Month: March 2019

Adjuvant KADCYLA® Superior to HERCEPTIN® in High Risk HER2-Positive 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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 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. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.Mechanism-of-Action-KADCYLA

It is well established that patients with HER2-positive early breast cancer following HERCEPTIN® based neoadjuvant therapies have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy. KATHERINE trial was conducted to evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.

The KATHERINE trial is an open-label, phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Both treatment groups were well balanced and hormone receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). The median duration of follow up was 41.4 months in the KADCYLA® group and 40.9 months in the HERCEPTIN® group.

At the prespecified interim analysis, invasive disease occurred in 12.2% of patients who received KADCYLA® and 22.2% of patients who received HERCEPTIN®. The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the KADCYLA® group and 77.0% in the HERCEPTIN® group. Invasive Disease Free Survival, which was the Primary end point of the study, was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (HR=0.50; P<0.001).This suggested that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%. Distant recurrence as the first invasive disease event occurred in 10.5% of patients in the KADCYLA® group and in 15.9% of the HERCEPTIN® group. A consistent benefit was seen across all prespecified subgroups. Adverse events were consistent with the known safety profile of KADCYLA®, with more toxicities associated with KADCYLA® than with HERCEPTIN®. Additional follow-up will be necessary to determine the Overall Survival benefit with adjuvant KADCYLA®.

It was concluded that among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, substituting KADCYLA® for adjuvant HERCEPTIN® reduced the risk of recurrence of invasive breast cancer or death by 50%, with the benefit seen across all patient subgroups. The authors added that even though KATHERINE trial focused on higher-risk patients with residual invasive breast cancer after completion of neoadjuvant chemotherapy, CNS recurrence remains a persistent problem. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. von Minckwitz G, Huang C-S, Mano MS, et al. for the KATHERINE Investigators. (published online December 5, 2018). N Engl J Med 2019;380:617-628

FDA Approves Single Agent XOSPATA® for FLT3 Positive Acute Myeloid Leukemia

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SUMMARY: The FDA in November 2018 approved XOSPATA® (Gilteritinib) for treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test. The FDA also approved an expanded indication for a companion diagnostic, to include use with XOSPATA®. The LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, Inc., is used to detect the FLT3 mutation in patients with AML. The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.

Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The Fms-Like Tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the cell surface (transmembrane) and plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. FLT3 mutations occur most often as Internal Tandem Duplications (FLT3-ITD) or point mutations at codon D835 (FLT3-Tyrosine Kinase Domain or TKD). Approximately 80% of AML patients with a FLT3 mutation will have the FLT3-ITD, and about 15% will have both FLT3-ITD and FLT3-TKD, and about 5% will have FLT3-TKD alone. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations are predicted to have poor outcomes with shorter remission duration and significantly decreased leukemia free and Overall Survival. FLT3-TKD can confer resistance to other Tyrosine Kinase Inhibitors.MUTATED-FLT3-INDUCES-LIGAND-INDEPENDENT-PATHWAY-ACTIVATION

XOSPATA® (Gilteritinib) is a highly selective FLT3/AXL Tyrosine Kinase Inhibitor with activity against both FLT3-ITD and FLT3-TKD mutations. This unlike RYDAPT® (Midostaurin), which is a not selective and is a multikinase inhibitor and inhibits FLT3, PDGFR, c-KIT (CD 117), VEGFR, and protein kinase C. The approval of XOSPATA® was based on an interim analysis of the ADMIRAL trial, which included 138 adult patients with relapsed or refractory AML having a FLT3 ITD, D835, or I836 mutation as detected by the LeukoStrat CDx FLT3 Mutation Assay. XOSPATA® was given orally at a dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit. The median patient age was 60 years and 59% of patients had untreated relapsed AML, 41% had primary refractory AML and 20% of patients had prior Stem Cell transplantation. With regards to FLT3 mutation status, 121 patients had ITD alone, 12 patients had TKD alone, and 5 patients had ITD and TKD.

At the time of interim analysis, the complete remission (CR)/Complete Remission with partial hematologic recovery (CRh) rate was 21%. The median duration of CR/CRh was 4.6 months. The rate of conversion from transfusion dependence to transfusion independence was 31.1% for any 56 day post-baseline period. For those patients who were independent of both RBC and platelet transfusions at baseline, 53.1% remained transfusion-independent during any 56-day post-baseline period. . For patients who achieved a CR/CRh, the median time to first response was 3.6 months. The CR/CRh rate was 29 of 126 in patients with FLT3-ITD or FLT3-ITD/TKD and 0 of 12 in patients with FLT3-TKD only. The most common adverse reactions included skin rash, fatigue, diarrhea, elevated AST and ALT. Approximately 10% of patients required dose reductions, most commonly for diarrhea or fatigue.

