Category: Hem/Onc Updates

FDA Approves LYNPARZA® for Germline BRCA-Mutated Metastatic Breast Cancer

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SUMMARY: The FDA on January 12, 2018, granted regular approval to LYNPARZA® (Olaparib), a Poly ADP-Ribose Polymerase (PARP) inhibitor, for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer, who have been treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. This is the first FDA-approved treatment for patients with gBRCAm HER2-negative metastatic breast cancer. Patients with Hormone Receptor (HR) positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Patients must be selected for therapy based on an FDA-approved companion diagnostic for LYNPARZA®.

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 are expected to be diagnosed in 2018 and about 40,920 women are expected to die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.Mechanism-of-Action-of LYNPARZA

The PARP (Poly ADP Ribose Polymerase) family of enzymes, which include PARP1 and PARP2 repair damaged DNA. LYNPARZA® is a PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations. The FDA approved LYNPARZA® in 2014 as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated advanced ovarian cancer.

The present approval was based on data from OlympiAD, a randomized, open-label, phase III study that evaluated the efficacy and safety of LYNPARZA® compared with physician’s choice of standard single agent chemotherapy, in patients with HER2-negative metastatic breast cancer, with inherited, germline BRCA mutations. In this study, 302 patients were randomized in a 2:1 ratio to receive LYNPARZA® tablets 300 mg PO BID (N=205) or physician’s choice of standard chemotherapy (N=97). The later included 21-day cycles of either XELODA® (Capecitabine) 2500 mg/m2 orally on days 1-14, NAVELBINE® (Vinorelbine) 30 mg/m2 IV days 1 and 8 or HALAVEN® (Eribulin)1.4 mg/m2 IV days 1 and 8. Treatment was continued until disease progression or unacceptable toxicity. The median age was 44 years, and all patients had received prior chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients in this study were stratified based on prior use of chemotherapy for metastatic disease, Hormone Receptor status (HR positive versus triple negative), and previous use of platinum-based chemotherapy. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), time to second progression or death, Objective Response Rate (ORR) and effect on health-related Quality of Life.

At a median follow up of about 14 months, the median PFS was 7 months in the LYNPARZA® group versus 4.2 months with standard chemotherapy (HR=0.58; P=0.0009), suggesting a 42% reduced risk of cancer progression in the LYNPARZA® group compared to those who received chemotherapy. Following disease progression, the time to second progression (which meant duration of time before the cancer worsened again), was also longer in the LYNPARZA® group (HR 0.57), suggesting that recurrent disease was not more aggressive following progression on LYNPARZA®. The ORR was 60% and 29% in LYNPARZA® and chemotherapy groups respectively. Severe side effects were more common in chemotherapy treated patients (50%) compared with LYNPARZA® group (37%). The most common side effects in the LYNPARZA® group included nausea, fatigue and cytopenias, whereas rash on hands and feet were most common in the chemotherapy group.

The authors concluded that LYNPARZA® monotherapy significantly improved Progression Free Survival in HER2-negative metastatic breast cancer patients, with inherited germline BRCA mutations, compared to standard chemotherapy. This “proof of the principle” study demonstrated that breast cancers with defects in a specific DNA damage repair pathway are sensitive to targeted therapy and this is the first of several phase III studies with PARP inhibitors that are underway. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). Robson ME, Im S-A, Senkus E, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA4).

Late Breaking Abstract – ESMO 2017 FDA Approves OPDIVO® for Adjuvant Treatment of Malignant Melanoma

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SUMMARY: The FDA on December 20, 2017, granted regular approval to the anti-PD1 monoclonal antibody, OPDIVO® (Nivolumab) for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection. OPDIVO® was previously approved for the treatment of patients with unresectable or metastatic melanoma. It is estimated that in the US, approximately 91,270 new cases of melanoma will be diagnosed in 2018 and about 9,320 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma 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 with stage IIIB and stage IIIC disease have a disease specific survival rates of 59% and 40% respectively.Adjuvant OPDIVO for Melanoma

Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoint proteins (“gate keepers”) suppress antitumor immunity. Antibodies targeting these, membrane bound, inhibitory, Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc., block the Immune checkpoint proteins and unleash T cells, resulting in T cell proliferation, activation and a therapeutic response.

