Author: RR

Periprocedural Bridging Increases Bleeding Risk without Reduction in VTE Rates for Patients on Long Term Anticoagulants

RR

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. It is estimated that in the US, more than 6 million patients are on chronic anticoagulation and approximately 250,000 patients need to temporarily interrupt their anticoagulant therapy annually, prior to an invasive procedure, to decrease the risk of excess periprocedural bleeding.

Despite a significant and rapid increase in the use of Direct Oral AntiCoagulants (DOACs) in the recent decade, Vitamin K Antagonists (VKAs) such as COUMADIN® (Warfarin) remain the most frequently prescribed anticoagulants in the US and worldwide. VKAs must be interrupted several days prior to a planned procedure to allow for regeneration of vitamin K-dependent coagulation factors (Factors II, X, VII and IX as well as protein C and S) and subsequent normalization of coagulation. Bridging with short-acting parenteral anticoagulants during the periprocedural period is often recommended for individuals at high thromboembolic risk. Previously published studies have shown a significantly higher incidence of major bleeding with bridging, with no difference in thromboembolic outcomes and further, current guidelines fail to identify patients with high-enough thromboembolic risk to justify periprocedural bridging. There is presently no randomized study that shows a clear benefit of periprocedural bridging for patients on long-term anticoagulants, whereas there are abundant data suggesting an increased bleeding risk with bridging.

In this publication, the authors performed a systematic review comparing recurrent VTE and bleeding outcomes, with and without periprocedural bridging, in order to better define risks and benefits of bridging in patients with previous VTE, requiring VKA interruption to undergo an elective invasive procedure. This systematic review involved searching the PubMed and Embase databases from inception to December 7, 2017 for randomized and nonrandomized studies and included adults with previous VTE requiring VKA interruption to undergo an elective procedure, and those that reported VTE or bleeding outcome. This analysis included 28 cohort studies, with 6915 procedures.

It was noted that the pooled incidence of recurrent VTE with bridging was 0.7% and 0.5% without bridging. The pooled incidence of any bleeding was 3.9% with bridging and 0.4% without bridging. In bridged patients at high thromboembolic risk, the pooled incidence for VTE was 0.8% for any bleeding.

The authors noted that this is the first study to systematically assess the risks and benefits of periprocedural bridging in the specific population of patients with previous VTE and they concluded that patients at low and moderate thromboembolic risk do not benefit from periprocedural bridging, and on the contrary, periprocedural bridging increases the risk of bleeding, compared with VKA interruption without bridging, without a significant difference in periprocedural VTE rates. Periprocedural Bridging in Patients with Venous Thromboembolism: A Systematic Review. Baumgartner C, Kouchkovsky I, Whitaker E, et al. The American Journal of Medicine 2019;132:722-732

FDA Approves ROZLYTREK® for NTRK Positive tumors and ROS1 Positive Non Small Cell Lung Cancer

RR

SUMMARY: The FDA on August 15, 2019, granted accelerated approval to ROZLYTREK® (Entrectinib) for adults and pediatric patients 12 years of age and older with solid tumors that have a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic, or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. The FDA on the same day approved ROZLYTREK® for adults with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors are ROS1-positive.

Next-Generation Sequencing (NGS) has enabled the detection of Neurotrophic Tropomyosin Receptor Kinase (NTRK) gene fusions, which was first discovered in Colon cancer in 1982. The three TRK family of Tropomyosin Receptor Kinase (TRK) transmembrane proteins TRK A, TRK B, and TRK C are encoded by Neurotrophic Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3, respectively. These Receptor Tyrosine Kinases are expressed in human neuronal tissue and are involved in a variety of signaling events such as cell differentiation, cell survival and apoptosis of peripheral and central neurons. They therefore play an essential role in the physiology of development and function of the nervous system. There are over 50 different partner genes that fuse with NTRK genes. Chromosomal fusion involving NTRK genes arise early in cancer development and remain so as tumors grow and metastasize. Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins which can confer oncogenic potential by increasing cell proliferation and survival. Early clinical evidence suggests that these gene fusions lead to oncogene addiction regardless of tissue of origin. (Oncogene addiction is the dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype). It is estimated that gene fusions involving NTRK genes occurs in about 0.5% to 1% of many common malignancies and have been identified in a broad range of solid tumor types including Non-Small Cell Lung Cancer (NSCLC), Cholangiocarcinoma, Colorectal, Gynecological, Neuroendocrine, Pancreatic tumors and in more than 90% of certain rare tumor types, such as Salivary gland tumors, a type of juvenile Breast cancer, and infantile Fibrosarcoma.

Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years), who are relatively young (average age of 50 years) and thus share similar characteristics with ALK-positive patients. ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing.

ROZLYTREK® is a pan-TRK, ROS1 and ALK Tyrosine Kinase Inhibitor (TKI), designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of malignancies. ROZLYTREK® has potent anti-neoplastic activity in various neoplastic conditions, particularly NSCLC, by blocking ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions.

The FDA approvals were based on results from the integrated analysis of the pivotal Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the Phase I/II STARTRK-NG study in pediatric patients. ROZLYTREK®, was studied in several solid tumor types, including NSCLC, Breast cancer, Mammary analogue secretory carcinoma, Cholangiocarcinoma, Colorectal, Gynecological, Neuroendocrine, Salivary gland, Pancreatic, Thyroid cancers and Sarcoma. Patients were enrolled across 15 countries and more than 150 sites, and safety was assessed from an integrated analysis of 355 patients across these four trials. The Primary endpoints included Overall Response Rate (ORR), Duration of Response (DoR) and Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS) in patients with and without baseline CNS disease, and Safety.

The efficacy of ROZLYTREK® in NTRK gene fusion-positive, locally advanced or metastatic solid tumors was evaluated in 54 adult patients, who received ROZLYTREK® at various doses and schedules in one of three multicenter, single-arm, clinical trials. About 94% of patients received ROZLYTREK® 600 mg orally once daily. The median age was 58 years, about 60% of the patients were women and more than 40% of the patients had received 2 or more prior lines of therapy. Positive NTRK gene fusion status was determined in local laboratories or a central laboratory using nucleic acid-based tests prior to enrollment. The Overall Response Rate as determined by independent review was 57%, and the Duration of Response (DoR) was 6 months or longer for 68% of patients and 12 months or longer for 45% of patients. Objective responses to ROZLYTREK® were seen in people, with CNS metastases at baseline.

The efficacy of ROZLYTREK® in ROS1-positive metastatic NSCLC was evaluated in 51 adult patients who received ROZLYTREK® at various doses and schedules in the same three trials and 90% of patients received ROZLYTREK® 600 mg orally once daily. The Overall Response Rate was 78% and the Duration of Response (DoR) was 12 months or longer for 55% of patients. The most common adverse reactions (20% or more) with ROZLYTREK® were fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, arthralgia and vision disorders.

It was concluded that based on this multicenter, pooled analysis of global clinical trials, ROZLYTREK® was well tolerated and induced clinically meaningful, durable systemic responses in patients with NTRK-fusion positive solid tumors, with or without CNS disease. This is the third tissue agnostic cancer therapy (cancer treatment based on a common biomarker across different tumor types rather than the location in the body where the tumor originated) approved by the FDA. The previous tissue agnostic cancer therapies approved by the FDA were KEYTRUDA® (Pembrolizumab) for tumors with MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) tumors in 2017 and VITRAKVI® (Larotrectinib) for NTRK gene fusion tumors in 2018. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Demetri GD, Paz-Ares L, Farago AF, et al. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.

INREBIC® (Fedratinib)

RR

The FDA on August 16, 2019 approved INREBIC® for adults with intermediate-2 or high-risk Primary or Secondary (post-Polycythemia Vera or post-Essential Thrombocythemia) Myelofibrosis (MF). INREBIC® is a product of Impact Biomedicines, Inc.

ROZLYTREK® (Entrectinib)

RR

The FDA on August 15, 2019 granted accelerated approval to ROZLYTREK® for adults and pediatric patients 12 years of age and older with solid tumors that have a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. ROZLYTREK® is a product of Genentech Inc.

TURALIO® (Pexidartinib)

RR

The FDA on August 2, 2019 approved TURALIO® capsules for adult patients with symptomatic Tenosynovial Giant Cell Tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. TURALIO® is the first systemic therapy approved for patients with TGCT. TURALIO® is a product of Daiichi Sankyo, Inc.

