Category: Hem/Onc Updates

FDA Approves Antibody-Drug Conjugate POLIVY® for Diffuse Large B-Cell Lymphoma

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SUMMARY: The FDA on June 10, 2019, granted accelerated approval to POLIVY® (Polatuzumab vedotin-piiq), a CD79b-directed Antibody-Drug Conjugate, indicated in combination with Bendamustine and a Rituximab product, for adult patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL), Not Otherwise Specified, after at least two prior therapies.

The American Cancer Society estimates that in 2019, about 74,200 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

CD79b is a B-cell specific surface protein, which is a component of the B-cell receptor. POLIVY® is a CD79b-directed Antibody-Drug Conjugate (ADC) with activity against dividing B cells. It consists of three components: 1) the humanized ImmunoGlobulin G1 (IgG1) monoclonal antibody specific for human CD79b; 2) the small molecule anti-mitotic agent MMAE (monomethyl auristatin E) and 3) a protease-cleavable linker that covalently attaches MMAE to the Polatuzumab antibody. Upon binding to CD79b, POLIVY® is internalized, and the linker is cleaved by lysosomal proteases thus enabling intracellular delivery of MMAE. MMAE then binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.

The present FDA approval was based on an open-label, randomized, multicenter, Phase II clinical trial (Study GO29365) which included a cohort of 80 transplant-ineligible patients with Relapsed or Refractory DLBCL. Patients who had received at least one prior regimen were randomized (1:1) to receive either POLIVY® in combination with Bendamustine and RITUXAN® (Rituximab) or GAZYVA® (Obinutuzumab) – (P+BR) or BR alone, every 21 days for up to 6 cycles. RITUXAN® or GAZYVA® were administered on day 1 of each cycle at 375 mg/m2 intravenously IV or 1000 mg IV respectively, POLIVY® 1.8 mg/kg IV, was given on day 2 of cycle 1 and on day 1 of subsequent cycles and Bendamustine 90 mg/m2 IV was administered on days 2 and 3 of cycle 1 and on days 1 and 2 of subsequent cycles. The median age was 68 years.

The Primary aim of this study was to assess the efficacy of P+BR versus BR at end of treatment, by an Independent Review Committee (IRC). Responses were assessed using the modified Lugano Classification, and Complete Response (CR) required Positron Emission Tomography (PET) negativity and negative bone marrow biopsy, if positive or unknown at the time of screening. Other end points included Duration of Response (DoR), Progression Free Survival (PFS) and Overall Survival (OS). Efficacy was also evaluated based on Cell of Origin – Activated B-cell-like (ABC), Germinal B-cell-like (GCB), as well as MYC/BCL2 double expression. The median follow up for this cohort of patients was 22.3 months.

The combination of POLIVY® plus BR (P+BR) showed significantly higher PET-CR rates vs BR alone (40% vs 18%; P=0.026). The Objective Response Rate (ORR) was 45% vs 18% with a significantly longer DoR of 10.3 months vs 4.1 months (HR=0.44; P=0.032), favoring P+BR regimen. Among those who achieved Partial or Complete Response to P+BR, 64% had response durations of at least six months and 48% had response durations of at least 12 months. The PFS was 7.6 months vs 2 months (HR=0.34; P<0.0001) and OS was 12.4 months vs 4.7 months (HR=0.42; P=0.0023), all favoring P+BR over BR. For ABC patients the median PFS with P+BR was 10.5 months vs 2.5 months for BR and the median OS was 13.9 vs 4.3 months, respectively. For GCB patients, median PFS with P+BR was 4.7 vs 1.5 months for BR and the median OS was 9.3 vs 3.2 months, respectively. Among those with MYC/BCL2 Double Expression, the median PFS was 7.0 months vs 0.7 months with P+BR, and median OS was 12.9 vs 3.8 months compared to BR. For non-Double Expression group of patients, the median PFS was 6.3 months vs 2.5 months and median OS was 10.5 vs 3.8 months with P+BR vs BR, respectively.

It was concluded that a combination of POLIVY® given along with Bendamustine and RITUXAN® or GAZYVA® provides a promising treatment option for Relapsed/Refractory DLBCL patients who are transplant ineligible, with durables responses in some patients of over 20 months and median OS surpassing 12 months. Polatuzumab vedotin (Pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (Ph) Ib/II study. Sehn LH, Herrera AF, Matasar MJ, et al. Blood. 2018;132:1683.

