SUMMARY: It is estimated that cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum account for approximately 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US. There are currently no screening tests available for cancers of the gallbladder, bile duct, and pancreatic cancer. Although screening tests do exist for other types of GI malignancies such as colorectal and stomach cancer, many of them are invasive. Further, when GI malignancies are diagnosed, they are frequently at advanced stages and are more difficult to treat.
A noninvasive, liquid biopsy assay based on circulating tumor DNA (ctDNA) has the potential to detect cancer in early stages among asymptomatic individuals. ctDNA refers to DNA fragments that are shed into the bloodstream by cancer cells after apoptosis or necrosis. ctDNA can detect almost all molecular alterations present in cancer cells and genotyping circulating cell-free tumor DNA (cfDNA) in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape. The proportion of cfDNA that originates from a tumor depends on the anatomic location, tumor burden and cell turnover. cfDNA also allows real-time monitoring for treatment response and resistance.
The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, is a joint effort between the National Cancer Institute and the National Human Genome Research Institute. This program began in 2006 and has molecularly characterized over 20,000 primary cancers and matched normal samples, across 33 different cancer types. After 12 years and contributions from over 11,000 patients, TCGA has deepened our understanding of the molecular basis of cancer, changed the way cancer patients are managed in the clinic, established a rich genomics data resource for the research community, and helped advance health and science technologies.
The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, case-control, observational study with longitudinal follow up, and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection based on cell-free DNA (cfDNA). This study completed enrollment of approximately 15,000 participants with and without cancer (56% with more than 20 tumor types and all clinical stages), across 142 sites in the US and Canada. The purpose of this study is to collect biological samples from patients with a new diagnosis of cancer (blood and tumor tissue) and from individuals who do not have a diagnosis of cancer (blood), in order to characterize the population heterogeneity in cancer and non-cancer participants, and to develop models for distinguishing cancer from non-cancer. The principal goal is to develop a noninvasive cancer detection assay and the CCGA was designed to characterize the landscape of genomic cancer signals in the blood and to detect and validate GRAIL, Inc.’s multi-cancer early detection blood test through three pre-planned sub-studies.
GRAIL, Inc., is a healthcare company focused on the early detection of cancer by using the power of Next-Generation Sequencing, population-scale clinical studies, and state-of-the-art computer science and data science to enhance the scientific understanding of cancer biology, and to develop its multi-cancer early detection blood test. GRAIL’s high efficiency methylation technology preferentially targets the most informative regions of the genome, and is designed to use its proprietary database and machine-learning algorithms to both detect the presence of cancer and identify the tumor’s Tissue of Origin. GRAIL’s sequencing database of cancer and non-cancer methylation signatures is believed to be the largest of its kind, and covers approximately 30 million methylation sites across the genome, with more than 20 cancer types across stages represented within the database.
Previously reported data from the first sub-study of CCGA showed GRAIL’s prototype technology could detect the presence of multiple deadly cancer types with a low rate of false positive results (high specificity). In this analysis blood samples from 166 participants who had a cancer diagnosis at the time of enrollment were evaluated, and cancer was detected using the methylation technology. Results showed that GRAIL’s prototype technology correctly identified the tumor’s Tissue of Origin in 87% of the blood samples evaluated (N=144/166), including 96% of breast cancer cases (N=22/23), 88% of lung cancer cases (N=29/33), 90% of liver cancer cases (N=9/10) and 100% of pancreatic cancer cases (N=17/17).
GRAIL has since selected methylation as its preferred approach and evaluated its refined methylation blood test in the second pre-planned sub-study of CCGA. It was determined that whole-genome bisulfite sequencing for DNA methylation was the most effective approach for early cancer detection. DNA methylation is a natural epigenetic mechanism used by cells to regulate gene expression with some regions of hypermethylation and some regions of hypomethylation, and is a chemical modification to DNA, that can change how a gene’s function is carried out by the body without changing the order of the DNA bases. In cancer, abnormal methylation patterns and the resulting changes in gene expression can contribute to tumor growth (hypermethylation can cause tumor-suppressor genes to be inactivated). Methylation patterns or signatures, are unique to the tumor DNA, enabling tumor detection and localization, but are not of value when it comes to precision therapies. This is unlike mutations and copy number changes, which can be detected in white blood cells in individuals without cancer as well, leading to false-positives.