The approved adjuvant therapies over the past two decades, for patients with high-risk melanoma have included high-dose INTRON® A (Interferon alfa-2b), SYLATRON® (peginterferon alfa-2b), and high-dose YERVOY® (Ipilimumab). The significant toxicities associated with these adjuvant interventions, precluded the wide spread use of adjuvant therapy in high risk melanoma. YERVOY® was approved by the FDA for the adjuvant treatment of patients with completely resected, Stage III melanoma, based on an improvement in Relapse Free Survival, when compared to placebo, in a randomized phase III trial. In this study however, over 50% of the patients treated with the recommended high dose YERVOY® experienced grade 3/4 toxicities. There is therefore an unmet need for adjuvant therapies, with improved benefit-risk ratio, for this patient group.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. Monotherapy with OPDIVO®, in heavily pretreated advanced Melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment. The present approval by the FDA was based on CheckMate 238 trial, which is a double-blind, phase III study that included 906 patients with completely resected, Stage IIIB/C or Stage IV melanoma. Patients were randomized in a 1:1 ratio to receive either OPDIVO® 3 mg/kg IV, every 2 weeks (N=453) or YERVOY® 10 mg/kg IV, every 3 weeks (N=453) for 4 doses, then every 12 weeks beginning at week 24, for up to 1 year. Both treatment groups were well balanced. The Primary end point was Recurrence Free Survival (RFS).

The Recurrence Free Survival rate at 18 months with OPDIVO® was 66.4% compared with 52.7% for YERVOY® (HR=0.65; P<0.0001). This meant a 35% reduction in the risk of recurrence or death with the OPDIVO® versus YERVOY®. The most common adverse reactions were headache, fatigue, nausea, diarrhea, abdominal discomfort, rash, pruritus and musculoskeletal pain. OPDIVO® was associated with significantly fewer treatment-related grade 3/4 toxicities compared to YERVOY® (14% versus 46%). Treatment was discontinued due to toxicities in approximately 10% of the patients in the OPDIVO® group, compared with 42% of patients in the YERVOY® group.

The authors concluded that OPDIVO® is a less toxic, better tolerated, adjuvant treatment option than YERVOY®, for patients with resected stage IIIB/C and IV melanoma, regardless of BRAF mutation, with a superior Relapse Free Survival rate. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238). Presented at ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA8_PR.

Late Breaking Abstract – ASH 2017 VENCLEXTA® plus RITUXAN® Superior to Bendamustine plus RITUXAN® in patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

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SUMMARY: The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. The FDA granted an accelerated approval to VENCLEXTA® in 2016, for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.VENCLEXTA plus RITUXAN for CLL

MURANO trial is an open-label, international, multicenter, phase III study which included 389 patients with relapsed/refractory CLL who had received 1-3 prior lines of therapy, including at least one chemotherapy regimen. Patients were randomized 1:1 to receive a combination of either VR – VENCLEXTA® plus RITUXAN® (N=194) or BR – Bendamustine plus RITUXAN® (N=195). In the VR group, VENCLEXTA® tablets were given once daily with a weekly dose ramp-up schedule (20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg and then the recommended daily dose of 400 mg), over a period of 5 weeks, given along with Tumor Lysis Syndrome prophylaxis. Patients were treated with the 400 mg daily dosing for a maximum of 2 yrs or until disease progression. RITUXAN® (Rituximab) was given beginning week 6, and was administered at 375 mg/m2 on day 1, cycle 1, followed by 500 mg/m2 on day 1 of cycles 2 thru 6, of a 28 day cycle. In the BR group, Bendamustine was given at 70 mg/m2 on days 1 and 2 of each 28 day cycle for a total of 6 cycles along with RITUXAN®, using the same RITUXAN® dosing schedule as in the VR group. Patients were stratified based on del(17p) status and responsiveness to prior therapy. The median age was 65 years, 26% of the patients had del(17p) and 15% of the patients were refractory to Fludarabine. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Overall Response Rate (ORR) and Complete Response (CR). The median follow up was 23.8 months.

