Month: May 2018

FDA Approves TAFINLAR® and MEKINIST® Combination for Locally Advanced or Metastatic BRAF V600E-Mutant Anaplastic Thyroid Cancer

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SUMMARY: The FDA on May 4, 2018, approved TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) in combination, for the treatment of patients with locally advanced or metastatic Anaplastic Thyroid Cancer (ATC) with BRAF V600E mutation, and with no satisfactory locoregional treatment options. ATC is a rare, highly aggressive, undifferentiated malignancy and accounts for 1-2% of all thyroid cancers in the United States and up to 10% of thyroid cancers worldwide. They are all considered Stage IV at diagnosis and are among the most lethal cancers. Despite multimodality therapy with surgery, external beam radiation, and systemic chemotherapy, response rates to standard therapies are less than 15% with a median survival of 5-12 months and a one year Overall Survival of 20-40%.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 demonstrated in 6-8% of all malignancies. Approximately 20-50% of ATCs harbor activating BRAF V600 mutations and in about 50% of ATCs, well-differentiated papillary thyroid cancer precedes or coexists with ATC. It has been postulated that BRAFV600 mutations may be a common and early driver in these well-differentiated thyroid tumors and additional mutations in the course of the disease lead to progressive de-differentiation to ATC. Inhibiting both BRAF and MEK kinases has been shown to enhance antitumor activity and prevent MAPK pathway reactivation, a known resistance mechanism. Combined BRAF plus MEK inhibition has been shown to increase Overall Response Rate (ORR), Duration of Response, Progression Free Survival (PFS), and Overall Survival (OS), compared with BRAF inhibitor monotherapy, in patients with BRAFV600–mutant Melanoma and Non Small Cell Lung Cancer.

This present FDA approval for Anaplastic Thyroid Cancer (ATC) was based on a multicenter, open-label, nonrandomized, phase II trial, which was designed to simultaneously evaluate efficacy and safety of a combination of TAFINLAR® and MEKINIST® in patients with BRAF V600E mutated cancer, in prespecified histologies. A total of 100 patients with BRAF V600E mutated rare cancers in seven prespecified tumor histologies were enrolled. Sixteen (N=16) patients with ATC enrolled in this study were evaluable for response. Patients received TAFINLAR® 150 mg twice daily and MEKINIST® 2 mg once daily, both given orally, until disease progression or unacceptable toxicity. The median patient age was 72 years, 88% had prior surgery, 81% had external beam radiotherapy and 38% had prior chemotherapy. The Primary end point was Overall Response Rate. Secondary end points included Duration of Response, Progression Free Survival, Overall Survival, and safety.

The confirmed Overall Response Rate was 69% and median Duration of Response, Progression Free Survival, and Overall Survival were not reached as a result of ongoing responses at the time of data cut off. Kaplan-Meier estimates at 12 months of Duration of Response, Progression Free Survival, and Overall Survival were 90%, 79%, and 80%, respectively. Responses typically occurred early in the treatment course (within the first 8 weeks of therapy). The most common adverse events were fatigue, pyrexia and nausea and the overall safety profile was similar to previous reports in advanced Metastatic Melanoma and Non Small Cell Lung Cancer.

It was concluded that the combination of TAFINLAR® plus MEKINIST® was well tolerated and is the first regimen to have demonstrated robust clinical activity in BRAF V600E mutated Anaplastic Thyroid Cancer. This is the first FDA approved treatment for patients with this aggressive form of thyroid cancer, and the third malignancy with BRAF V600E gene mutation (others being Melanoma and NSCLC), that this drug combination has been approved to treat. Dabrafenib and Trametinib Treatment in Patients with Locally Advanced or Metastatic BRAF V600–Mutant Anaplastic Thyroid Cancer. Subbiah V, Kreitman RJ, Wainberg AZ, et al. J Clin Oncol. 2018;36:7-13

Increased Risk of Anaplastic Large-Cell Lymphoma with Breast Implants

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SUMMARY: Breast implants are among the most commonly used medical devices and the number of women with breast implants diagnosed with Anaplastic Large Cell Lymphoma in the breast (breast-ALCL) have increased over the past 10 years. The FDA in 2011, identified a possible association between breast implants and the development of Anaplastic Large Cell Lymphoma (ALCL), and there has been growing body of medical literature describing the natural history and long term outcomes of the disease. In 2016, the World Health Organization designated Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) as a T-Cell Lymphoma that can develop following breast implants.