The researches in this second substudy reported the performance of methylation-based cfDNA early multi-cancer detection test, for GastroIntestinal (GI) tract cancers, and also provided data from individuals without known cancer (non-cancer controls). To test the current assay, the second substudy included approximately 4,500 individuals, both with and without cancer, who were split into a training cohort and a validation cohort. Of the 2,185 patients with newly-diagnosed cancer in the second substudy, 447 patients were diagnosed with GI malignancies. Plasma cfDNA was subjected to targeted methylation analysis to develop an algorithm that could identify the presence or absence of cancer, as well as the Tissue of Origin of the cancer. The GI malignancies included Esophagus/Stomach (N=67), Pancreas/Gallbladder/Extrahepatic bile duct (N=95), Liver/Intrahepatic bile duct (N=29), and Colon/Rectum (N=121). To minimize the likelihood of false-positives, the targeted methylation assay was pre-set to yield greater than 99% specificity.
The test showed a sensitivity level of approximately 82% for detecting GI cancers of all stages in the independent validation set. The predicted Tissue of Origin accuracy across all GI cancers was 92%.
It was concluded that this assay performed using a single noninvasive blood sample, has the potential to diagnose a variety of gastrointestinal cancers earlier, when they are more treatable, with good sensitivity and with a low rate of false positives. Performance of a blood-based test for the detection of multiple cancer types. Wolpin BM, Richards DA, Cohn AL, et al. J Clin Oncol. 2020;38(suppl 4; abstr 283).
Category: Precision Oncology
Biomarkers May Predict Response to BRAF and MEK inhibitors in Malignant Melanoma
Biomarkers May Predict Response to BRAF and MEK inhibitors in Malignant Melanoma
SUMMARY: It is estimated that in the US, approximately 100,350 new cases of malignant melanoma will be diagnosed in 2020 and about 6850 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 III 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.
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. Long term survival data pooled 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 TAFINLAR® along with MEKINIST® showed PFS rates of 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 LDH level plus fewer than three metastatic organ sites at baseline.
With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians based on the long term data supporting the durability of responses with immunotherapies. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear.
COMBI-AD is 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. At a median follow up of 2.8 years, the estimated 3-year Relapse Free Survival (RFS) rate was 58% with a combination of TAFINLAR® and MEKINIST® and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001). A prespecified exploratory outcome of this trial was assessment of biomarkers. The authors assessed intrinsic tumor genomic features in 368 patients using Next-Generation DNA sequencing, and tumor microenvironment characteristics were assessed in 507 patients by use of a NanoString RNA assay, in an attempt to provide prognostic and predictive information. Median follow up at data cutoff was 44 months in the TAFINLAR® plus MEKINIST® group and 42 months in the placebo group.
Baseline MAPK pathway genomic alterations did not affect treatment benefit or outcomes in either treatment groups. An Interferon Gamma gene expression signature higher than the median was prognostic for prolonged RFS in both treatment groups. Tumor Mutational Burden (TMB) was independently associated with better RFS in the placebo group (HR for top third versus bottom third of TMB values=0.56; P=0.0056), but this benefit was not seen in the TAFINLAR® plus MEKINIST® group (HR= 0.83; P=0.44). However, patients with TMB in the lower two terciles who received TAFINLAR® plus MEKINIST® combination had improved RFS compared to those who received placebo (HR=0.49: P<0.0001). Patients with high TMB appeared to have a less pronounced benefit with TAFINLAR® plus MEKINIST® targeted therapy, compared to placebo, especially if they had an Interferon Gamma gene expression signature lower than the median.