It was concluded that XOSPATA® is the first and only FLT3-targeting therapy approved by the FDA, that can be used as a single agent for the treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia with a FLT3 mutation. Studies are underway evaluating XOSPATA® as maintenance therapy after allogeneic hematopoietic stem cell transplant in patients with FLT3-ITD positive AML. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627045.htm

Aspirin Lowers Risk for Ovarian and Hepatocellular Carcinoma

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SUMMARY: Aspirin (AcetylSalicylic Acid) has been studied as a chemopreventive agent for several decades and the temporal relationship between systemic inflammation and cancer has been a topic of ongoing investigation. The US Preventive Services Task Force (USPSTF) found adequate evidence that Aspirin use reduces the incidence of ColoRectal Cancer (CRC) in adults after 5-10 years of use, and recommends initiating low-dose Aspirin use for the primary prevention of CardioVascular Disease (CVD) and ColoRectal Cancer (CRC) in adults aged 50-69 years, who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose Aspirin daily for at least 10 years.MOA-of-ASPIRIN

The molecular mechanisms underlying Aspirin’s chemoprevention effects as well as the dose, duration, and timing of Aspirin chemoprevention have remained unclear. More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of COX-2. Daily low dose Aspirin inhibits COX-1 and COX-2. It is postulated that Aspirin also works by COX-independent mechanisms such as, the inhibition of NF-kB and Wnt/ β-catenin signaling, which may play a role in its chemopreventive properties.

Two recently published studies examining different doses of Aspirin in different cancers, highlight the beneficial role of Aspirin in reducing cancer risk.

The first report is a large prospective study which attempted to reproduce findings from case-control studies that reported lower Ovarian cancer risk among low-dose Aspirin users. This prospective study evaluated whether regular Aspirin or nonaspirin NonSteroidal Anti-Inflammatory Drug (NSAID) use and patterns of use was associated with lower risk of Ovarian cancer. This cohort study analyzed NSAID use and Ovarian cancer diagnosis data on 205,498 women from 2 prospective cohorts; 93 664 women in the Nurses’ Health Study (NHS), who were 93% non-Hispanic white, with a mean age at baseline of 46 years, followed up from 1980 to 2014, and 111834 women in the Nurses’ Health Study II (NHSII), who were 92% non-Hispanic white, with a mean age at baseline of 34.2 years, followed up from 1989 to 2015. For each analgesic type (Aspirin, low-dose Aspirin, nonaspirin NSAIDs, and Acetaminophen), timing, duration, frequency, and number of tablets used were evaluated, and information was updated every 2-4 years.

It was noted that among both cohorts, there were 1054 women who developed epithelial Ovarian cancer. Recent use of low-dose Aspirin (100 mg or less) was associated with a lower risk of Ovarian cancer (HR=0.77), whereas there was no such association noted with standard-dose of 325 mg Aspirin (HR=1.17). The associations between Aspirin use and risk of Ovarian cancer did not differ among premenopausal versus postmenopausal women. This study also suggested that use of non-aspirin NSAIDs, such as Ibuprofen and Naproxen, when taken in quantities of at least 10 tablets per week for multiple years was positively associated with an increased risk of Ovarian cancer. There was however no clear associations for the use of Acetaminophen.

The authors concluded that consistent with case-control studies, this prospective analysis showed a reduced risk of Ovarian cancer among regular users of low-dose Aspirin and an increased risk of Ovarian cancer with the use of nonaspirin NSAIDs. These findings suggest that low-dose Aspirin recommended for cardiovascular prophylaxis and ColoRectal Cancer risk reduction can also reduce the risk of Ovarian cancer.

The second report is another large prospective study which analyzed the data on the risk of HepatoCellular Carcinoma (HCC) within 2 populations of a total of 133 371 health care professionals who self reported use of Aspirin. In this pooled analysis, 87 507 were women, with a mean age was 62 years, and 45 864 were men, with a mean age of 64 years. Women reported data biennially since 1980 and men since 1986, on frequency, dosage, and duration of Aspirin use, and data were accessed from November 2017 through March 2018. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded.