The incidence of ALCL is higher with macrotextured implants than smooth implants. It has been postulated that textured implants have an increased surface area and a local inflammatory response, elicited by silicone-derived products or specific bacterial species adherent to the prosthesis surface (Biofilm) may play a role, potentiating capsular contracture and increasing T-cell response and possible conversion to BIA-ALCL. It remains unclear however, whether certain women including those with proven BRCA mutations have a genetically determined increased risk to develop lymphoma when exposed to breast implants via a genetically determined altered or exaggerated local immunological response. There are presently no evidence-based guidelines on how this condition should be detected, treated or followed up. It is however, suggested that any seroma more than 6-12 months after breast implantation, in the absence of infection, should be evaluated with ultrasonography and mammography, to identify a mass or lymph nodes that are suspicious for lymphoma. The seroma should be aspirated and the fluid analyzed for cytology, cultures, flow cytometry and cell block. If cytology is negative, patients should be closely monitored for recurrence of seroma. Biopsy should be performed if a mass is present, and if ALCL is confirmed, patients will respond to capsulectomy and removal of the implant, as ALCL confined within the capsule often have an indolent course and good prognosis. In contrast, patients who present with a distinct mass may have a more aggressive disease course and poor prognosis, and require chemotherapy and/or radiation therapy. Postoperatively evaluation if BIA-ALCL is confirmed, should include a PET-CT scan and bone marrow biopsy to rule out systemic disease. It is recommended that patients receive clinical follow up at least every 6 months for 5 years along with breast ultrasonography for 2 years, and those who undergo reinsertion of the implant should be followed up beyond 5 years.

In this publication, a case-control study was conducted, comparing the prevalence of breast implants between women with primary breast-ALCL and women with primary breast lymphomas other than ALCL, using a comprehensive Dutch pathology database. The purpose of this study was to determine the relative and absolute risks of breast ALCL in women with breast implants. The authors identified all patients diagnosed with primary Non Hodgkin Lymphoma in the breast between 1990 and 2016 and retrieved clinical data, including breast implant status, from the treating physicians, through the population-based nationwide Dutch pathology registry. They then calculated the risk of breast-ALCL in women both with and without breast implants.

The estimated prevalence of breast implants in women aged 20-70 years was 3.3%. It was noted that among 43 patients with breast-ALCL (median age 59 years), 32 had ipsilateral breast implants, compared with 1 among 146 women with other primary breast lymphomas. The median time to development of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) was 13 years after an implant was placed. Most cases of BIA-ALCL (75%) in this Dutch study were associated with macrotextured implants and the Complete Remission rate was 90% after treatment and only 6% of the 32 affected women died of disseminated disease. In this study, the number of women with implants needed to cause 1 breast-ALCL case before age 75 years was 6920. Affected patients had implants for cosmetic reasons alone, for reconstruction in transgender surgery, after breast cancer surgery, and after prophylactic mastectomy for high breast cancer risk.

It was concluded that breast implants are associated with increased risk of breast-ALCL, but the absolute risk remains small. With an increasing number of breast implant insertions, the need for increased awareness among the public, medical professionals, and regulatory bodies is imperative and it is essential to promote alternative cosmetic procedures, and recognize this rare clinical entity. Breast Implants and the Risk of Anaplastic Large-Cell Lymphoma in the Breast. de Boer M, van Leeuwen FE, Hauptmann M, et al. JAMA Oncol. 2018;4:335-341.

FDA Approves KYMRIAH® for Relapsed or Refractory Large B-Cell Lymphoma

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SUMMARY: The FDA on May 1, 2018 approved KYMRIAH®, a CD19-directed genetically modified autologous T-cell immunotherapy, for adult patients with Relapsed or Refractory Large B-Cell Lymphoma, after two or more lines of systemic therapy including Diffuse Large B-Cell Lymphoma (DLBCL) Not Otherwise Specified (NOS), High grade B-Cell Lymphoma and DLBCL arising from Follicular Lymphoma. The American Cancer Society estimates that in 2018, about 74,680 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,910 individuals will die of this disease. Diffuse Large B-Cell Lymphoma is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. The etiology of DLBCL is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), ultraviolet radiation, pesticides, hair dyes, and diet.