Late Breaking Abstract – ASCO 2019 Front-Line Keytruda® Monotherapy for Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

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SUMMARY: The American Cancer Society estimates that in the US, about 27,510 cases of Gastric Cancer will be diagnosed in 2019 and about 11,140 people will die of the disease. The average age at diagnosis is 68 years and Gastric Cancer is one of the leading causes of cancer-related deaths in the world. Risk factors for gastric cancer include age, gender, ethnicity, geography and infection with Helicobacter pylori. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. KEYTRUDA® in the Phase II KEYNOTE-059 trial demonstrated promising antitumor activity and durable responses in patients with advanced Gastric/GastroEsophageal Junction cancer, who had progressed on more than 2 lines of therapy, with higher Objective Response Rates noted in patients with PD-L1-positive tumors.

KEYNOTE-062 is a randomized, phase III controlled study in which KEYTRUDA® monotherapy was compared to standard chemotherapy as first line treatment, in select patients with advanced Gastric or GastroEsophageal Junction (GEJ) Adenocarcinoma. This trial enrolled 763 newly diagnosed patients of whom 69% had Gastric Adenocarcinoma cancer and 30% had GEJ Adenocarcinoma. Patients were randomized 1:1:1 to receive KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=256), KEYTRUDA® plus Cisplatin 80 mg/m2 IV every three weeks along with either 5-Fluorouracil 800 mg/m2 daily on Days 1-5 every three weeks or XELODA® (Capecitabine) 1000 mg/m2 twice a day on Days 1-14 every three weeks (N=257 ) or placebo plus Cisplatin and either 5-FU or XELODA® given at a similar dose and schedule as the second group (N=250). The median patient age was 62 years and PD-L1 expression was assessed by Combined Positive Score (CPS). The Primary endpoints were Overall Survival (OS) in patients whose tumors expressed PD-L1 CPS 1 or more and CPS 10 or more in the KEYTRUDA® monotherapy group and in combination with chemotherapy group, as well as Progression Free Survival (PFS) in patients whose tumors expressed PD-L1 CPS 1 or more in the combination arm. Secondary endpoints included Overall Response Rate (ORR) and Duration of Response (DOR) in patients whose tumors express PD-L1 CPS 1 or more. In the current trial, all patients had a PD-L1 CPS of at least 1, and 281 patients (37%) had a PD-L1 CPS score of 10 or more. The median follow-up was 11.3 months.

The trial met its Primary endpoint and among patients with a PD-L1 CPS of 1 or more, Overall Survival was noninferior to chemotherapy. The median Overall Survival was 10.6 months in the KEYTRUDA® monotherapy group compared with 11.1 months in the chemotherapy group (HR=0.91). Among patients with a PD-L1 CPS 10 or more, Overall Survival with KEYTRUDA® was superior to chemotherapy. The median Overall Survival was 17.4 months for those receiving KEYTRUDA® compared with 10.8 months for those receiving chemotherapy. After 2 years, 39% of people taking KEYTRUDA® were alive compared with 22% of those taking chemotherapy (HR=0.69). The OS and PFS rates for the combination of KEYTRUDA® and chemotherapy were comparable with those of chemotherapy alone, regardless of PD-L1 CPS. The efficacy outcomes were not influenced by age, tumor size or location, histological subtype, number of metastatic sites and prior gastrectomy status.

It was concluded that KEYTRUDA® monotherapy is noninferior to chemotherapy for OS among patients with PD-L1 CPS 1 or more. There was however a clinically meaningful improvement in OS among patients with PD-L1 CPS 10 or more. Further, there was a more favorable safety profile for KEYTRUDA® over chemotherapy, making this a more desirable treatment option for elderly patients, for whom platinum based chemotherapy may not be appropriate. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. Tabernero J, Van Cutsem E, Bang Y-J, et al. J Clin Oncol 37, 2019 (suppl; abstr LBA4007)

Late Breaking Abstract – ASCO 2019 XTANDI® Improves Overall Survival in Metastatic Hormone-Sensitive Prostate Cancer

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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) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention.

The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is a nonsteroidal oral anti-androgen, that is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists. XTANDI® (Enzalutamide) is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens. Previously published studies have shown that XTANDI® improved Overall Survival in Castration-Resistant Prostate Cancer, regardless of whether it was used before or after Docetaxel chemotherapy. The benefits of adding Docetaxel or ZYTIGA® (Abiraterone) to testosterone suppression in men with metastatic, hormone-sensitive Prostate cancer have been established in randomized clinical trials.XTANDI - Mechanism-of-Action

ENZAMET (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer) is an open-label, international, randomized, Phase III trial, conducted to evaluate the benefits of adding XTANDI® to initial standard treatment of Androgen Deprivation Therapy (ADT) with or without early Docetaxel, among patients with metastatic hormone-sensitive Prostate cancer.

