer risks for non-Hispanic White women with Pathogenic Variants.

The researchers noted that the frequency of Pathogenic Variants in established breast cancer predisposition genes were identified in 3.18% of 13,762 women with breast cancer and 1.48% of the 12,945 age-matched unaffected controls. Pathogenic Variants in the high risk BRCA1, BRCA2, and PALB2 genes were found in 3.42% of women diagnosed with ER-negative breast cancer and 3.01% of women with Triple Negative Breast Cancer. The frequency of Pathogenic Variants in the high risk genes was low among women with no first degree relatives with breast cancer and ER-positive breast cancer. Pathogenic Variants in BRCA1, BRCA2, PALB2 and CHEK2 were associated with increased risks (Odds Ratio=2.9-4.0) of breast cancer. The remaining lifetime risk of breast cancer from age 66 to 85 years was more than 15% or more for those with Pathogenic Variants in BRCA1, BRCA2, and PALB2.

The authors concluded that based on this largest study to date of population-based US women over age 65 years, diagnosed with breast cancer, all women diagnosed with Triple Negative Breast Cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 Pathogenic Variants and perhaps with PALB2 and CHEK2 Pathogenic Variants should be considered for breast MRI screening, as they continue to be at an increased risk of breast cancer.

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women. Boddicker NJ, Hu C, Weitzel JN, et al. J Clin Oncol 2021;39:3430-3440.

Duration of Extended Adjuvant Letrozole after Tamoxifen in Postmenopausal Women with Early Stage Breast Cancer

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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 75% of patients with breast cancer are Hormone Receptor (HR) – positive (Estrogen Receptor/Progesterone Receptor positive), and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues.

It has been well established that treatment with 5 years of endocrine therapy in early stage, HR-positive breast cancer, significantly reduces the risks of locoregional and distant recurrence, contralateral breast cancer, death from breast cancer, and therefore death from any cause. Extended adjuvant endocrine therapy with either Tamoxifen or an Aromatase Inhibitor (AI) beyond 5 years can further reduce breast cancer recurrence. This however can result in treatment related side effects. Therefore, when considering extended adjuvant endocrine therapy beyond 5 years, the potential benefits should be weighed against the associated risk with such therapy. The absolute benefit of continuing endocrine therapy after 5 years depends on the absolute risk of later recurrence, if patient’s receives no further therapy.

Third generation Aromatase Inhibitors (AIs), including Anastrozole, Exemestane and Letrozole, have demonstrated improved efficacy, when compared to Tamoxifen, for the adjuvant endocrine treatment of postmenopausal patients with HR-positive breast cancer. Randomized trials such as the Intergroup Exemestane Study have shown improvements in Disease Free Survival (DFS) among patients who after 2-3 years on Tamoxifen treatment switch to Exemestane for the remainder of a 5-year endocrine treatment period, with a modest improvement in Overall Survival (OS). Whether there is added benefit by extending Aromatase Inhibitor therapy beyond 5 years has remained controversial.

The present study was conducted to compare extended therapy with Letrozole for 5 years versus the standard duration of 2-3 years of Letrozole, in postmenopausal patients with breast cancer, who had already received 2-3 years of Tamoxifen. This multicentre, open-label, randomized, Phase III trial included 2056 postmenopausal women patients with Stage I-III operable, invasive, HR-positive breast cancer, who had received adjuvant Tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, and had no signs of recurrent disease. Patients were randomly assigned (1:1) to receive Letrozole 2.5 mg orally once a day for 2-3 years (control group; N=1030) or Letrozole 2.5 mg orally once a day for 5 years (extended group; N=1026). Approximately 41% of patients had node-positive disease, 21% had Grade 3 tumors, 6% had HER2-positive disease and 55% had prior chemotherapy. The median duration of treatment with adjuvant Tamoxifen was about 2.5 years. The Primary endpoint was invasive Disease Free Survival. Safety analysis was done for patients who received at least 1 month of study treatment. About 80% of patients in the control group and 63% in the extended treatment group completed treatment. The median duration of Letrozole treatment was 5.0 years in the extended treatment group and 2.4 years in the control group. About 16% of patients in the extended treatment group and 11.7% in the control group received bisphosphonate treatment respectively.