What is (CAR) T-cell immunotherapy?

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. KYMRIAH® (genetically engineered T-cells) seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum Ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome.Chimeric-Antigen-Receptor-T-Cell-Immunotherapy

The CAR T-cells have been shown to also access sanctuary sites such as the central nervous system and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL).

The approval of KYMRIAH® was based on a single-arm, open-label, multi-center, global, pivotal phase II trial (JULIET), in adults with Relapsed or Refractory DLBCL and DLBCL after transformation from Follicular lymphoma. The study enrolled 147 patients, 99 of whom received the CAR T-cell infusion with a single dose of KYMRIAH®, which was manufactured at 2 sites (United States and Germany). Eligible patients were 18 years or older with Relapsed or Refractory DLBCL and had progressed after receiving two or more lines of chemotherapy, including an Anthracycline and Rituximab, and were ineligible for or failed Autologous Stem Cell Transplant (auto-SCT). The median number of prior lines of therapy was 3 and 47% of patients had prior auto-SCT. Prior to infusion with KYMRIAH®, 90% of patients received bridging therapy, 93% received lymphodepleting chemotherapy, which in most patients consisted of Fludarabine/Cyclophosphamide. The median age was 56 years and 77% of patients had Stage III or IV disease at the time of enrollment. The median time from infusion to data cutoff was 5.6 months. The Primary endpoint was best Overall Response Rate-ORR (Complete Response-CR + Partial Response-PR), per independent review committee.

In this primary analysis, the authors reported the outcomes among 81 patients who received KYMRIAH® manufactured in the United States, with more than 3 months of follow up. The Objective Response Rate was 53%, the Complete Response rate was 39.5% and Partial Response rate 13.6%. At month 3, the CR rate was 32% and the PR rate 6%. Among patients evaluable at 6 months (N=46), the CR Rate was 30% and PR rate was 7%. Response rates were consistent across prognostic subgroups, including those who received prior auto-SCT and those with Double-Hit lymphoma. The median Duration of Response and the median Overall Survival were not reached. The 6-month probability of being relapse free was 73.5% and the 6-month probability of Overall Survival was 64.5%. Grade 3 or 4 adverse events were reported in 86% of the patients and Cytokine-Release Syndrome occurred in 58%. CRS was managed with ACTEMRA® in 15% of patients with good response and 11% of patients received corticosteroids. Neurologic adverse events were reported in 12% of patients. No deaths were attributed to KYMRIAH®.

It was concluded that KYMRIAH® produces high Response Rates with 95% of Complete Responses at 3 months being sustained at 6 months, in heavily pretreated adult patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). This first global study of CAR T-cell therapy in DLBCL also demonstrated that centralized manufacturing of CAR T-cells is feasible. Schuster SJ, Bishop MR, Tam CS, et al. Primary Analysis of Juliet: A Global, Pivotal, Phase 2 trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 577.

KEYTRUDA® Plus Standard Chemotherapy Improves Overall Survival in Newly Diagnosed Metastatic 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 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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 Non Small Cell Lung Cancer (NSCLC), 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing 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®. The FDA approved KEYTRUDA® for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), and for previously treated advanced NSCLC with a PD-L1 Tumor Proportion Score of 1% or more. This present study provides convincing phase III evidence to support the use of triplet therapy in NSCLC.Unleashing-T-Cell-Function-with-Keytruda (Pembrolizumab)-for-Advanced-Non-Small-Cell-Lung-Cancer