A total of 1125 men with metastatic hormone-sensitive Prostate cancer were randomly assigned 1:1 to receive either ADT plus XTANDI® or NonSteroidal Anti-Androgens (NSAA). ADT consisted of parenteral injection of a testosterone-suppressing agent (such as Goserelin, Leuprolide, or Degarelix) with either a 160 mg dose of XTANDI® daily or one of the standard NSAA’s such as CASODEX®, EULEXIN® or NILANDRON®. Of the 1,125 men enrolled in the trial, 503 men received early doses of Docetaxel, and 602 did not. The decision to initiate early treatment with Docetaxel was at the treating physician’s discretion and was administered at 75 mg/m2 IV without prednisone every 3 weeks for a maximum of six cycles. Randomized patients were stratified according to the volume of disease (High Risk- defined as the presence of visceral metastases or at least four bone lesions with at least one lesion located beyond the vertebral bodies and pelvis or low), planned use of early Docetaxel, planned use of bone antiresorptive therapy, and score on ACE-27 (Adult Comorbidity Evaluation 27), with no coexisting conditions rated as 0, mild rated as 1, moderate rated as 2, and severe or multiple conditions rated as 3. The mean age was 68 years, 45% of patients received early Docetaxel as planned treatment and over 50% of the patients had high volume disease. The Primary end point was Overall Survival (OS) and Secondary end points included Progression Free Survival (PFS) as determined by the PSA level, clinical PFS, and adverse events. The median follow up was 34 months.

At the time of the first interim analysis, there was a 33% reduction in the risk of death in the XTANDI® group compared to the standard treatment group ((HR=0.67; P<0.002) and the estimated Overall Survival at 3 years were 80% in the XTANDI® group and 72% in the standard-of-care group. The addition of XTANDI® also improved PSA Progression Free Survival with a 61% reduction in the risk of PSA progression (HR=0.39; P<0.001) and 60% improvement in clinical PFS (HR=0.40; P<0.001). The effects of XTANDI® on clinical PFS were noted in all predefined subgroups, including those with early Docetaxel treatment. Among the patient group who also received early Docetaxel treatment, there was however no significant improvement in Overall Survival. Adding XTANDI® to standard ADT was associated with a higher frequency of toxic effects, especially peripheral neuropathy, associated with the concomitant use of Docetaxel, fatigue and slightly higher risk of seizures compared to standard therapy, and more patients discontinued treatment due to adverse events in the XTANDI® group.

It was concluded that XTANDI® was associated with significantly longer Progression Free Survival and Overall Survival than standard intervention, in men with metastatic, hormone-sensitive Prostate cancer receiving Androgen Deprivation Therapy. Patients who received early Docetaxel treatment, however did not have significant survival benefit. The authors added that ENZAMET is the first metastatic hormone-sensitive Prostate cancer trial to report Overall Survival data of an androgen receptor inhibitor (XTANDI®), and outcomes among a set of patients who also concurrently received Docetaxel. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. Davis ID, Martin AJ, Stockler MR, et al. for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. June 2, 2019. DOI: 10.1056/NEJMoa1903835

Five-Year Outcomes with TAFINLAR® plus MEKINIST® in Metastatic Melanoma

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SUMMARY: 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. Patients with locally advanced or metastatic Melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes. In treatment naïve patients receiving anti-PD-1 therapies such as KEYTRUDA® (Pembrolizumab) or OPDIVO® (Nivolumab) in phase 3 trials, the Progression Free Survival (PFS) rates have ranged from 27-31%, with an Overall Survival (OS) rate of 46% at 4 years. The 5-year OS among patients receiving KEYTRUDA® was 43%, and in those treated with a combination of OPDIVO® plus YERVOY® (Ipilimumab), 4-year PFS and OS rates were 37% and 53%, respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in Melanoma is at the V600E/K site and is detected in approximately 50% of Melanomas, and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. It has been well established that patients who have unresectable or metastatic Melanoma with a BRAFV600E or V600K mutation have prolonged PFS and OS when treated with a combination of BRAF and MEK inhibitors. However, long-term 4 and 5-year clinical outcomes in these patient’s have not been reported.

Two randomized Phase III trials helped address this issue. COMBI-d involved 423 patients randomized to TAFINLAR® plus MEKINIST® (N=211) or to TAFINLAR® plus placebo (N=212). In COMBO-v, 704 patients were randomized to TAFINLAR® plus MEKINIST® (N=352) or to single-agent ZELBORAF® (Vemurafenib; N=352). In a previously published pooled analysis of patients treated in the COMBI-d and COMBI-v trials, 3-year PFS and OS were 23% and 44% respectively. Further, there was a significant association between several baseline factors such as performance status, age, sex, number of organ sites with metastasis, serum LDH level and both PFS as well as OS.