After a median follow-up of 11.7 years, the 12-year Disease Free Survival was 62% in the control group and 67% in the extended treatment group (HR=0.78; P=0.0064). This benefit was seen across all patient subgroups. The Overall Survival was also significantly improved at 12 years, and was 84% in the control group versus 88% in the extended treatment group (HR=0.77; P=0.036).

With regards to Adverse Events, there was a slightly higher incidence of arthralgia, myalgia and osteoporosis in the extended treatment group, but there was no significant difference observed between the groups in the incidence of Skeletal Related Events.

It was concluded from this landmark study that, in postmenopausal patients with breast cancer who received 2-3 years of Tamoxifen, extended treatment with 5 years of Letrozole resulted in a significant improvement in Disease Free Survival, compared with the standard 2-3 years of Letrozole. The authors added that sequential endocrine therapy with Tamoxifen for 2-3 years followed by Letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with Hormone Receptor-positive breast cancer.

Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial. Del Mastro L, Mansutti M, Bisagni G, et al. Lancet Oncology. Published: September 17, 2021. DOI: https://doi.org/10.1016/S1470-2045(21)00352-1

Omitting Axillary Lymph Node Dissection in Patients with Clinically Positive Axillary Lymph Nodes Treated with Neoadjuvant Chemotherapy

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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.

Patients with locally advanced breast cancer with clinically positive axillary lymph nodes often receive chemotherapy in the neoadjuvant settings, and approximately 30-40% of patients achieve a pathological Complete Response (pCR), with eradication of disease in the axilla. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS).

Previously published prospective trials have demonstrated that breast cancer patients with clinically positive axillary lymph nodes, who disease following neoadjuvant therapy is converted to clinically node negative disease, can safely undergo Sentinel Lymph Node Biopsy (SLNB) rather than axillary lymph node dissection, as the false negative rates are less than 10%, when 3 or more sentinel lymph nodes are retrieved. However, the rates of axillary lymph node recurrence in this population, has remained unclear. The purpose of this study was to evaluate axillary nodal recurrence rates in a consecutive cohort of breast cancer patients with clinically positive axillary lymph nodes, treated with neoadjuvant chemotherapy, who had negative disease following treatment, on Sentinel Lymph Node Biopsy.

This study included 769 patients with Stage II-III, biopsy-proven, node-positive breast cancer, of whom 610 patients were eligible for Sentinel Lymph Node Biopsy following neoadjuvant chemotherapy. Ninety one percent (N=555) converted to clinical node negative disease on physical examination, following neoadjuvant chemotherapy and 513 patients had 3 or more SLNs retrieved. Overall Axillary Lymph Node Dissection was avoided in 234 patients with 3 or more pathologically negative sentinel lymph nodes. The median patient age in this study cohort of 234 patients was 49 years. Median tumor size was 3 cm, 62% were HER2-positive, and 18% were triple negative. Majority of the patients (91%) received Doxorubicin-based neoadjuvant chemotherapy, 88% received adjuvant Radiotherapy (RT), and 70% of these patients also received nodal RT. The Primary outcome was the nodal recurrence rate among breast cancer patients with clinically positive axillary lymph nodes, treated with Sentinel Lymph Node Biopsy alone after neoadjuvant chemotherapy. Nodal recurrence was defined as a recurrence in the ipsilateral axillary, supraclavicular, or internal mammary nodal basins. Local recurrence was defined as an ipsilateral breast tumor recurrence. Distant failure included any distant metastases.

At a median follow up of 40 months, there was 1 axillary nodal recurrence, synchronous with local recurrence, in a patient who refused Radiation Therapy. Among patients who received Radiation Therapy (N=205), there were no nodal recurrences. The 5-year distant Recurrence Free Survival was 92.7%. The 5-year Overall Survival was 94.2%.

It was concluded from this study that in patients with clinically positive axillary lymph nodes, rendered clinically node negative with neoadjuvant chemotherapy, with 3 or more pathologically negative sentinel lymph nodes on Sentinel Lymph Node Biopsy alone, nodal recurrence rates were low without routine Axillary Lymph Node Dissection. These findings support surgical de-escalation by omitting Axillary Lymph Node Dissection in patients with clinically positive axillary lymph nodes, treated with neoadjuvant chemotherapy.