Following recommendation from the Independent Data Monitoring Committee, the study arms were unblinded before the preplanned interim analysis. It was noted that the PFS was significantly superior in the VR group compared to BR (HR=0.17, P<0.0001; median Not Reached versus 17.0 months). This meant an 83% reduction in the risk of disease progression or death in the VR group compared with the BR group. The 24 month PFS estimates were 84.9% vs 36.3%, respectively favoring VENCLEXTA®. This PFS benefit was consistently seen in all subgroups assessed, including those with del(17p), p53 mutation and IgVH unmutated status. The ORR in the VR group was 93.3% versus 67.7% in the BR group (P<0.0001) and CR was achieved in 26.8% versus 8.2% of patients respectively. The rate of MRD (Minimal Residual Disease)-negativity, defined as less than 1 CLL cell in 10,000 leukocytes, attained at any time, was also higher with VR at 83.5% versus 23.1% with BR. Further, the MRD negativity was more durable in the VENCLEXTA® group. Overall Survival evaluation is ongoing. Grade 3/4 neutropenia was higher in VR group but there was no increase in febrile neutropenia or Grade 3/4 infection.

It was concluded from this primary analysis of MURANO trial that, VENCLEXTA® in combination with RITUXAN® resulted in a significant improvement in Progression Free Survival, Overall Response Rate, Complete Response rate, along with durable improvement in peripheral blood MRD negativity, when compared with Bendamustine and RITUXAN®, in patients with relapsed/refractory CLL. Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia – Results from Pre-Planned Interim Analysis of the Randomized Phase 3 Murano Study. Seymour JF, Kipps TJ, Eichhorst BF, et al. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, Georgia. Abstract LBA-2.

A Potential Cure for Hemophilia Using Gene Therapy

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SUMMARY: Hemophilia A is an X-linked, recessive bleeding disorder caused by mutations in the gene encoding coagulation Factor VIII, resulting in deficiency of functional plasma clotting Factor VIII (FVIII). Hemophilia A can also arise from spontaneous mutation in the gene encoding coagulation Factor VIII. Patients with severe Hemophilia A (Factor VIII activity level less than 1 IU/dl) are at a high risk for spontaneous bleeding in joints and soft tissue, resulting in painful disabling arthropathy as well as increased risk of intracranial hemorrhage and early death. These patients often are on prophylactic Factor VIII therapy and may also require on-demand therapy with Factor VIII for breakthrough bleeding. In spite of the availability of Factor VIII concentrates with extended half-life, patients still require frequent infusions, to maintain adequate hemostasis. This can have a negative impact on quality of life and additionally can result in the development the alloantibodies (inhibitors) that can neutralize the effect of exogenously administered replacement clotting factors.Gene Therapy

Gene therapy enables the introduction of a normal copy of the gene into the cells and thereby restores the function of the abnormal or missing protein. Because a gene cannot be inserted directly into a cell, a carrier called a vector is genetically engineered to deliver the gene. Majority of gene therapy clinical trials employ viruses as vectors, as these viruses are able to deliver the new gene by infecting the cell and hijacking the cellular machinery for propagation. The viruses are modified to prevent them from causing disease. As vectors, the most extensively studied viruses are Retroviruses, Adenoviruses and Adeno-Associated Viruses (AAVs). Retroviruses integrate their genetic material (including the new gene) into a chromosome in the human cell, whereas Adenoviruses introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected directly into a specific tissue in the body or given intravenously. Alternately, a sample of the patient’s cells can be exposed to the vector in the lab and the cells containing the vector can then be given back to the patient. If the treatment is successful, the new gene delivered by the vector, will start making a functioning protein.