It was concluded from this biomarker analysis that high Tumor Mutational Burden was independently associated with better Relapse Free Survival in the placebo group but not in the TAFINLAR® plus MEKINIST® combination group, and an Interferon Gamma gene expression signature higher than the median was prognostic for prolonged RFS in both treatment groups. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Dummer R, Brase JC, Garrett J, et al. The Lancet Oncology. Published:January 30, 2020DOI:https://doi.org/10.1016/S1470-2045(20)30062-0
Multigene Testing for All Patients with Breast Cancer Could Identify Many More Mutation Carriers
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. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. These mutations can be inherited from either of the parents in an Autosomal Dominant pattern and a child has a 50% 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 20-25% of hereditary breast cancers, about 5-10% of all breast cancers and 15% of ovarian cancers. Mutations in the BRCA1/2 genes increase breast cancer risk 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. PALB2 (Partner And Localizer of BRCA2) gene provides instructions to make a protein that works along with the BRCA2 protein, to repair damaged DNA. PALB2 mutation is rare in sporadic breast cancer, and is considered a high-penetrance breast cancer predisposing gene associated with 14% risk of developing breast cancer by age 50 and a 35% risk of developing breast cancer by age 70. Women with a PALB2 mutation face an increased risk of triple negative breast cancer and higher risk of death from breast cancer. PALB2 gene mutations have also been implicated in ovarian, pancreatic and other malignancies.
Current guidelines recommend genetic testing in women with breast cancer who fulfill recognized or established family history or clinical criteria. However, patients with breast cancer and genetic pathogenic variants do not always have a positive family history, and these criteria miss approximately 50% of pathogenic variant carriers. Further, genetic testing based on family history or clinical criteria depends on the awareness and understanding both by the health care providers and patients, and appropriate referrals to genetic counselors. Because of limited awareness and restricted access to genetic testing and counseling services, only 20-30% of eligible patients undergo genetic testing, and 97% of estimated carriers in the general population remain unidentified, thereby missing substantial opportunities for primary prevention.
Knowledge of a patient’s genetic pathogenic variant status has important therapeutic and prognostic implications. Identifying unaffected relatives carrying pathogenic variants enables early diagnosis and cancer prevention by offering risk management options such as enhanced MRI imaging and mammography screening, risk-reducing surgeries such as prophylactic mastectomy, salpingo-oopherectomy and chemoprevention with Selective Estrogen Receptor Modulators.
The authors in this study estimated the downstream health effects, costs and cost-effectiveness of multigene testing for all patients with breast cancer, compared with current practice of BRCA testing based on clinical criteria or family history alone. In this modeling study, data was incorporated from four large breast cancer clinical trials and/or research cohorts in the United States, United Kingdom, and Australia. This analysis included 11,836 women with invasive breast cancer, regardless of the family history, and compared lifetime costs and effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing of all unselected patients with breast cancer (Strategy A) with BRCA1/BRCA2 testing based on family history or clinical criteria (Strategy B), in UK and US populations, from January 1, 2018, through June 8, 2019.
Affected patients with BRCA/PALB2 mutations could undertake contralateral preventive mastectomy and BRCA carriers could choose Risk-Reducing Salpingo-Oophorectomy (RRSO). If patients had a BRCA1/BRCA2/PALB2 pathogenic variant, their first-degree relatives undergo testing for the familial pathogenic variant. If the first-degree relative had a BRCA1/BRCA2/PALB2 pathogenic variant, second-degree relatives undergo testing. Unaffected relative carriers could undergo MRI or mammography screening, chemoprevention, or risk-reducing mastectomy for breast cancer risk and RRSO for ovarian cancer risk. This analysis incorporated lifetime risks and long-term consequences to provide a lifetime horizon. Incidence of ovarian cancer, breast cancer, excess deaths due to heart disease, and the overall population effects were estimated.
