Category: Hem/Onc Updates

Metastatic Pancreatic Cancer ASCO Clinical Practice Guideline Update

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SUMMARY: The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with pancreatic cancer and about 45,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcomes for patients with advanced pancreatic cancer, has been dismal with a 5-year survival rate for metastatic pancreatic cancer of approximately 2%.

The ASCO Expert Panel in 2016 published a guideline to assist in clinical decision making in metastatic pancreatic cancer for initial assessment after diagnosis, first and second-line treatment options, palliative and supportive care, and follow-up. This present update incorporated new evidence related to second-line therapy, published between June 2015 and January 2018, for patients who have experienced disease progression or intolerable toxicities during first-line therapy.

INITIAL ASSESSMENT

Recommendation 1.1: A multiphase CT scan of the Chest, Abdomen, and Pelvis should be performed to assess extent of disease. Other staging studies should be performed only as dictated by symptoms.

Recommendation 1.2: The baseline Performance Status, symptom burden, and comorbidity profile of a patient with metastatic pancreatic cancer should be evaluated carefully.

Recommendation 1.3: The goals of care including a discussion of an advance directive, patient preferences, as well as support systems, should be discussed with every patient with metastatic pancreatic cancer and his or her caregivers.

Recommendation 1.4: Multidisciplinary collaboration to formulate treatment and care plans and disease management for patients with metastatic pancreatic cancer should be the standard of care.

Recommendation 1.5: Every patient with pancreatic cancer should be offered information about clinical trials, which include therapeutic trials in all lines of treatment as well as palliative care, biorepository/biomarker, and observational studies.

FIRST-LINE TREATMENT

Recommendation 2.1: FOLFIRINOX (Leucovorin, Fluorouracil, Irinotecan, and Oxaliplatin) is recommended for patients who meet all of the following criteria: an ECOG PS of 0-1, favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Recommendation 2.2: Gemcitabine plus NAB-Paclitaxel is recommended for patients who meet all of the following criteria: an ECOG PS of 0-1, a relatively favorable comorbidity profile, and patient preference and a support system for relatively aggressive medical therapy.

Recommendation 2.3: Gemcitabine alone is recommended for patients who have either an ECOG PS of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-directed therapy. The addition of either Capecitabine or Erlotinib to Gemcitabine may be considered in this setting.

Recommendation 2.4: Patients with an ECOG PS 3 or more or with poorly controlled comorbid conditions despite ongoing active medical care should be offered cancer-directed therapy only on a case-by-case basis. The major emphasis should be on optimizing supportive care measures.

SECOND-LINE TREATMENT

Recommendation 3.1: Routine testing for dMMR or MSI-H is recommended, using IHC, PCR, or NGS for patients who are considered to be candidates for checkpoint inhibitor therapy.

Recommendation 3.2: PD-1 immune checkpoint inhibitor pembrolizumab is recommended as second-line therapy for patients who have tested positive for dMMR or MSI-H.

Recommendation 3.3: Gemcitabine plus NAB-Paclitaxel can be offered as second-line therapy to patients who had received first-line treatment with FOLFIRINOX, have an ECOG PS of 0-1, with a relatively favorable comorbidity profile, and patient preference and a support system for aggressive medical therapy.

Recommendation 3.4: Fluorouracil plus nanoliposomal Irinotecan, or Fluorouracil plus Irinotecan where the former combination is unavailable, is preferred as second-line therapy for patients who meet all of the following criteria: first-line treatment with Gemcitabine plus NAB-Paclitaxel, an ECOG PS of 0-1, a relatively favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Recommendation 3.5: Fluorouracil plus Oxaliplatin may be considered as second-line therapy for patients who meet all of the following criteria: first-line treatment with Gemcitabine plus NAB-Paclitaxel, an ECOG PS of 0-1, a relatively favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Qualifying statement for Recommendations 3.4 and 3.5: A recent phase III trial comparing mFOLFOX6 with FU + LV demonstrated a higher rate of grade 3 or 4 adverse events and significantly reduced OS within the mFOLFOX6 arm of the trial. However, previous phase III data have demonstrated a benefit with the OFF regimen compared with FU + LV. Considering the inconsistency of these results, although Fluorouracil plus nanoliposomal Irinotecan is preferred, the Expert Panel continues to support the use of Fluorouracil plus Oxaliplatin as an option where the availability of Fluorouracil plus nanoliposomal Irinotecan is limited or where residual toxicity from first-line therapy or comorbidities preclude the use of Fluorouracil plus nanoliposomal Irinotecan.