The researchers noted that regular Aspirin use of 2 or more standard dose 325 mg tablets per week was associated with a 49% reduction in risk of HCC (adjusted HR=0.51) compared to non regular use. This benefit was dose-dependent with the greatest benefit among those taking more than 5 tablets per week (P for trend =0 .006). Further, significantly lower risk for HCC was observed with increasing duration of Aspirin intake (P for trend =0.03), with this decreasing risk noted with the use of 1.5 or more standard-dose Aspirin tablets per week for 5 or more years (adjusted HR=0.41). The use of nonaspirin NSAIDs however was not significantly associated with HCC risk.

The authors from this study concluded that regular and long-term use of standard dose (325 mg) Aspirin, taken at least 2 or more times per week is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use.

Taken together, these 2 studies provide the evidence supporting the ability of regular use of Aspirin to prevent Ovarian cancer and HepatoCellular Cancer (HCC). Aspirin is rapidly emerging as a valuable chemoprevention agent for various malignancies.

Association of Analgesic Use With Risk of Ovarian Cancer in the Nurses’ Health Studies. Barnard ME, Poole EM, Curhan GC, et al. JAMA Oncol. 2018;4:1675-1682.

Association Between Aspirin Use and Risk of Hepatocellular Carcinoma. Simon TG, Ma Y, Ludvigsson JF, et al. JAMA Oncol. 2018;4:1683-1690

FDA Approves KEYTRUDA® for Adjuvant Treatment of Melanoma

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SUMMARY: The FDA on February 15, 2019, approved KEYTRUDA® (Pembrolizumab) for the adjuvant treatment of patients with Melanoma with involvement of lymph node(s) following complete resection. It is estimated that in the US, approximately 96,480 new cases of Melanoma will be diagnosed in 2019 and about 7,230 patients are expected to die of the disease. The incidence of Melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage Melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Stage III malignant Melanoma however is a heterogeneous disease, and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78% whereas those patients with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively. Several agents are presently approved by the FDA for the adjuvant treatment of high-risk Melanoma and they include YERVOY® (Ipilimumab), OPDIVO® (Nivolumab), TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) for BRAF-mutant Melanoma and Interferon alfa. Unleashing-T-Cell-Function-with-Combination-Immunotherapy

KEYTRUDA® 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. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

The present FDA approval was based on the European Organization for Research and Treatment of Cancer (EORTC) 1325/(KEYNOTE-054) trial which is a randomized, double-blind, placebo-controlled Phase III study which involved high-risk patient population of patients with Stage III Melanoma. This study included 1019 patients with completely resected, Stage IIIA (more than 1 mm lymph node metastasis), IIIB or IIIC Melanoma. Patients were randomly assigned 1:1 to receive KEYTRUDA® 200 mg IV every three weeks (N=514) or placebo (N=505), as adjuvant therapy, for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. Enrolled patients required complete resection of Melanoma with negative margins and lymph node dissection. Patients with mucosal or ocular Melanoma were excluded. The Primary end points were Recurrence-Free Survival (RFS) in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-L1, as well as Safety.

At a median follow up of 15 months, KEYTRUDA® was associated with significantly longer Recurrence-Free Survival (RFS) compared to placebo in the overall intent-to-treat population, with a 1-year RFS rate of 75.4% versus 61.0% respectively (HR for recurrence or death=0.57; P<0.001). This suggested that the risk of recurrence or death in the total population was 43% lower in the KEYTRUDA® group than in the placebo group. Patients receiving KEYTRUDA® experienced fewer recurrences/deaths, 26% compared with 43% in the placebo group. The RFS benefit with KEYTRUDA® compared with placebo was observed regardless of tumor PD-L1 expression. In the subgroup of 853 patients with PD-L1-positive tumors, the 1-year RFS rate was 77.1% in the KEYTRUDA® group and 62.6% in the placebo group (HR=0.54; P<0.001). This suggested that the risk was 46% lower in the KEYTRUDA® group than in the placebo group, among patients with PD-L1-positive tumors. KEYTRUDA® was also consistently effective in patients with PD-L1-negative tumors and in those with undetermined tumor PD-L1 expression The Median RFS was 20.4 months in the placebo arm and not reached for those receiving KEYTRUDA®. The most common adverse reactions were rash, asthenia, influenza-like illness, diarrhea, pruritus, nausea, arthralgia and hypothyroidism.

It was concluded that KEYTRUDA® as adjuvant therapy for high-risk Stage III Melanoma, resulted in significantly longer Recurrence-Free Survival than placebo, with no new toxic effects identified. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. Eggermont AM, Blank CU, Mandala M, et al. N Engl J Med 2018;378:1789-1801