KEYNOTE-189 is a double-blind, phase III trial in which 616 patients with untreated stage IV non-squamous NSCLC, without sensitizing EGFR or ALK mutations, were randomly assigned in a 2:1 ratio to receive treatment with four cycles of KEYTRUDA®/Pemetrexed/Carboplatin or placebo plus the same chemotherapy. Patients received either KEYTRUDA® 200mg or saline placebo, both administered IV every 3 weeks for up to 35 cycles. All the patients received four cycles of the investigator’s choice of Cisplatin 75 mg/m2 IV or Carboplatin AUC 5 along with Pemetrexed 500 mg/m2, all administered IV every 3 weeks, followed by maintenance Pemetrexed 500 mg/m2 every 3 weeks. Patients in the placebo combination group were allowed to crossover to KEYTRUDA® monotherapy upon disease progression. Patients with symptomatic brain metastasis were excluded and patients were stratified according to PD-L1 expression (Tumor Proportion Score, 1% or more versus less than 1%), choice of platinum-based drug (Cisplatin versus Carboplatin), and smoking history. Both treatment groups were well balanced and about 17% had brain metastasis and one-third were untreated. A PD-L1 Tumor Proportion Score of 1% or more was reported in 63% of the patients, Carboplatin was the preferred platinum-based drug in 72% of the patients, and 88% of the patients were current or former smokers. The co-Primary end points were Overall Survival (OS) and Progression Free Survival (PFS).

After a median follow-up of 10.5 months, the estimated rate of Overall Survival (OS) at 12 months was 69.2% in the KEYTRUDA®-combination group versus 49.4% in the placebo-combination group. The median OS was not reached in the KEYTRUDA®-combination group and was 11.3 months in the placebo-combination group (HR=0.49; P<0.001). This represented a 51% reduction in the risk of death in the KEYTRUDA®-combination group. The OS benefit was seen across all PD-L1 subgroups including those with a PD-L1 Tumor Proportion Score of less than 1%. However, the greatest benefit was noted in the group expressing high levels of PD-L1 with Tumor Proportion Score 50% or more (12-month OS rate of 73% versus 48.1%; HR=0.42). The median Progression Free Survival was 8.8 months in the KEYTRUDA®-combination group and 4.9 months in the placebo-combination group (HR=0.52; P<0.001). This represented a 48% reduction in the risk of disease progression. The Objective Response Rate (ORR) was 47.6% in the KEYTRUDA®-combination group and 18.9% in the placebo-combination group (P<0.001) and ORR was highest among those with a PD-L1 Tumor Proportion Score of 50% or more (61.4% vs 22.9%). There was no significant difference in grade 3 adverse events in the two treatment groups.

It was concluded that in patients with previously untreated metastatic non-squamous NSCLC without EGFR or ALK mutations, the addition of KEYTRUDA® to standard chemotherapy of Pemetrexed and a platinum-based drug resulted in significantly longer Overall Survival and Progression Free Survival than chemotherapy alone, regardless of PD-L1 status and should therefore be considered as a new standard of care, in the front-line setting. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. for the KEYNOTE-189 Investigators. April 16, 2018 DOI: 10.1056/NEJMoa1801005

FDA Approves AndexXa®, The First Antidote for Factor Xa Inhibitors

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The FDA on May 3, 2018 approved AndexXa&reg; (Andexanet Alfa), a recombinant coagulation Factor Xa, inactivated-zhzo), for patients treated with XARELTO&reg; (Rivaroxaban) and ELIQUIS&reg; (Apixaban), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. The approval of AndexXa&reg; was based on data from two Phase III ANNEXA studies (ANNEXA-A and ANNEXA-R) as well as interim data from the ongoing ANNEXA-4 study. AndexXa&reg; significantly reduced anti-Factor Xa activity of Factor Xa Inhibitors by over 90% compared with placebo, with reversal persisting for 1 to 2 hours after completion of the infusion. The availability of this antidote assures both patients and Health Care Providers to consider Factor Xa inhibitors with greater confidence.

FDA Approves Adjuvant TAFINLAR® plus MEKINIST® for Stage III BRAF-Mutated Melanoma

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SUMMARY: The FDA on April 30, 2018, granted regular approval to TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib), in combination, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. 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. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Stage III malignant melanoma however is a heterogeneous disease, and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with stage IIIA disease have a disease-specific survival rate of 78% whereas those patients with stage IIIB and stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.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 demonstrated 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®,is a selective oral BRAF inhibitor and MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with stage III melanoma, with BRAFV600E or V600K mutations, after complete surgical resection.

This FDA approval was based on COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, phase III trial, in which 870 patients with completely resected, stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had stage IIIA disease, 41% had stage IIIB disease, and 40% had stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant metastasis-free survival, Freedom from relapse, and Safety.