The authors in this study developed AAV5-hFVIII-SQ (valoctocogene roxaparvovec), an AAV serotype 5 vector, in order to overcome specific challenges such as the large size of the Factor VIII coding region and inefficient expression of the human Factor VIII coding sequence. They then conducted a dose-escalation study involving nine patients. Eligible patients were adults with severe Hemophilia A, with no history of Factor VIII inhibitor development and without detectable immunity to the AAV5 capsid. Enrolled patients received a single IV infusion of AAV5-hFVIII-SQ and participants were enrolled sequentially into Low dose, Intermediate dose and High dose cohorts, and the follow up period was 52 weeks. All patients who had been receiving prophylactic Factor VIII therapy previously were withdrawn from prophylaxis. Patients were however permitted to self-administer Factor VIII therapy in the event of bleeding after gene transfer. The Primary end point was safety and the Primary efficacy goal was a Factor VIII activity level of at least 5 IU/dl, at week 16 after gene transfer. Secondary efficacy measures included the frequency of Factor VIII use and the number of bleeding episodes.

It was noted that in the High dose cohort (6×1013 vector genomes-vg/kg), the Factor VIII activity level was more than 5 IU/dl between weeks 2 and 9 after gene transfer and the level in six patients normalized (more than 50 IU/dl) and was maintained at 1 year after treatment with a single dose. Further in this high dose cohort, the median annualized bleeding rate among patients who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and by week 22, none of the patients in this cohort reported the use of Factor VIII for bleeding. The main adverse event was a slight elevation in the serum alanine aminotransferase (ALT) level. Neutralizing antibodies (inhibitors) to Factor VIII were not detected.

The authors concluded that gene therapy with a high dose infusion of AAV5-hFVIII-SQ was associated with the normalization of Factor VIII activity level over a period of 1 year with stabilization of hemostasis and a profound reduction in Factor VIII use. This landmark study has the potential to pave the way for a cure for Hemophilia patients. AAV5–Factor VIII Gene Transfer in Severe Hemophilia A. Rangarajan S, Walsh L, Lester W, et al. N Engl J Med 2017; 377:2519-2530

Recombinant Hyaluronidase Significantly Improves Progression Free Survival in Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2017, about 53,670 people will be diagnosed with pancreatic cancer in the United States and about 43,090 patients will die of the disease. Some important risk factors for pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The FDA approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use, in combination with GEMZAR® (Gemcitabine), for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved Overall Survival (OS) and Progression Free Survival (PFS) with this combination, when compared to single agent GEMZAR®, in a multicenter, international, open-label, randomized trial (MPACT study).

PEGPH20 is a PEGylated form of recombinant human Hyaluronidase, for the potential systemic treatment of tumors that accumulate Hyaluronan (HA). PEGPH20 is an enzyme that temporarily degrades Hyaluronan, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells and potentially constrict blood vessels and there by impede treatment access to tumor tissue. It is estimated that 35% to 40% of patients with pancreatic cancer have high expression of Hyaluronan and this biomarker may predict response to PEGPH20.