Recommendation 3.6: Gemcitabine or Fluorouracil can be considered as second-line therapy for patients who have either an ECOG PS of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-directed therapy.

Recommendation 3.7: No data are available to recommend third-line (or greater) therapy with a cytotoxic agent. Clinical trial participation is encouraged

PALLIATIVE CARE

Recommendation 4.1: Patients with metastatic pancreatic cancer should have a full assessment of symptom burden, psychological status, and social supports as early as possible, preferably at the first visit. In most cases, this assessment will indicate a need for a formal palliative care consult and services.

TREATMENT of PAIN and SYMPTOMS

Recommendation 5.1: Patients with metastatic pancreatic cancer should be offered aggressive treatment of the pain and symptoms of the cancer and/or the cancer-directed therapy.

FOLLOW-UP/SURVEILLANCE

Recommendation 6.1: For patients on active cancer-directed therapy outside a clinical trial, imaging to assess first response should be offered at 2-3 months from the initiation of therapy. CT scans with contrast are the preferred modality. Thereafter, clinical assessment, conducted frequently during visits for cancer-directed therapy, should supplant imaging assessment. The routine use of PET scans for the management of patients with pancreatic cancer is not recommended. CA19-9 is not considered an optimal substitute for imaging for the assessment of treatment response.

Recommendation 6.2: No data exist on the duration of cancer-directed therapy. An ongoing discussion of goals of care and assessment of treatment response and tolerability should guide decisions to continue or to hold or terminate cancer-directed therapy.

Metastatic Pancreatic Cancer: ASCO Clinical Practice Guideline Update. Sohal DPS, Kennedy EB, Khorana A, et al. J Clin Oncol. 2018;36:2545-2556.

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

Increased Risk of Breast Cancer after Recent Childbirth

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In a large International Premenopausal Breast Cancer study which included close to 900,000 women, compared with nulliparous women, parous women had an increased risk for breast cancer that peaked about 5 years after childbirth and then gradually decreased about 24 years after childbirth.The increase in breast cancer risk after childbirth may be due to proliferation of breast cells during pregnancy which could promote accelerated development of latent initiated tumor cells. Childbirth also brings about maternal changes beyond breast tissue including altered immune function and microbiota, increased stress, and accelerated aging processes. Health Care Professionals should take these factors into account when considering individual risk profiles for breast cancer in premenopausal women.

Increased Risk of Breast Cancer after Recent Childbirth

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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 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the most common cancer type in reproductive-aged women. Women with biological children (parous women) are at a lower risk for developing breast cancer compared to nulliparous women. However, parity as a protective factor largely applies to breast cancer developing after age 60 years and may not apply for younger premenopausal women. Evidence from national registry linkage studies in Scandinavian countries suggested that recent childbirth confers a short-term increase in breast cancer risk which may last for 10 years or more, and this risk may be further increased in women who are older at first childbirth. Studies published thus far have not shown consistent findings and have had limited ability to account for factors influencing breast cancer risk such as breastfeeding and family history of breast cancer.

One biological explanation for an increase in breast cancer risk after childbirth may be due to proliferation of breast cells during pregnancy which could promote accelerated development of latent initiated tumor cells. This may also explain the higher breast cancer risk, conferred by older age at first childbirth, as a result of higher proportion of latent initiated tumor cells at older ages. Further, the postpartum breast microenvironment, characterized by lactational involution may also facilitate cancer cell migration and metastasis. Childbirth also brings about maternal changes beyond breast tissue including altered immune function and microbiota, increased stress, and accelerated aging processes.