In this review, the researchers analyzed pooled long term survival data from two randomized Phase III COMBI-d and COMBI-v trials, which involved previously untreated, unresectable or metastatic Melanoma patients, with BRAFV600E or V600K mutation, who had received BRAF inhibitor TAFINLAR® 150 mg orally twice daily along with a MEK inhibitor MEKINIST® 2 mg orally once daily. These two trials evaluated the efficacy and safety of TAFINLAR® plus MEKINIST®, as compared with BRAF inhibitor monotherapy. The long term, 5-year survival data from these two trials was reported, along with clinical characteristics of the patients who derived long-term benefit from this treatment. The Primary end points in the COMBI-d and COMBI-v trials were PFS and OS, respectively. The median patient age in these trials was 55 years, 3% of patients had nonmetastatic disease and two-thirds had M1c metastatic disease.

A total of 563 patients (211 in the COMBI-d trial and 352 in the COMBI-v trial) were randomly assigned to receive TAFINLAR® plus MEKINIST®. The PFS rates were 21% at 4 years and 19% at 5 years. The OS rates were 37% at 4 years and 34% at 5 years. The 5-year OS rate was 71% among patients who had a Complete Response and 55% among those who had a normal Lactate Dehydrogenase level plus fewer than three metastatic organ sites at baseline.

It was concluded that first-line treatment with TAFINLAR® plus MEKINIST® led to long-term benefit in approximately one third of the patients who had unresectable or metastatic Melanoma with a BRAF V600E or V600K mutation. The authors added that this is the largest data set and longest follow-up in this patient population treated with BRAF and MEK inhibitors. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. Robert C, Grob JJ, Stroyakovskiy D, et al. June 4, 2019. DOI: 10.1056/NEJMoa1904059

REVLIMID® plus RITUXAN® (R2) Significantly Improves Progression Free Survival in Relapsed or Refractory Indolent Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2019, about 74,200 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas (FL).GELF-Criteria-for-Initiating-Treatment-of-Follicular-Lymphoma

The Ann Arbor classification divides FL into four stages. Patients with Stages I and II have localized disease and those with Stages III and IV have advanced disease. The World Health Organization (WHO) further classified FL based on histology into low grade (grades 1 and 2) and high grade (grade 3a) FLs. Grade 3b FL which demonstrates diffuse areas of involvement is designated as Diffuse Large B-cell Lymphoma (DLBCL) and is treated as such. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median PFS of 6-8 yrs and a median OS of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments.

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent (IMiD) with activity in lymphoid malignancies, primarily through immune modulation, by reactivating and heightening immune system responses to malignant cells. REVLIMID® synergizes with anti-CD20 antibodies such as RITUXAN® and GAZYVA® (Obinutuzumab) and enhances the function of T and NK cells, increases Antibody-Dependent Cellular Cytotoxicity (ADCC), and repair defective synapse formation in B-cell lymphoma cells, thereby restoring the immune system’s ability to kill tumor cells, without permanently damaging the healthy microenvironment, or causing long-term immune suppression. Chemo-free combination immunotherapy with REVLIMID® and RITUXAN® or the R2 regimen, has shown promising activity in phase II studies. RELEVANCE phase III trial compared REVLIMID® plus RITUXAN®, followed by RITUXAN® maintenance, with the standard of care treatment of RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance, in patients with previously untreated Follicular Lymphoma and concluded that R2 regimen showed similar efficacy, with a more favorable safety profile, making it a potential chemo-free first line option, for patients with Follicular Lymphoma. Single agent RITUXAN® is commonly used in the second-line treatment of Follicular Lymphoma (25-47% of patients), according to studies in the United States and Europe.

AUGMENT trial is a prospective, Phase III, multicenter, randomized study in which 358 patients with relapsed or refractory grades 1-3a Follicular Lymphoma (82%) or Marginal Zone Lymphoma (18%) were randomly assigned to receive either REVLIMID® plus RITUXAN® (N=178) or placebo plus RITUXAN® (N=180). Eligible patients had at least one prior chemotherapy, immunotherapy, or chemoimmunotherapy and two or more previous doses of RITUXAN®, and had relapsed, refractory, or progressive disease, but not RITUXAN®-refractory. Patients with greater than grade 1 neuropathy were excluded. The median age was 63 years, over 50% of the patients had high tumor burden based on GELF criteria, and over 40% of patients had at least 2 prior systemic regimens. REVLIMID® plus RITUXAN® regimen consisted of REVLIMID® 20 mg orally daily (10 mg for Creatinine Clearance 30-59 mL/min) on days 1 to 21 plus RITUXAN® 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 every 28 days for 12 cycles. Placebo plus RITUXAN® was administered similarly. The Primary end point was PFS assessed by the Independent Review Committee (IRC) and Secondary end points included Overall Response Rate (ORR), Complete Response (CR), Duration of Response, Overall Survival (OS), and time to next anti-lymphoma treatment. The median follow-up was 28.3 months.