Nodal Recurrence in Patients with Node-Positive Breast Cancer Treated With Sentinel Node Biopsy Alone After Neoadjuvant Chemotherapy—A Rare Event. Barrio AV, Montagna G, Mamtani A, et al. JAMA Oncol. Published online October 7, 2021. doi:10.1001/jamaoncol.2021.4394

Late Breaking Abstract – ESMO 2021: ENHERTU® Superior to KADCYLA® in Patients with HER2 Positive Metastatic Breast Cancer

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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-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®.

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®, 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.

In the DESTINY-Breast 01 Phase II registration trial involving patients with HER2-positive metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, the Objective Response Rate (ORR) was 60.9%, with 6% Complete Responses and 54.9% Partial Response, with a median response duration of 14.8 months. The median PFS was 16.4 months. This benefit was consistent across all key subgroups, including patients who had previously received PERJETA® therapy.

DESTINY-Breast 03 is a global, multicenter, open-label, randomized Phase III study, in which the efficacy and safety of ENHERTU® was compared with KADCYLA®, in patients with HER2-positive metastatic breast cancer previously treated with Trastuzumab and a Taxane. In this study, 524 pts were randomized 1:1 to receive ENHERTU® 5.4 mg/kg (N=261) or KADCYLA® 3.6 mg/kg (N=263) once every 3 weeks. The median patient age was 54 years and patients in both treatment groups were comparable in terms of baseline characteristics including age, HER2-positivity status, ECOG Performance Status, prior treatment for breast cancer, brain metastases, and prior cancer therapy with agents including Trastuzumab. The Primary endpoint was Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Duration of Response, PFS by investigator, and Safety.

At the time of the prespecified interim analysis of this study, the median follow up was approximately 16 months and the median PFS by BICR review was Not Reached with ENHERTU® and was 6.8 months with KADCYLA® (HR=0.28; P= 7.8 × 10−22). This represented a very statistically significant 72% reduction in the risk for progression or death with ENHERTU® compared to KADCYLA®. The investigator-assessed PFS was similar (25.1 versus 7.2 months, HR=0.26, P<0.0001). This PFS benefit was observed as early as 4 weeks and remained consistent throughout the follow up period. PFS was significantly higher with ENHERTU® in all prespecified key subgroups, including Hormone Receptor status, prior treatment with PERJETA®, visceral disease, number of prior lines of therapy, and the presence or absence of brain metastases. Majority of patients in the ENHERTU® group experienced a reduction in tumor size, and the ORR was significantly higher among patients in the ENHERTU® compared to those who received KADCYLA® (79.7% versus 34.2%; P<0.0001), with a near doubling of the Complete Response rate in the ENHERTU® group, at 16.1% compared to 8.7% in the KADCYLA® group. The estimated 12-month Overall Survival rate was 94.1% versus 85.9% respectively (HR=0.56; P=0.007), but was not considered significant as it did not cross the prespecified boundary for significance, likely due to the immaturity of the dataset.

Adjudicated treatment related Interstitial Lung Disease/pneumonitis was more common in the ENHERTU® compared with the KADCYLA® treatment arm, at rates of 10.5% and 1.9%, respectively and most of the events were Grade 1 or 2 in severity, and none at Grade 4 or 5 in either treatment group. Interstitial Lung Disease profile was of less concern, than was seen in previous trials of ENHERTU® in more heavily pretreated patients. All Left Ventricular Ejection Fraction decreases were Grade 1 or 2 and were seen in 2.7% of the ENHERTU® group and in 0.4% of KADCYLA® group.

The researchers concluded that ENHERTU® demonstrated a highly statistically significant and clinically meaningful improvement in Progression Free Survival, when compared to KADCYLA®, in patients previously treated with Trastuzumab and Taxane for HER2-positive metastatic Breast cancer, with manageable toxicity and a significant improvement in Interstitial Lung Disease profile. The authors added that these data support ENHERTU® becoming the standard of care for second line treatment of HER2-positive metastatic breast cancer.

Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Cortés J, Kim SB, Chung WP, et al. Presented at: European Society for Medical Oncology 2021 Virtual Congress. September 16-21, 2021; virtual. Abstract LBA1.

KEYTRUDA® in Combination with Chemotherapy Improves Overall Survival in Triple Negative Breast Cancer

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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. 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. 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. 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. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first line treatment of advanced TNBC.