The authors in this study used data from the International Premenopausal Breast Cancer Collaborative Group and conducted a pooled analysis of individual-level data from 15 prospective cohort studies. In this analysis, the researchers included women younger than 55 years and evaluated the risk of breast cancer in relation to recent childbirth, while taking into account other factors that relate to breast cancer risk such as breastfeeding, numbers of pregnancies and births and family history of breast cancer. It is felt that understanding these risk patterns may have implications for identifying risk-reducing strategies among vulnerable subgroups. A total of 889, 944 women, were available for analysis after excluding women who reported a first birth before age 13 years, women who were 50 years or older at study entry and at most recent birth, or reached parity greater than 10 births before enrollment. All these events were considered to have greater potential for data errors. The mean age at study entry was 42 years.

The researchers noted that compared with nulliparous women, parous women had an increased risk for breast cancer that peaked about 5 years after childbirth and then gradually decreased about 24 years after childbirth. These findings however were not noted among women who had only 1 child, or had their first child before age 25 years. The risk was highest in women who were older at the time of first childbirth, multiparous women and those who had a family history of breast cancer. Among those women with a family history of breast cancer, the risk was the greatest for Estrogen Receptor negative breast cancer. Breast feeding did not influence breast cancer risk patterns.

It was concluded that compared with nulliparous women, parous women have an increased risk for breast cancer after childbirth that is highest the first 5 years but decreases over the following 20 years. Health Care Professionals should take these factors into account when considering individual risk profiles for breast cancer in premenopausal women. Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies. Nichols HB, Schoemaker MJ, Cai J, et al. Ann Intern Med. 2019;170:22-30

Late Breaking Abstract – ASH 2018 New Simplified Practice-Changing Protocol for Interrupting Direct Oral Anticoagulants for Surgery/Procedure

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SUMMARY: Direct Oral AntiCoagulants (DOACs) are often prescribed for thromboembolic events. This class of anticoagulants, have a rapid onset and offset of action, short half-life, predictable anticoagulant effects, no laboratory monitoring and fixed dosing schedule. The half-life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and direct oral anticoagulants are ineffective in patients with mechanical heart valves. In several clinical studies, DOACs have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN® (Warfarin).Anticoagulants

It is estimated that each year 10-15% of patients on DOACs will undergo an invasive procedure or surgery and will require temporary interruption of anticoagulation prior to standard-risk procedures and procedures with increased risk for bleeding. There are presently five DOACs approved in the US. They include PRADAXA® (Dabigatran), which is a Direct Thrombin Inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors.

The perioperative management of patients who are taking a Direct Oral AntiCoagulant (DOAC) for Atrial Fibrillation and require an elective surgery/procedure, has remained unclear, as there is no published data on the timing of perioperative DOAC interruption and resumption, and if perioperative Heparin bridging and coagulation function testing before surgery are needed. The purpose of the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study was to establish a simple protocol that did not require perioperative anticoagulant bridging or coagulation function testing.

PAUSE is a prospective study of DOACs, which included 3 parallel cohorts of patients with Atrial Fibrillation taking ELIQUIS® (N=1257), PRADAXA® (N=668) or XARELTO® (N=1082), and requiring anticoagulant interruption for an elective surgery/procedure. This current analysis included patients from Canada, U.S. and Europe. A third of the patients (33.5%) were scheduled to undergo a high-bleeding risk surgery and the adjusted stroke risk among these patients was about 4.5%, based CHADS2 scores. The mean patient age was 72.5 years and 66% of patients were men.