The median PFS was 39.4 months in the REVLIMID®/ RITUXAN® group versus 14.1 months in the placebo plus RITUXAN® group (HR=0.46, P<0.001). This meant a reduced risk of disease progression by 54% and increased median PFS by more than 2 years compared with RITUXAN® monotherapy. This benefit was consistent across all prespecified subgroups, except for the Marginal Zone Lymphoma subgroup and it may be difficult to draw strong conclusions in this small subgroup because these patients made up only 18% of the overall patient population. Response rates as assessed by IRC were 78% in the REVLIMID®/ RITUXAN® group versus 53% in the placebo plus RITUXAN® group (P<0.001), with Complete Response occurring in 34% versus 18% respectively (P=0.001). The median Duration of Response was 36.6 versus 21.7 months (P =0.0015), median Event-Free Survival was 27.6 versus 13.9 months (HR = 0.51, P<0.001) and the median time to next anti-lymphoma treatment was Not Reached versus 32.2 months (P=0.007).

It was concluded that the R2 regimen (REVLIMID® plus RITUXAN®) significantly prolonged Progression Free Survival in patients with relapsed or refractory indolent lymphoma and represents an important new treatment option for this patient group. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. Leonard JP, Trneny M, Izutsu K, et al. J Clin Oncol 2019;37:1188-1199.

Late Breaking Abstract – ASCO 2019 Five-Year Survival Data for KEYTRUDA® in Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019 about 228,150 new cases of lung cancer will be diagnosed and 142,670 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. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression, and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.Unleashing-T-Cell-Function-with-PD-1-and-PDL1-Antibodies

The FDA approved KEYTRUDA® for the first-line treatment of patients with Stage III Non-Small Cell Lung Cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, as well as those with metastatic NSCLC whose tumors express PD-L1 (Tumor Proportion Score-TPS of 1% or more), as determined by an FDA-approved test. KEYTRUDA® is also approved for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), based on KEYNOTE-024 trial, as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic non-squamous NSCLC, based on KEYNOTE-021 study. It is also indicated for previously treated advanced NSCLC with a much lower level of PD-L1 expression such as PD-L1 Tumor Proportion Score of 1% or higher, based on KEYNOTE-010 trial.

The authors in this publication presented the 5-year Overall Survival (OS) for patients enrolled in the Phase 1b KEYNOTE-001 study, which was the first trial evaluating KEYTRUDA® in advanced NSCLC. In this trial, 550 patients were enrolled of whom 101 patients were treatment-naïve (N=101) and 449 patients were previously treated (N=449). Patients received KEYTRUDA® 2 mg/kg IV every 3 weeks or KEYTRUDA® 10 mg/kg IV every 2 or 3 weeks. The protocol in the recent years was changed to a straight dose of KEYTRUDA® 200 mg IV every 3 weeks, which is the typical regimen used in clinical practice. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS) and Duration of Response (DOR). The median follow up was 60.6 months and 18% of participants (N=100) were still alive at that point.

The 5-year OS in the treatment-naïve patients (N=101) was 23.2% and 15.5% in previously treated patients (N=449). In treatment-naive patients, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 29.6%, compared with 15.7% with PD-L1 expression levels below 50%. In patients who had received previous treatment, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 25% compared with 12.6% with PD-L1 expression levels between 1% and 49%. Only 3.5% of people with PD-L1 expression levels below 1% were alive after 5 years. The investigator-reported ORR was 41.6% in treatment-naïve patients and 22.9% in previously treated patients. Median Duration of Response was 16.8 months and 38.9 months respectively. Immune-mediated adverse events were reported in 17% of patients at 5 years. Hypothyroidism was the most commonly reported immune-mediated adverse event, followed by pneumonitis, hyperthyroidism and skin toxicities.

It was concluded that the 5-year data from the KEYNOTE-001 trial showed that treatment with KEYTRUDA® was safe and effective and substantially increased Overall Survival in patients with advanced NSCLC. These data provide the longest efficacy and safety follow-up for NSCLC patients treated with KEYTRUDA®. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. Garon EB, Hellmann MD, Costa EC, et al. J Clin Oncol. 2019;37(suppl; abstract LBA9015).