Multigene testing was restricted to BRCA1/BRCA2/PALB2, to comply with the ACCE framework for genetic testing, which was advocated for clinical applicability of genetic testing. The ACCE framework includes Analytic validity which is technical test performance, Clinical validity which is the ability of a genetic test to identify or predict accurately and reliably the clinically defined disorder or phenotype of interest, Clinical utility which is evidence that a genetic test improves clinical outcomes measurably and that it adds value for patient management decision making compared with current management without genetic testing, and ELSI which are the complex Ethical, Legal, and Social Implications associated with genetic tests.
This study showed that unselected BRCA1/BRCA2/PALB2 testing for all patients at breast cancer diagnosis was extremely cost-effective compared with BRCA1/BRCA2 testing based on clinical criteria or family history for both UK and US health systems, with incremental cost-effectiveness ratios of £10,464 or £7,216 and $65,661 or $61,618 per Quality-Adjusted Life-Year, respectively. Quality-Adjusted Life-Year (QALY) is a measurement of health outcomes in economic evaluations recommended by NICE (National Institute of Health and Clinical Excellence). This is well below UK and US cost-effectiveness thresholds. The authors estimated that one year’s unselected panel genetic testing could prevent 1142 cases of breast cancer, 959 cases of ovarian cancer, and 633 deaths related to breast or ovarian cancer in the UK. In the US, one year’s unselected panel genetic testing could prevent 5478 cases of breast cancer, 4255 cases of ovarian cancer, and 2406 deaths related to breast or ovarian cancer.
It was concluded from this analysis that unselected, high-risk multigene testing for all women with breast cancer is extremely cost-effective, compared with testing based on family history or clinical criteria, and could identify many more mutation carriers who can benefit from precision prevention. The authors added that these findings support changing current policy to expand genetic testing to all women with breast cancer. A Cost-effectiveness Analysis of Multigene Testing for All Patients with Breast Cancer. Sun L, Brentnall A, Patel S, et al. JAMA Oncol. 2019;5:1718-1730
Circulating Tumor DNA in the Peripheral Blood Predicts Recurrence Risk After Surgery and Adjuvant Chemotherapy in Stage III Colon Cancer
SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 145,600 new cases of CRC were diagnosed in the United States in 2019 and about 51,020 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with Stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. In spite of these advancements, defining patient subsets at high risk of recurrence following standard adjuvant therapy remains challenging and treatment failure can only be acknowledged when clinical recurrence is documented.
Cell-free DNA (cfDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis. A specific portion of cfDNA that originates from tumor cells is referred to as circulating tumor DNA (ctDNA), which can be detected in the cell-free component of peripheral blood samples in almost all patients with advanced solid tumors including advanced colorectal cancer. ctDNA is a valuable biomarker and allows early detection of relapse. Several studies have shown that detectable ctDNA following surgery for early stage cancers, is associated with a very high risk of recurrence. The authors in this publication report on the results of a correlative biomarker study in patients with Stage III colon cancer, undergoing standard adjuvant chemotherapy.
A multicenter, population-based, cohort study was conducted to determine whether serial post-surgical and post-chemotherapy ctDNA analysis could provide a real-time indication of efficacy of adjuvant therapy in Stage III colon cancer. In this study, 100 patients with newly diagnosed Stage III colon cancer who were planned to receive 24 weeks of adjuvant chemotherapy were enrolled. Patients had R0 resection with no evidence of metastatic disease on staging CT of the chest, abdomen, and pelvis before surgery. The chemotherapy regimen was chosen by the treating physician, who was blinded to the ctDNA result. High-risk patients were defined as those having pT4 and/or pN2 disease according to the pTNM staging system. Blood samples for ctDNA and CEA (CarcinoEmbryonic Antigen) analysis were collected 4-10 weeks after surgery prior to commencement of adjuvant chemotherapy and at the completion of adjuvant therapy, within 6 weeks of the final cycle of chemotherapy. All patients had a surveillance CT scan 4-8 weeks after completion of adjuvant chemotherapy. Follow up surveillance included clinical exam every 3 months along with CEA measurement and annual CT imaging for 3 years. Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patient tumors were identified by massively parallel sequencing of 15 genes commonly mutated in colorectal cancer, and personalized assays were designed to quantify ctDNA. For each patient, one mutation identified in the tumor tissue was assessed in the plasma for the presence of ctDNA. The median duration of follow up was 28.9 months and the primary aim of this study was to demonstrate the association between postsurgical and post-chemotherapy ctDNA detection and the risk of recurrence.