KEYTRUDA® (Pembrolizumab)

RR

The FDA on July 30, 2019 approved KEYTRUDA® for patients with recurrent, locally advanced or metastatic Squamous Cell Carcinoma of the Esophagus (ESCC), whose tumors express PD-L1 (Combined Positive Score-CPS of 10 or more), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy. FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients for the above indication. KEYTRUDA® is a product of Merck & Co., Inc.

Adjuvant Treatment with PROLIA® Improves Disease Free Survival in Early Stage Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant Aromatase Inhibitors is the standard of care.

ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors that bind reversibly to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase Inhibitors however are associated with accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD) and can thus cause osteopenia and osteoporosis, thereby increasing fracture risk.Interplay-of-Bone-Formation-and-Bone-Resorption

PROLIA® (Denosumab) is a monoclonal antibody that inhibits osteoclast formation, function and survival, by selectively targeting the RANK ligand. The RANK-RANK ligand system is an important mediator of signaling in the genesis of osteoclasts and bone resorption. Additionally, the RANK-RANK ligand system has been implicated in antitumor immunity and may have a role in suppressing tumor agenesis. It has been hypothesized that targeting RANK with anti-RANK inhibitor might reverse the immunosuppressive effect of the RANK-RANK ligand signaling pathway.

ABCSG-18 is a randomized, double-blind, placebo controlled, Phase III trial in which the authors evaluated the benefits of the anti-RANK ligand antibody PROLIA® on bone health, in postmenopausal patients, with early stage hormone receptor-positive breast cancer, treated with Aromatase Inhibitors. Of the 3425 patients enrolled in this study, 3420 patients were randomly assigned 1:1 to receive PROLIA® 60 mg (N=1711) or matching placebo (N=1709), subcutaneously every 6 months, during Aromatase Inhibitor therapy. Majority of the patients participating in this study had breast cancer with good prognosis and only 25% of the patients required adjuvant chemotherapy. Patient received a median of 7 doses of PROLIA®. The Primary endpoint was the time to first clinical fracture after randomization. The Secondary endpoint was Disease Free Survival (defined as time from randomization to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. The Primary endpoint of the ABCSG-18 trial was met (The Lancet 2015;386:433-443) and the use of PROLIA® as an adjuvant to Aromatase Inhibitor therapy significantly delayed time to first clinical fracture, compared to Placebo (HR=0.50; P<0.0001). The authors in publication reported the Secondary endpoint of Disease Free Survival (DFS) outcomes from this study.

After a median follow-up of 73 months, there was a significant improvement in the Disease Free Survival among patients in the PROLIA® group compared to the placebo group (HR=0•82; P=0.026). In the PROLIA® group, the DFS was 89.2% at 5 years and 80.6% at 8 years of follow-up, compared with 87.3% at 5 years and 77.5% at 8 years in the placebo group. The total number of adverse events was similar in the PROLIA® and placebo groups and there were no reported cases of osteonecrosis of the jaw bone or atypical femoral fractures.

It was concluded that PROLIA® constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving Aromatase Inhibitor therapy, with a Disease Free Survival benefit similar to bisphophonates, but with a better toxicity profile and convenient subcutaneous injections twice yearly. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Gnant M, Pfeiler G, Steger GG, et al. Lancet Oncol 2019;20:339-351

Telomerase Inhibitor Imetelstat Provides Durable Transfusion Independence in Myelodysplastic Syndrome

RR

SUMMARY: It is estimated that in the United States approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are aged 65 years and older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years. The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient's disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia).

Management of patients with MDS includes supportive care with Erythropoiesis Stimulating Agents (ESAs), hypomethylating agents such as VIDAZA® (Azacitidine) and DACOGEN® (Decitabine), Immunomodulatory agents such as REVLIMID® (Lenalidomide), and Immunosuppressive agents such as AntiThymocyte Globulin (ATG) and Cyclosporine. Symptomatic patients with MDS are often treated with either VIDAZA® or DACOGEN® as these agents have been shown to improve survival in higher-risk MDS patients. It has remained unclear however, if one is better than the other.

Erythropoiesis Stimulating Agents (ESAs) are first-line therapy for anemia associated with lower-risk non-del(5q) MDS. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. There are however limited treatment options for RBC Transfusion Dependent (TD), Low Risk (IPSS Low/Int-1) MDS patients, who are Relapsed/Refractory to ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients. Imetelstat is a first-in-class Telomerase inhibitor that targets cells with short telomere length and active Telomerase, a feature often observed in some MDS patients across all stages of their disease. Higher Telomerase activity and shorter Telomeres in the blood cells of some patients with lower-risk MDS are known to predict for shorter overall survival.

IMerge is an ongoing global Phase II/III study of Imetelstat in RBC Transfusion Dependent patients with Low Risk-MDS (IPSS Low or Int-1). Previously reported data have demonstrated clinical benefit with Imetelstat in Low Risk-MDS patients inducing durable Transfusion Independence (Steensma et al ASH 2018 Abstr463). The authors now reported updated efficacy data in Low Risk, non-del(5q) MDS patients, Relapsed/Refractory to ESAs and Lenalidomide/HypoMethylating Agents naïve, from the open-label, single-arm Part 1 of IMerge study.

Part 1 of the IMerge study included patients with Low Risk MDS, who were heavily transfused (4 or more units /8wks), were Refractory or Relapsed on ESA or had serum EPO level of more than 500 mU/mL. This part of the study included 38 patients who were non-del(5q) and had not received either Lenalidomide/HypoMethylating Agents. Imetelstat was administered at 7.5 mg/kg IV every 4 weeks. The median patient age was 72 years, median baseline RBC transfusion burden was 8U/8weeks (range 4-14), 37% of the patients had IPSS Intermediate-1 risk score, 71% had WHO 2001 classification RARS (Refractory Anemia with Ringed Sideroblasts) or RCMD-RS (Refractory Cytopenia with Multilineage Dysplasia and Ringed Sideroblast) subtype and 32% with evaluable serum EPO levels had baseline level of more than 500 mU/mL. The Primary endpoint was 8-week Transfusion Independence rate. Secondary endpoints included 24-week Transfusion Independence rate, Safety, Duration of Transfusion Independence, and Hematologic Improvement rate. The median follow up was 12.1 months. The authors in this publication reported long-term efficacy, safety and biomarker data from these 38 patients.

Treatment with single-agent Imetelstat resulted in 8-week Transfusion Independence rate of 45% and the median Transfusion Independence duration was 8.5 months. Among those responding to Imetelstat, 59% remained transfusion free for over 24 weeks. The presence of Ring Sideroblasts or baseline serum EPO levels did not have an impact on 8-week Transfusion Independence rate. The 24-week Transfusion Independence rate was 26%. Erythroid Hematologic Improvement, defined as transfusion reduction by at least 4 units/8 weeks (IWG2006), was achieved in 68% of the patients. All patients (N=6) who had IPSS- Intermediate/poor cytogenetic risk achieved 8-week Transfusion Independence and 2 patients achieved partial cytogenetic response. Post treatment decrease in Telomerase (human Telomerase Reverse Transcriptase-hTERT) RNA level was observed in 73.5% of patients. Further, among patients with pre and post-treatment mutation analyses, six patients had SF3B1 mutations at baseline, and 2 patients who had a decrease in the mutation burden had longest Transfusion Independence duration on study. The most frequently reported adverse events were manageable and reversible grade 3 cytopenias.

It was concluded that treatment with single agent Imetelstat resulted in meaningful and durable Transfusion Independence, in Transfusion Dependent patients with non-del(5q) Lower-Risk MDS, who had relapsed or were refractory to ESA. Transfusion Independence was observed across different clinical subgroups, including patients with Intermediate and Poor cytogenetic risk, with a positive effect on malignant mutant clones. TREATMENT WITH IMETELSTAT PROVIDES DURABLE TRANSFUSION INDEPENDENCE (TI) IN HEAVILY TRANSFUSED NON-DEL(5Q) LOWER RISK MDS (LR-MDS) RELAPSED/REFRACTORY (R/R) TO ERYTHROPOIESIS STIMULATING AGENTS (ESAS). Fenaux P, Steensma DP, Eygen KV, et al. Presentation during European Hematology Association, Jun 15, 2019; 267420; S837