FDA Approves First PI3K Inhibitor, PIQRAY®, for Breast Cancer

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SUMMARY: The FDA on May 24, 2019 approved PIQRAY® (Alpelisib) in combination with FASLODEX® (Fulvestrant), to treat postmenopausal women and men, with Hormone Receptor (HR) positive, Human Epidermal growth factor Receptor 2 (HER2) negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by an FDA-approved test), following progression on or after an endocrine-based regimen. The FDA also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Patients who are negative by the therascreen test using the liquid biopsy should undergo tumor biopsy for PIK3CA mutation testing. 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. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.Alpelisib - Mechanism-of-Action

The PhosphoInositide 3-Kinase (PI3K) pathway is an intracellular signaling pathway important in the regulation of cancer cell proliferation and metastasis. PI3K is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta, which play a unique role in the survival of different tumor types and establishment of supportive tumor microenvironments. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are primarily expressed in hematopoietic cells such as B and T cells. The PI3K alpha isoform is particularly important in breast cancer and plays an important role in tumorigenesis, supporting tumor angiogenesis and stromal interactions, making this a viable target. PIK3CA is an oncogene that codes for the alpha isoform of PI3K, (PI3Kα), more specifically for the alpha isoform of p110. The PI3k pathway is the most frequently altered pathway in human cancers including breast cancer, and has been implicated in disease progression in a significant number of patients with breast cancer. Activation of the PI3K pathway in breast cancer has been associated with resistance to endocrine therapy and disease progression. Approximately 40% of patients with Hormone Receptor positive (HR+), HER2 negative breast cancers, harbor activating mutations in the PIK3CA isoform of PI3K, which is the most common mutation in HR+ breast cancer. Patients with advanced breast cancer harboring PIK3CA mutations typically have a poor prognosis. This provides a strong rationale for targeting the PI3K pathway in breast cancer.

PIQRAY® is an oral, alpha-specific PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase signaling pathway. Further, it was shown in preclinical studies that cancer cells with PIK3CA mutations are more sensitive to PIQRAY® than those without the mutation, across a broad range of tumor types. SOLAR-1 clinical trial, which was conducted to test this hypothesis, became the basis for this FDA approval.

SOLAR-1 is a global, double-blind, placebo-controlled, randomized phase III trial, which studied the benefit of PIQRAY® in combination with FASLODEX® (Fulvestrant) among postmenopausal women and men with PIK3CA-mutated HR+/HER2 negative advanced or metastatic breast cancer, who had progressed on or following prior Aromatase Inhibitor (AI) treatment with or without a Cyclin-Dependent Kinase (CDK) 4/6 inhibitor. In this study, 572 patients were randomized in a 1:1 ratio to receive PIQRAY® 300 mg orally daily or placebo once daily, in combination with FASLODEX® 500mg IM on days 1 and 15 of the first cycle and day 1 of each subsequent 28-day cycle. Patients were stratified based on visceral metastases and prior CDK4/6 inhibitor treatment. A total of 341 patients had PIK3CA mutations upon testing of the tumor tissue with 169 patients receiving the PIQRAY® combination and 172 patients receiving FASLODEX® alone. Enrolled patients had received one or more prior lines of hormonal therapy, but no chemotherapy for advanced breast cancer. They had not previously received FASLODEX® or any PI3K, Akt or mTOR inhibitor, and were not on concurrent anticancer therapy. Approximately half of the patients in each treatment group had lung or liver metastases and 6% had received prior CDK4/6 inhibitor therapy. The Primary endpoint was Progression Free Survival (PFS) for patients with the PIK3CA mutation. Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate, Health-Related Quality of Life, Efficacy in PIK3CA non-mutant cohort, Safety and Tolerability.

The Primary endpoint was met and at a median follow up of 20 months, the PFS was nearly twice as long in patients with PIK3CA mutations randomized to PIQRAY® plus FASLODEX® compared to the placebo plus FASLODEX® group. The median PFS was 11.0 months in the PIQRAY® group compared to 5.7 months in the placebo group (HR=0.65; P=0.00065). In patients with measurable, PIK3CA-mutated advanced breast cancer (N=262), the Overall Response Rate was 36% for the PIQRAY® plus FASLODEX® group versus 16% for placebo plus FASLODEX® group (P=0.0002). There was no significant PFS benefit noted in the PIK3CA-nonmutant patient group receiving PIQRAY® plus FASLODEX® The most frequent toxicities with PIQRAY® were hyperglycemia which could be managed with Metformin, nausea, decreased appetite and skin rash.

It was concluded that PIQRAY® given along with FASLODEX® significantly improved Progression Free Survival compared to Placebo plus FASLODEX® with manageable toxicities. The authors commented that this is the first study to show statistically significant, clinically meaningful PFS improvement with an alpha-specific PI3K inhibitor in PIK3CA-mutated HR+, HER2 negative advanced breast cancer, highlighting the importance of clinical genomics in advanced breast cancer. PIQRAY® is also the first novel drug approved under the Real-Time Oncology Review pilot program. It however remains unclear whether PIQRAY® should be incorporated into the current treatment paradigm upfront, along with endocrine therapy and a CDK 4/6 inhibitor, or sequentially following disease progression on a combination of endocrine therapy and a CDK 4/6 inhibitor. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. André F, Ciruelos EM, Rubovszky G, et al. Presented during the Presidential Symposium 1 at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3_PR.