Among the 96 evaluable patients, circulating tumor DNA was detectable in 20 of 96 (21%) post-surgical samples and these patients had an increased risk of recurrence with associated inferior Recurrence-Free Survival, (HR=3.8; P<0.001). The estimated 3 year Recurrence Free Interval (RFI) for patients with positive ctDNA findings was 47% and for those with ctDNA-negative findings was 76%. Circulating tumor DNA was detectable in 15 of 88 (17%) post-chemotherapy samples. The estimated 3 year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR=6.8; P<0.001). Postsurgical ctDNA status was an independent predictor of disease recurrence after adjusting for known clinicopathologic risk factors (HR=7.5; P<0.001).
The authors concluded that post-surgical and post-chemotherapy circulating tumor DNA analyses is a promising prognostic marker in Stage III colon cancer, and may identify patients at high risk of recurrence, despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches. Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer. Tie J, Cohen JD, Wang Y, et al. JAMA Oncol. 2019;5:1710-1717.
FDA Approves ADAKVEO®, A New Targeted Therapy for Sickle Cell Disease
SUMMARY: The FDA on November 15, 2019 approved ADAKVEO® (Crizanlizumab-tmca), a treatment to reduce the frequency of vaso-occlusive crisis, for patients age 16 years and older. Vaso-occlusive crisis is a common and painful complication of Sickle Cell Disease (SCD), that occurs when blood circulation is obstructed by sickled red blood cells. Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the United States is approximately 40-60 years.
HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (vaso-occlusive crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 thalassemia (double heterozygote for HbS and b-0 thalassemia) is clinically indistinguishable from HbSS disease.
P-Selectin is a Cell Adhesion Molecule (CAM) expressed on the surfaces of activated vascular endothelial cells and platelets. In unactivated endothelial cells and platelets, it is stored in Weibel-Palade bodies and alpha granules respectively. P-Selectin is released from endothelial cells and platelets when activated by inflammation or trauma and mediates the binding of erythrocytes and leukocytes to the vessel wall. In patients with Sickle Cell Disease (SCD), adherent masses of sickled red cells and leukocytes contribute to vaso-occlusive pain crises. ADAKVEO® is a first-in-class humanized anti-P-Selectin antibody, and the SUSTAIN study evaluated the safety and efficacy of ADAKVEO® on the frequency of Sickle Cell-related Pain Crises (SCPC) in Sickle Cell Disease patients.
The present FDA approval of ADAKVEO® was based on SUSTAIN, a multicenter, randomized, placebo controlled, double-blind clinical trial in which 198 Sickle Cell Disease patients with a history of vaso-occlusive crisis, were randomly assigned to receive ADAKVEO® at doses of 5 mg/kg, 2.5 mg/kg, or placebo, administered intravenously, 14 times over 52 weeks. Treatment groups were well balanced and patients receiving Hydroxyurea or Erythropoietin were included, if prescribed for the preceding 6 months and dose was stable for at least 3 months. The Primary end point was Sickle Cell-related Pain Crises (SCPC), defined as acute sickle cell-related pain that resulted in a visit to a medical facility and required a parenteral or oral narcotic or parenteral NSAID. Acute Chest Syndrome (ACS), priapism, hepatic and splenic sequestration were also included in this definition.