The researchers in this study used a standardized protocol based on pharmacokinetic properties of the DOACs, procedure-associated bleeding risk, Creatinine Clearance, and held DOACs for 1 day before and 1 day after surgery for procedures with low bleeding risk, and for 2 days before and 2 days after for procedures with high bleeding risk. Patients on PRADAXA® with a creatinine clearance of less than 50 mL/min and who were planned for a procedure with a high bleeding risk, stopped the drug four days before and two days after surgery. Blood samples were obtained just before the procedure to measure residual DOAC levels. Bridging with Heparin and preoperative coagulation testing were not used to manage patients. Participants were followed weekly for 30 days post-procedure to measure incidence of major bleeding and Arterial ThromboEmbolism, which was the Primary endpoint.

The 30-day postoperative major bleeding rates were 1.35% in the ELIQUIS® group, 0.9% in the PRADAXA® group and 1.85% in the XARELTO® group. The rate of Arterial ThromboEmbolism was 0.16% in the ELIQUIS® group, 0.6% in the PRADAXA® group and 0.37% in the XARELTO® group. The researchers also measured preoperative DOAC levels in 85% of patients and noted that 99% of these patients having a high bleeding risk procedure had DOAC levels less than 50 ng/mL.

It was concluded that a standardized DOAC-specific perioperative management strategy was safe for patient care among patients with Atrial Fibrillation, who were taking a DOAC and required anticoagulant interruption for an elective surgery/procedure. Utilizing this standardized protocol was associated with low rates of perioperative major bleeding (less than 2%) and Arterial ThromboEmbolism (less than 1%). The authors added that PAUSE is the largest practice-changing study to date, that addresses perioperative DOAC management, and will very likely establish a treatment standard, impacting practice guidelines in perioperative care. Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant. Douketis J, Spyropoulos AC, Duncan JM, et al. Abstract LBA-5. Presented at the 2018 ASH Annual Meeting, December 4, 2018; San Diego, CA.

FDA Approves CABLIVI® for Thrombotic Thrombocytopenic Purpura

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SUMMARY: The FDA on February 6, 2019, approved CABLIVI® (Caplacizumab-yhdp) for adult patients with acquired Thrombotic Thrombocytopenic Purpura (aTTP), in combination with Plasma Exchange and immunosuppressive therapy. Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and Atypical Hemolytic Uremic Syndrome (aHUS) are life-threatening Thrombotic MicroAngiopathies (TMAs) associated with systemic microvascular thrombosis, MicroAngiopathic Hemolytic Anemia (MAHA), thrombocytopenia and organ failure. Even though their clinical presentation has some similarities, they are distinct entities with different pathophysiology and hence managed differently.Microangiopathic-Hemolytic-Anemia-Thrombocytopenia

Patients with TTP have either severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) secondary to anti-ADAMTS13 autoantibodies or rarely due to ADAMTS13 gene mutations. A diagnosis of TTP is therefore based on clinical presentation and laboratory results and is confirmed by documentation of severe ADAMTS13 deficiency, with ADAMTS13 activity levels of less than 10%. The physiological role of ADAMTS13 is to prevent intravascular platelet thrombosis. ADAMTS13 accomplishes this by cleaving ultralarge von Willebrand Factor multimers (which bind to platelets and induce aggregation), thereby mitigating the tendency of von Willebrand Factor (vWF) and platelets to form aggregates in normal microcirculation. Deficiency of ADAMTS13 causes vWF-platelet aggregation in the arterioles and capillaries, characteristic of TTP, resulting in tissue ischemia from microthrombi and end organ damage. Thus the microthrombi in TTP are platelets bound to vWF and not to fibrinogen. Rapid initiation of Plasma Exchange, the frontline therapy in patients with TTP, removes the anti-ADAMTS13 autoantibodies and ultra large vWF multimers and replenishes ADAMTS13. Immunosuppressive therapy with Glucocorticoids and RITUXAN® (Rituximab) inhibits anti-ADAMTS13 autoantibody formation, by targeting the B lymphocytes. These interventions have significantly improved the survival rate among patients with TTP. Despite these advances with the use of Plasma Exchange, approximately 20% of the patients with TTP will succumb to their disease. There is a persistent risk of life-threatening recurrences, which can occur as late as 10 or 20 years after an initial episode of TTP. Persistent or recurrent ADAMTS13 deficiency is a strong risk factor for recurrence.