HALO-202 is a phase 2 multicenter, randomized clinical trial, in which PEGPH20 in combination with ABRAXANE® and GEMZAR® (N=166) – PAG, was compared with ABRAXANE® and GEMZAR® – AG (N=113), in treatment-naive patients, with metastatic pancreatic carcinoma. In this study, following enrollment of 146 patients in the first stage of the trial, the study was placed on hold to address concerns regarding thromboembolic events, in the group receiving PEGPH20. The protocol was amended to exclude those at high risk for a thromboembolic event and prophylaxis with Low Molecular Weight Heparin was required. One hundred thirty-three patients (N=133) were enrolled into the second stage of the trial for a total of 279 patients. Patients enrolled in stage 2 received Low Molecular Weight Heparin at a starting dose of 40 mg/day or 1 mg/kg/day, to prevent thromboembolic events. Each 4-week treatment cycle consisted of 3 weekly treatments and 1 week off. PEGPH20 was administered at 3 µg/kg twice weekly for cycle 1 followed by weekly administration in subsequent cycles. ABRAXANE® and GEMZAR® were administered weekly at their standard FDA-approved doses of 125 mg/m2 and 1,000 mg mg/m2 respectively. Tumor biopsy samples for the Hyaluronan analysis were available for 138 patients treated with PEGPH20 and 79 patients treated in the control group, across both stages of the study. Overall, 49 patients in the PEGPH20 arm and 35 in the control group had Hyaluronan expression of 50% or more. The Primary endpoint of the study was Progression Free Survival (PFS) across the entire treatment group. Following change in the treatment protocol, a second Primary endpoint was added to assess thromboembolic event rate. Secondary endpoints included Objective Response Rate, PFS by Hyaluronan level, and Overall Survival. The second stage of this study was also utilized to validate a companion diagnostic for Hyaluronan (HA) levels.

It was noted that across the overall study population, there was a statistically significant increase in Progression Free Survival (PFS) in the PEGPH20 group compared to the control group (6 months versus 5.2 months; HR=0.73; P=0.49). In patients with high levels of Hyaluronan (HA-High), the PFS was 9.2 months among those treated with PEGPH20 plus ABRAXANE® and GEMZAR® versus 5.2 months among patients receiving ABRAXANE® and GEMZAR® alone (HR = 0.51, P = 0.048). The additional Primary endpoint of a reduction in the rate of thromboembolic events was achieved, in the PEGPH20 group. Across all patients, thromboembolic events were experienced by 14% of those in the PEGPH20 group versus 10% of those in the ABRAXANE® and GEMZAR® group. These events were lower in those receiving Low Molecular Weight Heparin at 1 mg/kg/day dose versus 40 mg/day (6% vs 10%, respectively). The most common adverse events were cytopenias.

The authors concluded that the addition of PEGPH20 to ABRAXANE® and GEMZAR® resulted in significant improvement in Progression Free Survival compared with ABRAXANE® plus GEMZAR® alone, in treatment naïve patients with advanced pancreatic cancer. Patients with high levels of expression of the biomarker Hyaluronan, had the best outcomes suggesting that a biopsy-based biomarker for hyaluronan content can potentially identify patients who will have a meaningfully greater response when PEGPH20 is added to standard chemotherapy. A phase III study is underway, evaluating PEGPH20 in combination with ABRAXANE® and GEMZAR® in patients with metastatic pancreatic cancer, with high Hyaluronan levels. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. Hingorani SR, Zheng L, Bullock AJ, et al. DOI: 10.1200/JCO.2017.74.9564 Journal of Clinical Oncology – published online before print December 12, 2017

Hormonal Contraception Increases Breast Cancer Risk

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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. It is estimated that 252,710 new cases of invasive breast cancer and 63,410 new cases of non-invasive breast cancer will be diagnosed in women in 2017 and 40,610 women are expected to die from the disease. It is estimated that approximately 140 million women worldwide use hormonal contraception and this number accounts for approximately 13% of women between the ages of 15 and 49 years. The use of hormonal contraception has been on the rise.

Estrogen promotes the development of breast cancer. Previous published studies had shown positive associations between the use of oral contraceptives and breast cancer risk, but the results have been inconsistent from no increase in risk to a 20-30% increase in risk. Further, unlike contemporary hormonal contraception, oral contraceptives in the past contained a higher estrogen dose in the combined estrogen/progestin hormonal contraceptives, and the higher dose of estrogen has been implicated in the development of breast cancer. Contemporary products with new progestins and new routes of delivery (intrauterine system, contraceptive patches, vaginal rings, progestin-only implants, and injections) has raised new concerns, with some studies suggesting that the addition of progestin appears to increase the risk of breast cancer among postmenopausal women who receive hormone therapy. There is evidence to suggest that use of hormonal contraception at a young age may confer a higher risk of breast cancer than initiation of use later in life.