KEYNOTE-355 is a randomized, double-blind, Phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-Paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2, IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (Yes versus No). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and Safety.

The authors had previously reported that KEYTRUDA® in combination with chemotherapy, significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. Among patients with CPS of 1 or greater, the median PFS was 7.6 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for the placebo plus chemotherapy arm (HR= 0.74; P=0.0014). This however based on prespecified statistical criteria, was not considered statistically significant. Among the entire Intention-To-Treat (ITT) population, the median PFS was 7.5 months in the KEYTRUDA® plus chemotherapy group, compared with 5.6 months for chemotherapy plus placebo group (HR=0.82).

The researchers have now reported the Overall Survival results after a median follow up of 44.1 months. The OS in the subgroup of patients with PD-L1 CPS of 10 or more was significantly better with first line KEYTRUDA® plus chemotherapy versus placebo plus chemotherapy (23.0 months versus 16.1 months, respectively; HR=0.73; P=0.0093). This represented a 27% reduction in the risk of death with the KEYTRUDA® combination. Among this subgroup, factors significantly associated with superior outcomes included age 65 yrs and older, use of Paclitaxel as the on-study chemotherapy, no prior adjuvant therapy, de novo metastasis, Disease Free Interval of 12 months or more, and less than 3 metastatic sites. However, this OS benefit was not noted in the subgroup of patients with PD-L1 CPS scores of 1 or less. In this subgroup, the median OS was 17.6 months in the KEYTRUDA® group and 16 months in the placebo group (HR=0.86; P=Not Significant). The same was true among the Intention-To-Treat (ITT) population, including all randomized patients regardless of PD-L1 tumor status. In this patient group, the median OS was 17.2 months in the KEYTRUDA® group and 15.5 months in the placebo group, and this was not statistically significant (HR=0.89).

The authors concluded that these updated results support KEYTRUDA® in combination with chemotherapy as a new standard-of-care treatment regimen for patients with locally recurrent unresectable or metastatic Triple Negative Breast Cancer, whose tumors express PD-L1, with CPS of 10 or more.

KEYNOTE-355: Final results from a randomized, double-blind phase 3 study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Cortes J, Cescon DW, Rugo HS. et al. European Society for Medical Oncology (ESMO) Annual Meeting 2021: Abstract LBA16. Presented on September 19, 2021.

Updated Overall Survival with KISQALI® plus FASLODEX® in Advanced Breast Cancer

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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 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. 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. 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-RIBOCICLIB

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

In the MONALEESA-2 Phase III trial, KISQALI® in combination with FEMARA® (Letrozole) was compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior therapy for their advanced breast cancer. The addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS), compared to FEMARA® alone. In the MONALEESA-7 Phase III study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with placebo in combination with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS and OS, compared with placebo plus endocrine therapy. The MONALEESA-7 trial recently reported an exploratory updated OS analysis with a median follow up of 53.5 months. In this analysis, KISQALI® plus endocrine therapy showed a clinically relevant and significant median OS benefit of 58.7 months compared with 48.0 months in the placebo plus endocrine therapy group.

MONALEESA-3 is a multicenter, international, randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior endocrine therapy or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first line versus second line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Overall Response Rate (ORR), and Safety. The authors had previously reported that in the MONALEESA-3 trial, there was a significant OS benefit for KISQALI® plus FASLODEX® versus placebo plus FASLODEX®, with an median OS of Not Reached (NR) versus 40.0 months (HR=0.72; P=0.00455).

The researchers in this publication reported an exploratory OS analysis update for MONALEESA-3, with an extended follow up (median, 56.3 months) in order to analyze the long-term OS benefit of KISQALI® plus FASLODEX® versus placebo plus FASLODEX®, similar to MONALEESA-7 trial. There was a significant OS benefit with a median OS of 53.7 months in the KISQALI® group versus 41.5 months in the placebo group (HR=0.73). The estimated 4-year survival rates were 54% and 45% for KISQALI® and placebo, respectively, while the 5-year survival rates were estimated to be 46% and 31% respectively. Subgroup analysis according to prior lines of endocrine therapy showed that patients in the first line subgroup had an median OS of Not Reached in the KISQALI® group and 51.8 months in the placebo group (HR=0.64). In the second line setting, the median OS was 39.7 months in the KISQALI® group versus 33.7 months in the placebo group (HR=0.78). No new safety signals were observed.