Treatment with ADAKVEO® experienced fewer health care visits for vaso-occlusive crisis annually and significantly lowered the median annual rate of vaso-occlusive crisis by 45% from 2.98 visits to 1.63 visits, compared with placebo. Reductions in the frequency of vaso-occlusive crisis were observed among patients regardless of Sickle Cell Disease genotype and/or Hydroxyurea use. More than one third (36%) of patients who received ADAKVEO® did not experience vaso-occlusive crisis during the study, compared with 17% of placebo-treated patients. ADAKVEO® delayed the time that patients first experienced vaso-occlusive crisis after starting treatment from a median of 1.4 months to 4.1 months. Common side effects associated with ADAKVEO® included back pain, nausea, fever and arthralgia. Patients should be monitored for infusion-related reactions and treatment should be discontinued for severe reactions. Patients should also be monitored for interference with automated platelet counts or platelet clumping and it is advised that CBC be performed using citrate tubes to avoid platelet activation.
It was concluded that ADAKVEO® significantly reduced Sickle Cell-related Pain Crises (SCPC) and increased the time to first and second SCPC. The authors added that chronic inhibition of P-Selectin with once a month IV dosing of ADAKVEO® represents a novel and potentially new disease-modifying, prophylactic treatment option for patients with Sickle Cell Disease. SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises. Ataga KI, Kutlar A, Kanter J, et al. N Engl J Med 2017; 376:429-439
Late Breaking Abstract – ASTRO 2019 Detectable HPV Circulating Tumor DNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression
SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a signiï¬cant increase in incidence during the past several decades. They represent approximately 70% of all OPSCC in the United States and Canada. HPV is a non-enveloped, double-stranded, DNA virus that infects epithelial cells and majority of the HPV subtypes cause epithelial lesions such as warts or papillomas, which are of low malignant potential. However, there is a subset of high-risk HPV that can cause cancer by integrating its DNA into the host genome, with the resulting expression of two important oncogenes E6 and E7 in the host cell. The E6 oncogene binds and degrades tumor suppressor TP53 via ubiquitin-mediated processes thereby preventing the host cell from engaging in cell cycle checkpoints and enduring an apoptotic response. The E7 oncogene binds to and destabilizes tumor suppressor retinoblastoma (pRb) resulting in transcription of genes involved in proliferation and cell cycle progression. One of the main molecular pathways amplified through E7 is the CDKN2A/p16 gene pathway, which results in the overexpression of p16 protein. E7 also induces cellular proliferation by disrupting the activity of Cyclin Dependent Kinase inhibitors p21 and p27. In essence, HPV infection induces failures in cell cycle checkpoints, resulting in genetic instability and over time, progression of premalignant lesions to invasive Squamous Cell Carcinoma. Unlike tobacco induced HNSCC where TP53 and pRb pathways are nullified due to mutation and epigenetic alterations, in HPV-related HNSCC, wild-type TP53 and pRb are functionally inactivated by the viral oncogenes.
Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV infection. The HPV-positive primary Squamous Cell Carcinoma tends to be smaller in size, with early nodal metastases, and HPV status particularly in OroPharyngeal Squamous Cell Carcinoma is an independent prognostic factor for Overall Survival (OS) and Progression Free Survival (PFS). These patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Further, HPV positive patients demonstrate higher Response Rates to chemoradiation as well as an improved Overall Survival. However, approximately 20% of patients diagnosed with HPV-positive OPSCC experience cancer progression within 5 years.
The role of circulating tumor DNA (ctDNA) as a cancer biomarker in the post-operative surveillance of patients with HPV-associated OPSCC has remained unclear. The authors in this study aimed to investigate ctDNA detectability rates by post-op risk category and association with prognosis in this patient population. The researchers prospectively collected and tested serum samples from 29 patients with HPV-associated OPSCC who had not yet undergone treatment, for assay validation. As a control, 7 HPV negative OPSCC patients were included. A cohort of 46 patients with HPV-associated OPSCC who had undergone surgery for the disease had serum samples collected prior to beginning adjuvant therapy. The serum collected from this total group of 82 patients (N=29+7+46) was analyzed in a blinded fashion for E6/E7 HPV ctDNA using ddPCR multiplex assay (HPV 16, 18, 31, 33), and HPV ctDNA detectability was compared statistically across groups. Associations of patient and tumor characteristics with recurrence were assessed and estimates of Progression Free Survival (PFS) and Overall Survival (OS) were made using the Kaplan-Meier (KM) method.