This Danish study, using their national registry, reported the risk of invasive breast cancer risk among women of reproductive age, who were using currently available hormonal contraception. This prospective cohort study conducted in Denmark included 1.8 million women between 15-49 years of age, who did not have a diagnosis of cancer or venous thromboembolism, and who had not received treatment for infertility. Individually updated information about the use of hormonal contraception, breast cancer diagnoses, and potential contributing factors, was obtained from nationwide registries.

It was noted that when compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (20% higher than average). This risk increased from 1.09 (9% higher than average) with less than 1 year of use to 1.38 (38% higher than average) with more than 10 years of hormonal contraception use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer continued to be higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives, with a relative risk of 1.21 (21% higher than average). Outcomes in this study however, could not be adjusted for age at menarche, breast feeding, alcohol consumption, physical activity or Body Mass Index.

It was concluded from this large study population that, the risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use. Additionally, these results unequivocally suggest that no hormonal contraceptives are free of risk. Contemporary Hormonal Contraception and the Risk of Breast Cancer. Mørch LS, Skovlund CW, Hannaford PC, et al. N Engl J Med 2017; 377:2228-2239

FDA Approves BOSULIF® for Newly Diagnosed Chronic Myeloid Leukemia

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SUMMARY: The FDA on December 19, 2017 granted accelerated approval to BOSULIF® (Bosutinib) for treatment of patients with newly diagnosed Chronic Phase Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML). Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,950 new CML cases will be diagnosed in the United States in 2017 and about 1,080 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. BOSULIF® is a potent, dual Abl and Src tyrosine kinase inhibitor and was approved by the FDA in 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML) with resistance or intolerance to prior therapy.

Monitoring MMR in CMLThis new approval for BOSULIF® was based on the efficacy and safety data from BFORE trial, which is an ongoing randomized, open-label, multicenter, phase III study in which in 487 patients with Ph+ newly diagnosed Chronic Phase CML were randomized to receive either BOSULIF® 400 mg once daily (N=246) or GLEEVEC® (Imatinib) 400 mg once daily (N=241). The median age of patients was 53 years, the Sokal risk group was intermediate and high for 40% and 21% of patients, respectively, and over two thirds of the patients had an ECOG PS score of 0. Sokal score is calculated using a formula that includes Age, Spleen size, Platelet count and percentage of Myeloblasts and has three risk groups: Low-risk (Sokal score<0.8), Intermediate-risk (Sokal score 0.8-1.2) and High-risk (Sokal score >1.2). The Primary endpoint was Major Molecular Response (MMR) at 12 months, defined as BCR-ABL ratio on International Scale of 0.1% or less, which corresponded to 3 or more log reduction from standardized baseline.

After 12 or more months of follow up, the MMR at 12 months was 47.2% in the BOSULIF® group and 36.9% in the GLEEVEC® group (P=0.02) and the time to achieve a MMR was shorter in the BOSULIF® group (P<0.02). The Complete Cytogenetic Response (CCyR) at 12 months was also significantly higher with BOSULIF® versus GLEEVEC® (77.2% vs 66.4%; P< 0.008), with the time to achieve a CCyR, shorter for BOSULIF® (P<0.001). The most common adverse reactions in the BOSULIF® group included rash, nausea, diarrhea, abdominal discomfort, thrombocytopenia, increased ALT and AST levels.

It was concluded that BOSULIF® is an important and useful treatment option for patient with newly diagnosed Chronic Phase CML. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): Initial results from the BFORE trial. Cortes JE, Gambacorti-Passerini C, Deininger MWN, et al. J Clin Oncol. 2017;35 (suppl; abstr 7002).