FDA Approves JAKAFI® for Acute GVHD

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SUMMARY: The FDA on May 24, 2019 approved JAKAFI® (Ruxolitinib) for steroid-refractory acute Graft-Versus-Host Disease (GVHD) in adult and pediatric patients 12 years and older. Acute GVHD is a frequent and severe inflammatory complication of allogeneic Hematopoietic Cell Transplantation (HCT), and is a reaction of donor immune cells against host tissues. It is estimated that in the US over 8000 patients undergo allogeneic HCT each year and about 35-50% of recipients will develop acute GVHD, which remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Following the preparative regimen, a series of inflammatory reactions lead to damage to the host epithelial cells by activated donor T cells. GVHD can be acute or chronic, with acute GVHD typically occurring within the first 100 days following an allogeneic transplant. Approximately 40% of patients with acute GVHD have severe disease, with a one year survival of 50% or less. Acute GVHD typically involves the skin, often starting in the palms and soles (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). Acute GVHD is a clinical diagnosis, although histologic confirmation may be extremely helpful, if the symptoms and presentation are atypical. Risk factors for the development of acute GVHD include degree of HLA disparity, gender disparity, increased age of both the recipient and the donor, multiparous female donors, ineffective GVHD prophylaxis, intensity of the transplant conditioning regimen and the source of graft (peripheral blood or bone marrow greater than umbilical cord blood).

Patients with acute GVHD are often treated by optimizing their immunosuppression and adding methylprednisolone, with approximately 50% of patients responding to this intervention. If symptoms do not improve after a week or if progression is noted after 3 days of treatment, patients receive salvage immunosuppressive intervention, since no standard treatment with meaningful benefit has been identified.

JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor and exerts its mechanism of action by targeting and inhibiting the dysregulated JAK2-STAT signaling pathway. JAKAFI® in animal models was shown to reduce IL-1β, IL-6, or IFN-γ and TNF and other cytokines implicated in lymphocyte activation characteristic of GVHD. In previously published studies, JAKAFI® when used in patients with refractory GVHD demonstrated an Overall Response Rate of 85% in acute or chronic GVHD, with a 25% Complete Remission rate.

The present FDA approval was based on data from REACH1 study, which is an open-label, single-arm, multicenter, phase II trial of JAKAFI® in combination with corticosteroids, in patients with steroid-refractory grade II-IV acute GVHD. Of the 71 patients enrolled in this study, 49 patients were refractory to steroids alone, 12 patients had received two or more prior therapies for GVHD and 10 patients did not otherwise meet the FDA definition of steroid-refractory state. JAKAFI® was administered at 5 mg orally twice daily, and the dose could be increased to 10 mg twice daily after three days, in the absence of toxicity.

The Primary endpoint of this trial was the Day 28 Overall Response Rate (ORR), defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR), based on the Center for International Blood and Marrow Transplant Research (CIBMTR) criteria. The Day 28 ORR in the 49 patient’s refractory to steroids alone was 57% with a CR rate of 31%. The most frequently reported adverse reactions were infections (55%) and edema (51%), and the most common laboratory abnormalities were anemia, thrombocytopenia and neutropenia.

It was concluded that for patients with acute GVHD who do not adequately respond to steroids, therapies are limited and JAKAFI® is a new treatment option that fulfills this unmet need. Results from REACH1, a Single-Arm Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease. Jagasia M, Perales M-A, Schroeder MA, et al. Blood 2018 132:601; doi: https://doi.org/10.1182/blood-2018-99-116342

FDA Approves Fixed Duration VENCLEXTA® for Frontline Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

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SUMMARY: The FDA on May 15, 2019 approved VENCLEXTA® (Venetoclax) for adult patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The FDA in 2018 had approved VENCLEXTA® for patients with CLL or SLL with or without 17p deletion, who have received at least one prior therapy. The American Cancer Society estimates that for 2019, about 20,720 new cases of CLL will be diagnosed in the US and 3,930 patients will die of the disease. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies.

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® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. BCR-Signal-Pathways-and-MOA-of-New-Agents

CLL14 Trial is a prospective, multicenter, open-label, randomized Phase III study, conducted in close collaboration with the German CLL Study Group (DCLLSG). This study was designed to evaluate the efficacy and safety of a fixed duration combination of VENCLEXTA® and GAZYVA® (Obinutuzumab) versus GAZYVA® and Chlorambucil in previously-untreated patients with CLL and coexisting medical conditions. In this trial, 432 treatment-naïve patients with CLL were randomized in a 1:1 ratio to receive fixed duration of 12 months of VENCLEXTA® in combination with six cycles of GAZYVA®, or 6 cycles of GAZYVA® in combination with Chlorambucil. Both treatment groups were well balanced and the median patient age was 72 years. The Primary endpoint was Progression Free Survival (PFS) assessed by an Independent Review Committee. Secondary endpoints included Minimal Residual Disease (MRD) status, Overall Response Rate, Complete Response, Complete Remission with Incomplete Hematologic Recovery (CRi), Overall Survival, duration of response, time to next CLL treatment, and safety.