At a median follow up of 2.8 years, the estimated 3-year RFS rate was 58% in the combination therapy group and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. At the time of this analysis, median RFS rate had not yet been reached in the combination therapy group and was 16.6 months in the placebo group. The improved RFS benefit with the combination therapy was consistent across patient subgroups, regardless of lymph node involvement or primary tumor ulceration. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001). The safety profile of TAFINLAR® plus MEKINIST® was consistent with that observed with the combination, in patients with metastatic melanoma, and the common side effects were pyrexia, fatigue, nausea, vomiting, diarrhea, headache, rash, arthralgia, and myalgia.

It was concluded that adjuvant combination therapy with TAFINLAR® plus MEKINIST® in patients with stage III melanoma with BRAF V600E or V600K mutations, resulted in a significantly lower risk of recurrence, compared to placebo, with no new adverse events. With more than half the patients with stage III melanoma having a recurrence after surgery, this first effective oral targeted combination therapy, will be an important adjuvant treatment option. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long GV, Hauschild A, Santinami M, et al. N Engl J Med 2017; 377:1813-1823

FDA Approves AndexXa®, The First Antidote for Factor Xa Inhibitors

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SUMMARY: The FDA on May 3, 2018 approved AndexXa® (Andexanet Alfa), a recombinant coagulation Factor Xa, inactivated-zhzo), for patients treated with XARELTO® (Rivaroxaban) and ELIQUIS® (Apixaban), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. It is estimated that 4 million individuals are presently on Factor Xa inhibitors, and in the US there were approximately 117,000 hospital admissions attributable to Factor Xa inhibitor-related bleeding and nearly 2000 bleeding related deaths per month. There are presently five New Oral Anticoagulants approved in the US for the treatment of Venous ThromboEmbolism (VTE). They include PRADAXA® (Dabigatran), which is a direct thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® (Warfarin), 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 half-life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and direct oral anticoagulants are ineffective in patients with mechanical heart valves. In several clinical studies, these New Oral Anticoagulants have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN®. Unlike bleeding caused by COUMADIN®, which can be reversed using Vitamin K or Fresh Frozen Plasma, until now, there were no specific agents available, for reversing bleeding caused by the New Oral Anticoagulants or for stopping the anticoagulant effects of these drugs, in patients who need urgent surgical intervention. The FDA in 2015, granted accelerated approval to PRAXBIND® (Idarucizumab), for the treatment of patients treated with PRADAXA®, a direct thrombin inhibitor, when reversal of the anticoagulant effects of PRADAXA® is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. However, the Factor Xa inhibitors approved in the US for the treatment of VTE did not have an antidote until this new approval. As such, some Health Care Providers discouraged their patients from taking these direct oral anticoagulants until an antidote became available, should their patients need urgent surgical intervention.MOA-of-New-Oral-Anticoagulants

AndexXa® (Andexanet alfa) is a recombinant, modified human Factor Xa decoy protein without intrinsic catalytic activity, that binds Factor Xa inhibitors. The approval of AndexXa® was based on data from two Phase III ANNEXA studies (ANNEXA-A and ANNEXA-R) as well as interim data from the ongoing ANNEXA-4 study. ANNEXA-A and ANNEXA-R are randomized, double-blind, placebo-controlled, Phase III studies which evaluated the safety and efficacy of AndexXa® in reversing the anticoagulant effect of ELIQUIS® and XARELTO® respectively, in healthy volunteers aged 50-68 years. A two-part randomized placebo-controlled study was conducted for each Factor Xa inhibitor, to evaluate AndexXa® administered as a bolus or as a bolus plus a 2-hour infusion. The Primary endpoint was reduction in anti-Factor Xa activity levels, a measure of Factor Xa inhibition by the anticoagulant. Secondary endpoints included reduction in plasma levels of free unbound XARELTO® or ELIQUIS® and restoration of the endogenous thrombin potential (ETP), a measure of thrombin generation.