It was concluded that this extended follow up analysis of MONALEESA-3 is the longest reported follow up for any CDK4/6 inhibitor clinical trial in the postmenopausal women, and demonstrated a durable Overall Survival benefit with KISQALI® plus FASLODEX®, compared to FASLODEX® alone, in patients with HR-positive, HER2-negative advanced breast cancer. Further, this benefit was maintained when KISQALI® was given both as first line as well as second line therapy, and across subgroups of patients studied.

Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Slamon DJ, Neven P, Chia S, et al. Annals of Oncology 2021; 32:1015-1024.

Duration of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer

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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.

Luminal breast cancer is the most prevalent molecular subtype in postmenopausal females, accounting for over 70%. Despite substantial improvements in adjuvant therapies, the risk of disease recurrence continues indefinitely, with more than half the recurrences occurring after the first 5 years following diagnosis. Following initial adjuvant endocrine therapy with Tamoxifen for 5 years, the addition of extended adjuvant therapy has resulted in 40% longer Disease Free Survival (DFS), when compared to placebo or no extended therapy. However the benefit of extending adjuvant Aromatase Inhibitor therapy for 5 years beyond the initial 5-year duration regimen is less well established. Further, the most effective duration of such extended adjuvant endocrine therapy remains unclear. Added to this dilemma are the side effects associated with Aromatase Inhibitor therapy including hot flushes, arthralgia, and bone pain, as well as treatment-induced osteoporosis, which can have a significant impact on patient’s quality of life. Researchers in the Secondary Adjuvant Long-Term Study with Arimidex [Anastrozole] (SALSA) prospectively investigated whether an additional 2 years or 5 years of Anastrozole therapy would result in better outcomes, following the initial 5 years of endocrine therapy, in postmenopausal women with Hormone Receptor-positive breast cancer.

The authors conducted a prospective, multicenter, randomized, Phase III trial, which included 3,470 eligible postmenopausal women with Stages I, II or III early stage breast cancer with no evidence of recurrence. Enrolled patients had invasive Hormone Receptor-positive breast cancer, and had received 5 years (plus or minus 12 months) of adjuvant endocrine therapy with Tamoxifen, Aromatase Inhibitors, or both sequentially, up until 12 months before randomization. Patients were randomly assigned 1:1 to receive Anastrozole 1 mg, orally daily, for either 2 additional years for a total of 7 years (N=1732) or 5 additional years for a total of 10 years (N=1738). The two treatment groups were well balanced. The median age at the time of randomization was 64 years, 72% of patients had tumors that were smaller than 2 cm, 66% had node-negative disease, and 19% had high-grade tumors. Stratification criteria included pathological tumor stage, pathological node stage, primary adjuvant endocrine therapy and adjuvant chemotherapy.

The primary analysis included all the patients who were still participating in the study (N=3208), including 1,603 in the 2-year group versus 1,605 in the 5-year group. In the primary analysis population of 3208 patients, 51% had received Tamoxifen alone for the initial 5 years, 7.3% had received an Aromatase Inhibitor alone, and 41.7% had received an Aromatase Inhibitor in combination with Tamoxifen. The Primary end point was Disease Free Survival (DFS). Secondary end points were Overall Survival (OS), contralateral breast cancer, second primary cancer, and clinical bone fracture. The median follow-up after randomization was 118 months.

The researchers observed no difference in DFS with 2 versus 5 additional years of adjuvant endocrine therapy with Anastrozole. The DFS 10 years since randomization was 73.6% in the 2-year group versus 73.9% in the 5-year group (HR=0.99; P=0.90). Contralateral breast cancer occurred in 2.2% versus 2.1% of patients (HR= 1.15), and local recurrence occurred in 3% versus 2.4% in the 2 year and 5 year groups, respectively. There was no difference noted for Overall Survival at 8 years between the two treatment groups (87.5% in the 2-year group and 87.3% in the 5-year group, HR for death from any cause=1.02). The risk of clinical bone fracture however was higher in the 5-year group than in the 2-year group (HR=1.35).