The researchers found that ctDNA was detectable in 27 of 29 patients who had not yet undergone treatment, for a sensitivity rate of 93%, whereas none of the 7 HPV-negative patients had detectable ctDNA, for a specificity rate of 100%. Post-op serum was collected at a median of 25 days after surgery prior to beginning adjuvant therapy and ctDNA was detectable in 43% of patients including 47% with high-risk features (Extra Nodal Extension or R1-microscopic residual tumor). All detected ctDNA was HPV type 16.
At a median follow up of 20 months for the post-op HPV-OPSCC cohort, 24% of these patients had recurrent disease. Among those who recurred, 64% had detectable ctDNA compared with 35% whose disease did not recur (P=0.1). There was a significant association between detectable ctDNA and 24-month Progression Free Survival (45% versus 84%; P=0.04) and Overall Survival (80% versus 100%; P=0.02). Overall, detectable ctDNA, T4 tumors, and more than 4 positive lymph nodes were positively associated with disease recurrence.
It was concluded that detectable HPV circulating tumor DNA is a highly sensitive and specific means of determining HPV-status and was significantly associated with worsened Progression Free Survival and Overall Survival among post-op patients with Human Papilloma Virus (HPV)-associated OroPharyngeal Squamous Cell Carcinoma. HPV circulating tumor DNA as a cancer biomarker may also assist in risk stratification, treatment assessment, and surveillance. Detectable HPV ctDNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression. Routman DM, Chera BS, Jethwa KR, et al. International Journal of Radiation Oncology • Biology • Physics 2019;105, 682-683. LBA5
Clinical Utility of NETest®, a Liquid Biopsy Assay for Diagnosis, Monitoring Therapy and Prognosis, in Patients with Neuroendocrine Tumors
SUMMARY: It is estimated that in the United States, more than 12,000 people are diagnosed with a Neuroendocrine tumor each year. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and the most common sites of NETs are the lung, stomach, appendix, cecum, duodenum, pancreas, jejunum/ileum, colon, and rectum. NeuroEndocrine Tumors originating in the gastrointestinal tract and pancreas are also known as GastroEnteroPancreatic NETs (GEP-NETs). They constitute about 2% of all neoplasms and account for about 50-70% of all NETs. They are more frequent in gastric fundus/body, proximal duodenum, Vater’s papilla, pancreas, tip of the appendix, terminal ileum, and lower rectum. Majority of GEP-NETs are not symptomatic (nonfunctioning tumors), difficult to diagnose, and present with advanced disease at initial diagnosis. They often metastasize to the mesentery, peritoneum and liver. The functioning tumors however secrete biologically active substances that can lead to the development of characteristic clinical syndromes. NeuroEndocrine Tumors may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.
Chromogranin A is a glycoprotein precursor to several functional peptides and is considered a standard biomarker for NETs. However, serum Chromogranin A levels can be elevated in several non-oncologic conditions such as atrophic gastritis, pancreatitis, chronic hepatitis, liver cirrhosis, irritable bowel, and inflammatory bowel diseases. The use of proton pump inhibitors can also result in elevated Chromogranin A levels. Diagnostic imaging as well as serum biomarkers lack the sensitivity and are unable to detect early changes in disease state. As such, the absence of a clinically useful blood biomarker remains an important unmet need.