CABLIVI® is an anti-von Willebrand Factor, humanized, bivalent, variable-domain-only immunoglobulin fragment (Nanobody), directed against the A1 domain of von Willebrand Factor and prevents the interaction of vWF with the platelet glycoprotein Ib-IX-V receptor and thus prevents microvascular thrombosis.

In a phase II study (TITAN trial), CABLIVI® given as an adjunct to Plasma Exchange significantly reduced the median time to a response, with more rapid normalization of platelet count, LDH and creatinine, and also reduced the incidence of major thromboembolic events as well as mean number of Plasma Exchange days, compared with placebo. However, patients who had persistent ADAMTS13 deficiency had a relapse soon after treatment with CABLIVI® was stopped, suggesting that monitoring of ADAMTS13 could be useful, to guide the continuation of therapy.

HERCULES trial is a multicenter, randomized, double blind, placebo controlled, phase III trial which evaluated the efficacy and safety of CABLIVI® in patients with acquired Thrombotic Thrombocytopenic Purpura. The trial also evaluated the benefit of CABLIVI® in reducing the risk of recurrence, by allowing for treatment to continue until immunosuppressive therapy resolved the underlying autoimmune disease. TTP was diagnosed based on clinical presentation (the presence of both thrombocytopenia and MicroAngiopathic Hemolytic Anemia with schistocytes seen on blood smear) and if they had received exactly one Plasma Exchange treatment. Severe ADAMTS13 deficiency was not an eligibility requirement and patients were excluded if they had suspected thrombotic microangiopathies that were not associated with TTP, such as Hemolytic Uremic Syndrome, or if they had congenital TTP.

This study randomly assigned 145 patients with TTP to receive CABLIVI® (N=72) or placebo (N=73). Patients in both groups received daily Plasma Exchange at 1 to 1.5 times the estimated plasma volume, until at least 2 days after normalization of the platelet count and Glucocorticoids (Prednisone or Prednisolone at a dose of 1 mg/kg or more of body weight per day during the daily Plasma Exchange period and continuing for the first week after the end of the daily Plasma Exchange period. Patients received CABLIVI® 10 mg IV loading bolus or placebo before the start of the first Plasma Exchange after randomization followed by 10 mg daily subcutaneously until 30 days after the last daily Plasma Exchange. Treatment was extended at 7-day intervals for a maximum of 28 days, if signs of persistent underlying disease such as suppressed ADAMTS13 activity levels were still present. The Primary outcome was the time to normalization of the platelet count, with discontinuation of daily Plasma Exchange within 5 days thereafter. Key Secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period, refractory TTP and normalization of organ-damage markers.

It was noted that the median time to normalization of the platelet count was shorter with CABLIVI® than with placebo and patients who received CABLIVI® were 1.55 times as likely to have a normalization of the platelet count as those who received placebo (P=0.01). The composite outcome event was 74% lower with CABLIVI® than with placebo (12% versus 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with CABLIVI® than with placebo (12% versus 38%, P<0.001). None of the patients in the CABLIVI® group developed refractory disease whereas 3 three patients in the placebo group did. Patients who received CABLIVI® required fewer Plasma Exchanges and had a shorter hospital stay, than those who received placebo. The most common adverse reactions in at least 15% of patients receiving CABLIVI® were epistaxis, headache, and gingival bleeding.

It was concluded that among patients with TTP, treatment with CABLIVI® resulted in a more rapid normalization of the platelet count, a lower incidence of a composite of TTP-related death, a lower incidence of recurrence of TTP or a thromboembolic event during the treatment period, and a lower rate of recurrence of TTP during the trial period, compared to placebo. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. Scully M, Cataland SR, Peyvandi F, et al., for the HERCULES Investigators. N Engl J Med 2019; 380:335-346.

Late Breaking Abstract – ESMO 2018 Radiation Therapy to the Primary Tumor Improves Overall Survival in a Subgroup of Metastatic Prostate Cancer Patients

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention. 