It was concluded from this study that in postmenopausal women with Hormone Receptor positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending endocrine therapy with an Aromatase Inhibitor by an additional 5 years provided no benefit over a 2-year extension, but was associated with a greater risk of bone fracture.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. Gnant M, Fitzal F, Rinnerthaler G, et al. N Engl J Med 2021; 385:395-405.

FDA Approves KEYTRUDA® for High Risk Early Stage Triple Negative Breast Cancer

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SUMMARY: The FDA on July 26, 2021, approved KEYTRUDA® (Pembrolizumab) for high risk, early stage, Triple Negative Breast Cancer (TNBC), in combination with chemotherapy, as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment following surgery. The FDA also granted regular approval to KEYTRUDA® in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score – CPS 10 or more), as determined by an FDA approved test. FDA granted accelerated approval to KEYTRUDA® for this indication in November 2020.

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. 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. 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. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. For all these reasons, pCR is considered a valid endpoint for clinical testing of neoadjuvant therapy in patients with early stage TNBC. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. Cytotoxic chemotherapy releases tumor-specific antigens and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Preliminary results from Phase I and II trials have shown that in patients with TNBC, KEYTRUDA® given along with chemotherapy in a neoadjuvant setting resulted in a high rate of pCR.

The present FDA approvals were based on KEYNOTE-522, which is an international, randomized, multicenter, double-blind, placebo controlled Phase III trial, conducted to evaluate the safety and efficacy of neoadjuvant KEYTRUDA® plus chemotherapy followed by adjuvant KEYTRUDA® or placebo, in patients with early stage TNBC. In this study, 1,174 patients were randomly assigned in a 2:1 ratio to receive neoadjuvant KEYTRUDA® 200 mg IV every 3 weeks (N=784) or placebo (N=390). All patients received 4 cycles of Carboplatin plus Paclitaxel, followed by 4 cycles of Doxorubicin or Epirubicin plus Cyclophosphamide, in the neoadjuvant setting. Following definitive surgery, adjuvant KEYTRUDA® or placebo was continued every 3 weeks for 9 cycles or until disease recurrence or unacceptable toxicity. Enrolled TNBC patients were newly diagnosed, early stage, high risk, treatment naïve, and included both node-negative and node-positive patients with nonmetastatic disease (Tumor Stage T1c, Nodal Stage N1-N2 or Tumor Stage T2-T4, Nodal Stage N0-N2, per AJCC criteria). Patients were enrolled regardless of tumor PD-L1 expression. Treatment groups were well balanced and patients were stratified according to nodal status, tumor size, and Carboplatin schedule (weekly versus every 3 weeks). The two Primary endpoints were pathological Complete Response (pCR) at the time of definitive surgery and Event Free Survival (EFS).

At the first interim analysis, at a median follow up of 15.5 months, the pCR among the first 602 patients who underwent randomization was 64.8% in the KEYTRUDA® plus chemotherapy group, compared with 51.2% in the placebo plus chemotherapy group (HR=0.63; P<0.001). At the median follow-up of 39 months, EFS data were made available, and this showed that KEYTRUDA® demonstrated a statistically significant EFS benefit compared with chemotherapy alone. The number of patients who experienced an EFS event was 16% and 24%, respectively (HR=0.63; P=0.00031). Among patients who were in the PD-L1 positive, defined as those with a CPS of 1 or higher, there was a 33% reduced risk of EFS events with KEYTRUDA® compared with the placebo group (HR=0.67). In the PD-L1 negative group, patients receiving the KEYTRUDA® combination had a reduced risk for EFS events by 52% compared with the placebo-chemotherapy group (HR=0.48). Across all treatment phases, Grade 3 or higher treatment-related toxicities were 78.0% in the KEYTRUDA® plus chemotherapy group and 73.0% in the placebo plus chemotherapy group

It can be concluded from this study that among patients with early stage Triple Negative Breast Cancer, the addition of KEYTRUDA® to neoadjuvant chemotherapy significantly increased the pathological Complete Response rate, compared to those who received placebo plus neoadjuvant chemotherapy, with a statistically significant Event Free Survival benefit. This KEYTRUDA® combination therapy is a meaningful milestone for breast cancer patients, and is the first immunotherapy regimen to be approved in high risk, early stage Triple Negative Breast Cancer.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer.