Month: August 2019

FDA Approves INREBIC® for Myelofibrosis

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SUMMARY: The FDA on August 16, 2019, approved INREBIC® (Fedratinib) for adults with Intermediate-2 or High-risk Primary or Secondary (post-Polycythemia Vera or post-Essential Thrombocythemia) Myelofibrosis (MF).

Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be Primary (PMF) or Secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET).JAK-STAT-Signaling-Pathway The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling. Currently, JAKAFI® (Ruxolitinib) is the only drug that has been approved by the FDA for Myelofibrosis.

INREBIC® is a highly selective JAK2 inhibitor and is active against a broader family of kinases and kinase mutants. This is unlike JAKAFI® which is a JAK1/2 inhibitor. The approval of INREBIC®was based on findings from the Phase III JAKARTA-2 study, which evaluated INREBIC® in patients with Primary or Secondary Myelofibrosis. In this double-blind, randomized, placebo-controlled trial, 289 patients with Intermediate-2 or High-risk MF, post-Polycythemia Vera MF, or post-Essential Thrombocythemia MF with splenomegaly, were randomized to receive either INREBIC® 500 mg (N=97), 400 mg (N=96) or placebo (N=96), once daily for at least 6 consecutive 4-week cycles. The Primary endpoint was the proportion of patients achieving 35% or more reduction in spleen volume from baseline at the end of cycle 6 measured by MRI or CT, with a follow up scan 4 weeks later. Secondary end point was symptom response (50% or more reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).

The Primary end point was achieved by 37% of the patients receiving INREBIC® at the 400 mg dose compared with 1% of patients who were in the placebo group (P <0.0001). The median duration of spleen response was 18.2 months for the INREBIC® 400 mg group. Further, 40% of patients who received INREBIC® at the 400 mg dose, experienced a 50% or more reduction in Myelofibrosis-related symptoms, whereas only 9% of patients receiving placebo experienced a decrease in these symptoms (P<0.0001). The most common adverse reactions seen in 20% or more patients who received INREBIC® were diarrhea, nausea, anemia, and vomiting.

In conclusion, INREBIC® therapy significantly reduced splenomegaly and symptom burden in patients with Myelofibrosis. This FDA approval represents an important milestone for patients with Myelofibrosis and clinicians now have a new treatment option for these patients, including those previously treated with JAKAFI®. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis

US Preventive Services Task Force Recommendations on BRCA Mutation Testing

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the second leading cause of cancer death in the US. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. These mutations can be inherited from either of the parents in an autosomal dominant pattern and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.

It is estimated that BRCA1/2 gene mutations occur in approximately 1 in 400 women in the general population and account for 5-10% of breast cancer cases and 15% of ovarian cancer cases. The estimated prevalence of potentially harmful BRCA1/2 mutations is 6% in women with cancer onset before age 40 years, and 2.1% among Ashkenazi Jewish women. Among individuals with a family history of breast or ovarian cancer, BRCA1 mutation prevalence is approximately 13%, BRCA2 mutation prevalence is about 8%, and prevalence of either mutation is about 20%. Mutations in the BRCA1/2 genes increase breast cancer risk by 45-65% by age 70 years. The risk of ovarian, fallopian tube, or peritoneal cancer, increases to 39% for BRCA1 mutations, and 10-17% for BRCA2 mutations.

The US Preventive Services Task Force (USPSTF) in this publication updated the 2013 recommendations on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. These recommendations are based on the evidence of both the benefits and harms of the service and this assessment does not consider the costs of providing a service.

The USPSTF reviewed the evidence on risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1/2 mutations in asymptomatic women who have never been diagnosed with BRCA-related cancer, as well as those with a previous diagnosis of breast, ovarian, tubal, or peritoneal cancer who have completed treatment and are considered cancer free. In addition, the USPSTF reviewed interventions to reduce the risk for breast, ovarian, tubal, or peritoneal cancer in women with potentially harmful BRCA1/2 mutations, including intensive cancer screening, medications, and risk-reducing surgery.

Recommendations

1) The USPSTF recommended that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations, with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing.

2) The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations.

Risk Assessment

Clinicians should obtain medical and family history specifically inquiring patients about specific types of cancer, primary cancer sites, which family members were affected, whether relatives had multiple types of primary cancer, the age at diagnosis, age at death, and sex of affected family members, both immediate (parents and siblings) as well as more distant (aunts, uncles, grandparents, and cousins). Women who have a family or personal history of breast, ovarian, tubal, or peritoneal cancer should be evaluated by clinicians, to determine the need for in-depth genetic counseling, using appropriate familial risk assessment tools, recognized by the USPSTF. Familial risk assessment factors include breast cancer diagnosis before age 50 years, bilateral breast cancer, presence of both breast and ovarian cancer in one individual, male family members with breast cancer, multiple cases of breast cancer in the family, one or more family members with 2 primary types of BRCA-related cancer (such as ovarian cancer), and Ashkenazi Jewish ancestry. Breast cancer risk assessment models such as the National Cancer Institute Breast Cancer Risk Assessment Tool, which is based on the Gail model are not designed to identify BRCA-related cancer risk and should not be used for this purpose.

Genetic Counseling

Genetic counseling includes detailed kindred analysis and risk assessment for potentially harmful BRCA1/2mutations, identification of individuals for testing, discussion of the benefits and harms of genetic testing, interpretation of results after testing, and discussion of management options. Genetic counseling should be performed by trained health professionals, including suitably trained primary care clinicians.

Genetic Testing

Testing for BRCA1/2 mutations should be performed only when an individual with history suggesting inherited cancer susceptibility, is willing to talk with a qualified health professional, trained to provide genetic counseling and interpret test results, and when test results will aid in decision-making. BRCA mutation testing should begin with a relative with known BRCA-related cancer, including male relatives, to determine if a clinically significant mutation is detected in the family, before testing individuals without cancer. If an affected family member with a BRCA-related cancer is not available, then the relative with the highest probability of mutation should be tested. Reporting BRCA1/2 mutations identified by genetic tests should include a 5-tier terminology system, using the terms “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign.

Treatment and Interventions for women with harmful BRCA1/2 mutations

The USPSTF recommends that clinicians offer intensive screening and risk-reducing medications such as Tamoxifen, Raloxifene, or Aromatase Inhibitors to women at increased risk for breast cancer and at low risk for adverse medication effects. General care for these individuals may include risk-reducing mastectomy and salpingo-oophorectomy.

US Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:652-665.

Dramatic Increase in ColoRectal Cancer Incidence among Young Adults

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Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than 50 years of age, according to data in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Based on these findings, the American Cancer Society in 2018 updated its guidelines to include a “qualified recommendation” to begin CRC screening at the age of 45 yrs. 

In a recently published retrospective study, the proportion of the total number of patients diagnosed with CRC under the age of 50 yrs rose from 10% in 2004 to 12.2% in 2015 (P<0.0001). Younger adults presented with more advanced stage of disease (Stage III/IV) than those 50 yrs or older (51.6% versus 40.0% respectively). When racial and ethnic groups were stratified by sex, among men with a diagnosis of CRC before age 50, non‐Hispanic whites showed a proportional increase in diagnosis (P<0.0001), whereas among women, both Hispanic whites (P<0.05) and non‐Hispanic whites (P<0.001) had increases in the proportion of CRC diagnosed before age 50. The rates of CRC diagnosis in young adults increased over time, regardless of income level (P<0.001).The highest proportion of young adult CRC diagnoses occurred in the highest income group. The proportion of CRC cases diagnosed in younger individuals rose in urban areas (P<0.001), but not in rural areas. Health Care Providers should be mindful of these data, when screening guidelines are discussed with patients. 

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

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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.

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

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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. 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

INREBIC® (Fedratinib)

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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)

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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)

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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)

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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.