Hormonal Contraception Increases Breast Cancer Risk

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It is estimated that approximately 140 million women worldwide use hormonal contraception and this number accounts for approximately 13% of women between the ages of 15 and 49 years. Estrogen promotes the development of breast cancer and there is evidence to suggest that use of hormonal contraception at a young age may confer a higher risk of breast cancer than initiation of use later in life.
In a recent study (N Engl J Med 2017; 377:2228-2239), it was noted that the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (20% higher than average). This risk increased from 1.09 (9% higher than average) with less than 1 year of use to 1.38 (38% higher than average) with more than 10 years of hormonal contraception use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer continued to be higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives, with a relative risk of 1.21 (21% higher than average). These findings unequivocally suggest that no hormonal contraceptives are free of risk.

Direct Oral Anticoagulant SAVAYSA® Noninferior to Subcutaneous FRAGMIN® for Cancer-Associated Venous Thromboembolism

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.

Approximately 20% of cancer patients develop VTE and the current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations, based on efficacy data. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. Direct Oral Anticoagulant agents have been proven to be as effective as Warfarin, a Vitamin K antagonist, for the treatment of VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. However, the efficacy and safety of Direct Oral Anticoagulants for the treatment of cancer-associated VTE have not been established.Anticoagulants

SAVAYSA® (Edoxaban)‎ an oral Factor Xa inhibitor was compared with subcutaneous Low Molecular Weight Heparin FRAGMIN® (Dalteparin), for the treatment of patients with cancer-associated VTE in the Hokusai VTE Cancer trial. This open-label, noninferiority trial randomized 1050 patients in a 1:1 ratio to receive either SAVAYSA® or FRAGMIN®. SAVAYSA® was given after an initial course of physician’s choice of Low Molecular Weight Heparin, given subcutaneously in therapeutic doses, for at least 5 days. SAVAYSA® was administered orally at a fixed dose of 60 mg once daily. FRAGMIN® was given subcutaneously at a dose of 200 IU/kg once daily for 30 days and at a dose of 150 IU/kg once daily thereafter. This treatment was continued for up to 12 months. The median age was 64 years and 90% of the patients had solid tumors and were on various chemotherapy regimens. The primary endpoint was a composite of recurrent VTE or major bleeding during the 12 months after randomization, regardless of treatment duration.

It was noted that SAVAYSA® was noninferior to FRAGMIN® with regards to composite rates of recurrent VTE and bleeding, which occurred in 12.8% of those receiving SAVAYSA® and 13.5% of those receiving FRAGMIN®. The similarity between the two treatment groups met statistical criteria for demonstrating noninferiority for SAVAYSA® (P=0.006). The rate of recurrent VTE was numerically lower with SAVAYSA® compared with FRAGMIN® (7.9% vs 11.3%, HR=0.71; P=0.09). The rate of major bleeding was however significantly higher with SAVAYSA® compared with FRAGMIN® (6.9% vs 4.0%, HR=1.77; P=0.04). This difference was mainly due to higher rate of upper gastrointestinal bleeding with SAVAYSA® in patients with gastrointestinal cancers. The frequency of severe major bleeding (category 3 or 4) however was similar in both treatment groups.

It was concluded that Direct Oral Anticoagulant, SAVAYSA® was noninferior to subcutaneous Low Molecular Weight Heparin, FRAGMIN® with respect to the composite outcome of recurrent Venous ThromboEmbolism or major bleeding. The lower rate of recurrent VTE observed with SAVAYSA® was offset by a similar increase in the risk of major bleeding. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. Raskob GE, Van Es N, Verhamme P, et al. for the Hokusai VTE Cancer Investigators. December 12, 2017DOI: 10.1056/NEJMoa1711948