The ASCO clinical practice guideline published in 2018, recommended the addition of either TAXOTERE® (Docetaxel) or ZYTIGA® (Abiraterone acetate) to ADT, based on CHAARTED trial and STAMPEDE/LATITUDE trials respectively, for men with newly diagnosed metastatic Prostate cancer, based on the Overall Survival benefit with these combinations, when compared with the use of ADT alone. It is also well established that the addition of Radiation Therapy (RT) to Androgen Deprivation Therapy (ADT) improves Overall Survival compared to ADT alone, in patients with locally advanced Prostate cancer. Patients with metastatic Prostate cancer however are often treated with systemic therapy alone without any local intervention such as Radiation Therapy to the Prostate gland.

The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial is an ongoing phase III study and uses a novel multi-arm, multi-stage (MAMS) platform design, to test whether the addition of further treatments to ADT improves Overall Survival, when used in first-line setting, for patients with hormone sensitive, locally advanced or metastatic Prostate cancer. This group previously reported that there was a significantly improved Overall Survival with the addition of TAXOTERE® to initial ADT and also concluded that ZYTIGA® and prednisolone along with ADT results in significantly higher rates of Overall Survival as well as Failure-Free Survival, compared with ADT alone, among men with hormone sensitive, locally advanced or metastatic Prostate cancer.

The authors in this study had hypothesized based on studies in animal models that local treatment of the Prostate might not only improve local control but also slow progression of metastatic disease and improve Overall Survival in men presenting with metastatic Prostate cancer, and that survival benefit would be greater in men with lower metastatic burden. The accompanying results are from a preplanned analysis of one group in the multi-arm, multi-stage STAMPEDE study.

The study included 2,061 patients with newly diagnosed metastatic Prostate cancer who were randomized 1:1 to Standard of Care treatment consisting of lifelong Androgen Deprivation Therapy with or without early TAXOTERE® or the same Standard of Care plus Radiation Therapy to the Prostate. Radiotherapy was administered in two different schedules – either daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in 6 fractions for 6 weeks) based on investigator’s choice. The median age was 68 years, the median PSA level was 97 ng/mL and 18% received early TAXOTERE® treatment at the investigator’s discretion. Metastatic disease burden was characterized as Low in 40% and High in 54% and 6% was unknown. A High Prostate cancer disease burden was defined as 4 or more bone metastases, with at least 1 metastasis outside the axial skeleton and/or visceral metastases. The rest of the patients were characterized as having Low disease burden. The Primary outcome measure was Overall Survival and Secondary outcomes included Failure-Free Survival (FFS), and toxicity.

It was noted that Radiation Therapy to the Prostate improved FFS (HR=0.76; P<0.001) but not Overall Survival. However subgroup analysis showed that Radiation Therapy to the Prostate improved Overall Survival by 32% in the 819 men with lower metastatic disease burden (HR=0.68) and the 3 year Overall Survival rates were 81% in the Radiation Therapy arm versus 73% for Standard of Care, suggesting an absolute benefit of 8% and this was statistically significant (P =0 .007). By contrast, the 1120 men with higher metastatic disease burden did not benefit from Radiation Therapy. The Radiation Therapy schedule did not have any impact on outcomes. Radiation Therapy to the Prostate was well tolerated, with 5% of patients experiencing grade 3 or 4 adverse events during treatment and 4%, after treatment.

It was concluded that Prostate Radiotherapy in addition to systemic drug therapy improves the Overall Survival of men with newly diagnosed metastatic Prostate cancer who have a low metastatic disease burden, and should now be a standard treatment option. The authors added that this study did not include patients with pelvic node-positive nonmetastatic disease (N1, M0), where the addition of Radiotherapy to systemic drug therapy could be curative. Radiotherapy (RT) to the primary tumour for men with newly diagnosed metastatic prostate cancer (PCa): survival results from STAMPEDE (NCT00268476). Parker CC, James ND, Brawley C, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA5.