ANNEXA-A Study: In Part 1, 33 healthy participants were given ELIQUIS® 5 mg twice daily for 3.5 days and then randomized in a 3:1 ratio to receive either AndexXa® administered as a 400 mg IV bolus or placebo. Within 2-5 minutes of completion of the bolus dose, AndexXa® rapidly reduced the anticoagulant activity of ELIQUIS® by 94% compared with placebo (P<0.001), as measured by anti-Factor Xa activity. The reversal of anti-factor Xa activity persisted for 2 hours. Further, AndexXa® significantly reduced the level of free (unbound) ELIQUIS® in the plasma compared with placebo (P<0.001) and fully restored thrombin generation in 100 percent of subjects (P<0.001 vs. placebo). In Part 2, 31 healthy participants received ELIQUIS® 5 mg twice daily for four days and then randomized in a 3:1 ratio to receive either AndexXa® administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes or placebo. AndexXa® significantly reduced anti-Factor Xa activity by 92% compared with placebo (P<0.001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound ELIQUIS® was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound ELIQUIS® compared with placebo (P<0.001). AndexXa® also restored thrombin generation to normal in all participants who received the compound (p<0.001 vs. placebo).

ANNEXA-R Study: In Part 1, 41 healthy volunteer participants were given XARELTO® 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either AndexXa® administered as an 800 mg IV bolus or placebo. Within 2-5 five minutes of completion of the bolus dose, AndexXa® significantly reversed the anticoagulant activity of XARELTO® by 92% compared with placebo (P<0.001), as measured by anti-Factor Xa activity. Further, AndexXa® significantly reduced the level of free (unbound) XARELTO® in the plasma compared with placebo (P<0.001) and fully restored thrombin generation in 96% of participants (P<0.001 versus placebo). In Part 2, 39 healthy volunteers were given XARELTO® 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either AndexXa® administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or placebo. AndexXa® significantly reduced anti-Factor Xa activity by 97% compared with placebo (P<0.001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound XARELTO® was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound XARELTO® compared with placebo (P<0.001). AndexXa® also restored thrombin generation to normal in all participants who received this agent (P<0.001 versus placebo).

ANNEXA-4 Study: This is an ongoing, multicenter, prospective, open-label, single-group study designed to evaluate the use of AndexXa® in patients with acute potentially life-threatening major bleeding, within 18 hours after the administration of one of four Factor Xa inhibitors – ELIQUIS®, XARELTO®, SAVAYSA®, or LOVENOX® (Enoxaparin). . All patients received a bolus dose of AndexXa® within 3-6 hours following presentation to the ER followed by a 2-hour infusion of the drug. The two co-primary outcomes were the percent change in the anti-Factor Xa activity and the rate of excellent or good hemostatic efficacy, 12 hours after the AndexXa® infusion. Anti-Factor Xa activity was measured by means of a validated chromogenic assay of Factor Xa enzymatic activity. Among the 185 evaluable high-risk patients in this open-label study, hemostatic efficacy was adjudicated as excellent or good by the independent committee, 12 hours after the AndexXa® infusion in 83% of patients. It was noted that following the bolus dose of AndexXa®, the median anti-Factor Xa activity decreased by 90% from baseline, among patients receiving XARELTO® and by 93% among patients receiving ELIQUIS® and these levels remained the same during the 2-hour infusion.

In conclusion, AndexXa® is the first and only antidote indicated for patients treated with XARELTO® and ELIQUIS® when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. The availability of this antidote assures both patients and health care providers to consider Factor Xa inhibitors with greater confidence. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. Siegal DM, Curnutte JT, Connolly SJ, et al. N Engl J Med 2015; 373:2413-242. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. Connolly SJ, Milling TJ, Eikelboom JW, et al. N Engl J Med 2016; 375:1131-1141

TAFINLAR® and MEKINIST®

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The FDA on May 4, 2018 approved TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) for Anaplastic Thyroid Cancer with BRAF V600E mutation. TAFINLAR® and MEKINIST® are products of Novartis Pharmaceuticals Corp.

AndexXa® (Andexanet Alfa)

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The FDA on May 3, 2018 approved AndexXa®, a recombinant coagulation Factor Xa, inactivated-zhzo), for patients treated with XARELTO® (Rivaroxaban) and ELIQUIS® (Apixaban), when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. AndexXa® is a product of Portola Pharmaceuticals.

KYMRIAH® (Tisagenlecleucel)

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The FDA on May 1, 2018 approved KYMRIAH®, a CD19-directed genetically modified autologous T-cell immunotherapy, for adult patients with relapsed or refractory large B-cell lymphoma, after two or more lines of systemic therapy including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from Follicular Lymphoma. KYMRIAH® is a product of Novartis Pharmaceuticals Corp.