Consolidation with IMFINZI® after Chemoradiotherapy Improves Outcomes in Patients with Unresectable Stage III Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Approximately one third of all patients with NSCLC have stage III, locally advanced disease at the time of initial presentation. Worldwide, about 500,000 patients are diagnosed with unresectable, stage III NSCLC, each year. These patients include those with locally advanced primary tumors with tumor invading the vital mediastinal organs, as well as those with involvement of locoregional mediastinal lymph nodes. These patients are often treated with platinum-based doublet chemotherapy with concurrent radiation and have a median Progression Free Survival (PFS) of approximately 8 months and 5 year survival of only 15%. There is hence a significant unmet need for this patient group, with no major treatment advances thus far.PD1 and PDL1 Inhibitors

Preclinical evidence had suggested that chemotherapy and radiotherapy may upregulate PD-L1 expression in tumor cells. IMFINZI® (Durvalumab) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) and CD80, thereby unleashing the T cells to recognize and kill tumor cells. IMFINZI® showed encouraging antitumor activity in an early phase clinical study involving multiple advanced solid tumors, including stage IIIB or IV NSCLC. IMFINZI® was recently approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who had received prior platinum-based chemotherapy.

The authors in this publication evaluated the role of immune checkpoint blockade in locally advanced, unresectable, stage III NSCLC. PACIFIC trial is a randomized, double-blind, international, phase III study in which IMFINZI® as consolidation therapy was compared with placebo, in patients with stage III, locally advanced, unresectable NSCLC, that had not progressed following platinum-based chemoradiotherapy. Eligible patients received two or more cycles of platinum-based doublet chemotherapy concurrently with definitive radiation therapy (54-66 Gy). Following completion of concurrent chemoradiation treatment, 713 patients were randomized, of whom 709 patients in a 2:1 ratio received consolidation treatment, within 6 weeks after completion of chemoradiation with IMFINZI® 10 mg/kg every 2 weeks (N=473) or placebo (N=236), for up to 12 months. The median age was 64 years, and the majority of patients were men (70%) and 46% had a squamous histology. The coprimary end points were Progression Free Survival (PFS) and Overall Survival (OS). Secondary end points included 12-month and 18-month PFS rates, Objective Response Rate (ORR), Duration of Response, time to death or distant metastasis, and safety. The authors reported the results of a preplanned interim analysis after a median follow up of 14.5 months.

The median PFS from randomization to consolidation treatment was 16.8 months with IMFINZI® versus 5.6 months with placebo (HR=0.52; P<0.001). This meant a 48% decrease in the probability of disease progression with IMFINZI® and this improvement was consistent across all patient subgroups that were analyzed. The 12-month PFS was 55.9% vs 35.3%, and the 18-month PFS rate was 44.2% vs 27.0%, in favor of IMFINZI®. The ORR was higher with IMFINZI® compared to placebo (28.4% vs 16.0%; P<0.001), and the median Duration of Response was longer as well, with 73% of the patients in the IMFINZI® group having an ongoing response at 18 months versus 47% of the patients in the placebo group. Patients in the IMFINZI® group also had a lower incidence of new brain metastases. The median time to death or distant metastasis was longer with IMFINZI® compared with placebo (23.2 months vs 14.6 months; P<0.001). Adverse events of any grade occurred in 68% of patients in the IMFINZI® group compared to 53% in the placebo group and majority of the toxicities were grade 1 or 2, and grade 3 or higher toxicities were infrequent (less than10%), in both treatment groups. Treatment had to be discontinued due to pneumonitis in 6.3% of patients on IMFINZI® and 4.3% on placebo.

It was concluded that IMFINZI® significantly prolonged PFS in all prespecified groups of patients with locally advanced stage III NSCLC, and toxicity profile was acceptable. Biomarkers, such as mutational load or immunosignature, may be of value, as PD-L1 expression had little or no impact on outcomes. The National Comprehensive Cancer Network (NCCN) Guidelines have been updated to include one year of consolidation therapy with IMFINZI®, after curative-intent chemoradiation, for inoperable stage III lung cancer. Durvalumab after Chemoradiotherapy in Stage III Non-Small Cell Lung Cancer. Antonia SJ, Villegas A, Daniel D, et al. for the PACIFIC Investigators. N Engl J Med 2017; 377:1919-1929