The trial demonstrated a statistically significant improvement in PFS for patients who received VENCLEXTA® plus GAZYVA® compared with those who received GAZYVA® plus Chlorambucil (HR 0.33; P<0.0001), suggesting a 67% reduction in the risk of progression or death with the VENCLEXTA® plus GAZYVA® combination. The median PFS was not reached in either treatment groups after a median follow-up of 28 months. The Overall Response Rate was 85% in VENCLEXTA® plus GAZYVA® group compared to 71% in GAZYVA® plus Chlorambucil group (P=0.0007). The trial also demonstrated statistically significant improvements in rates of Minimal Residual Disease (MRD) negativity (less than one CLL cell per 104 leukocytes) in bone marrow and peripheral blood. The rate of MRD-negativity in the bone marrow was 57% in the VENCLEXTA® group compared with 17% in the GAZYVA® plus Chlorambucil group. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively. Overall Survival data were not mature at this analysis. The most common adverse events in the VENCLEXTA® plus GAZYVA® group included neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

It was concluded that a combination of VENCLEXTA® and GAZYVA® among patients with previously untreated CLL significantly improved Progression Free Survival, compared to patients treated with standard of care GAZYVA® plus Chlorambucil. The authors added that VENCLEXTA® plus GAZYVA® is the only chemotherapy-free regimen of fixed duration, and is a major step forward in the management of previously untreated CLL patients. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-and-sll

ELIQUIS® for Thromboprophylaxis in Ambulatory Patients with Cancer

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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 (DVT)/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. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life. Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The benefit of thromboprophylaxis in this patient population however is uncertain. This is because previously published randomized trials included cancer patients both at both low and high risk for VTE.Predicting-VTE-in-cancer-patients-using-a-Risk-Score

Khorana score is a validated risk tool which helps to identify patients at increased risk for VTE. Several studies have suggested benefit from thromboprophylaxis in patients with a score of 3 or higher, whereas the benefit of thromboprophylaxis in patients with a score of 2 is unclear, although there is a substantial risk of VTE in this group as well. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Edoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule.

The AVERT (Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients ) trial is a randomized, placebo-controlled, double-blind clinical trial which evaluated the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score 2 or more). Eligible patients (N=574) were randomized in a 1:1 ratio to receive apixaban or placebo and 563 patients were included in the modified intention-to-treat analysis. The first dose of apixaban or placebo was administered within 24 hours after the initiation of chemotherapy. The mean patient age was 61 years, and the common types of primary malignancies were gynecologic (25.8%), lymphoma (25.3%), and pancreatic (13.6%). Eligible patients included those who had a newly diagnosed cancer or progression of known cancer after complete or partial remission and who were initiating a new course of chemotherapy with a minimum treatment intent of 3 months. Inclusion required a Khorana score of 2 or higher. Exclusion criteria included hepatic disease associated with coagulopathy, platelet count of less than 50,000 per cubic millimeter, acute leukemia, myeloproliferative neoplasm, planned stem-cell transplantation and GFR of less than 30 ml/min. The Primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main Safety outcome was a major bleeding episode.

Venous thromboembolism occurred in 4.2% in the apixaban group and 10.2% in the placebo group (HR=0.41; P<0.001). This benefit and was predominantly driven by a lower rate of pulmonary embolism in the apixaban group than in the placebo group. The rate of major bleeding was significantly higher with apixaban than with placebo in the modified intention-to-treat analysis (3.5% versus 1.8%, respectively; HR=2.00), but the rate however was not significantly higher with apixaban than with placebo in the analysis of outcomes during the treatment period (2.1% versus 1.1%, respectively; HR=1.89). There was no significant difference in the Overall Survival between the treatment groups and the authors attributed this to trial design and the fact that most of the patients had advanced cancer, which was the most common cause of death.

It was concluded that thromboprophylaxis with apixaban at a dose of 2.5 mg twice daily resulted in a significantly lower risk of venous thromboembolism when compared to placebo, among ambulatory cancer patients who were initiating chemotherapy, and had an intermediate to high risk of venous thromboembolism. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. Carrier M, Abou-Nassar K, Mallick R, et al. for the AVERT Investigators. N Engl J Med 2019;380:711-719