The NETest® is a novel blood-based (liquid biopsy) molecular diagnostic test intended to aid in the identification of neuroendocrine tumor disease activity. The assay involves measurement of 51 neuroendocrine tumor gene transcripts, by Polymerase Chain Reaction (PCR). The gene expression signatures, which is the tumor activity score, stratifies patients into three groups: low score (40% or less), moderate/intermediate score (41-79%) and high score (80% or more). A higher score at the time of testing indicates a higher risk of tumor activity. Previously published prospective clinical studies have demonstrated the value of NETest® in predicting the effectiveness of surgery, in its ability to monitor tumor progression during SomatoStatin Analog (SSA) therapy, in its utility for watchâ€andâ€wait programs, as well as its ability in predicting response to Peptide Receptor RadioTherapy (PRRT) prior to treatment initiation.
The authors in this study examined the clinical utility of NETest® multigene assay in a realâ€world setting, utilizing a registry of NETs in the USA. This registry was established to include clinical and biomarker data from patients enrolled by interested physicians who could then use it to answer specific clinical questions. NETest® registry patients were evaluated from large referral practices, and their subsequent clinical data, including decisionâ€making, were interfaced with NETest® data. This study addressed five important questions: 1) What is the diagnostic accuracy of the NETest®? 2) Does the NETest® score accurately reflect the disease status? 3) Does it have clinical utility in decisionâ€making? 4) Can it alter the frequency and type of imaging? 5) Does the NETest® have greater clinical utility than Chromogranin A?. The diagnostic accuracy and relationship to clinical disease status were evaluated in two patient cohorts (treated and watchâ€andâ€wait).
A total of 100 patients with pathological confirmation of a NET were enrolled over a 22 month period and NETest® was performed at enrollment. The primary site of the NET was gastroenteropancreatic (68%), lung 20%, and of unknown origin (12%). Stage IV disease was present in 96% of patients, 70% had undergone surgery before enrollment, 97% had wellâ€differentiated, lowâ€grade tumors and 56% were on drug therapy. The median age was 62 years and the median follow up was 6 months.
The diagnostic accuracy of NETest® was more than 96% and the NETest® was concordant with imageâ€confirmed disease in 96% of patients. Scores were reproducible (97%) and concordant with clinical status (98%). Chromogranin A was ordered for 53 of the 100 patients, but was not elevated in 75% of these patients despite documented clinical evidence of disease. NETest® was positive in 100% of these patients (P=0.0004 for accuracy). NETest® scores were reproducible (97%) and concordant with clinical status (98%). Multivariate analyses identified the NETest® score as the only variable significantly related to Progression Free Survival (PFS). High NETest® score correlated with progressive disease (81%; median PFS, 6 months), and low NETest® score correlated with stable disease (87%; median PFS, Not Reached)-P<0.0001). The NETest® score was the only feature linked to PFS (odds ratio, 6.1; p < .0001). In the watchâ€andâ€wait group of patients, low NETest® scores were concordant with stable disease in 100% of patients, and high NETest® scores were associated with management changes in 83% of patients. In the treated group, all patients with low NETest® scores (100%) remained stable. A high NETest® score was linked to treatment intervention and disease stabilization (100%). Further, the utilization of NETest® was associated with reduced imaging (biannual to annual) in 36-38% of patients.
It was concluded that realâ€time liquid biopsy assessment of Neuroendocrine tumors with NETest® has more than 96% diagnostic accuracy, and has clinical utility in monitoring disease status, as well as patient management. Assessment of NETest Clinical Utility in a U.S. Registryâ€Based Study. Liu E, Paulson S, Gulati A, et al. The Oncologist 2019;24:783-790.
Liquid Biopsy DNA Methylation Assay Highly Specific for Cancer Detection and Prognosis
SUMMARY: Screening both healthy and high-risk populations with a peripheral blood sample (liquid biopsy) has the potential to detect cancer at an early stage, with an increased opportunity to offer curative therapies. Screening assays for cancer should be highly specific with a low rate of false-positive results and overdiagnosis. Analysis of cell-free DNA (cfDNA) with a Liquid Biopsy is presently approved to select EGFR targeted therapies (cobas EGFR mutation test), in patients with advanced Non Small Cell Lung Cancer. However, the role of cell-free DNA analysis for early detection of cancer is not well established.
The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, is a joint effort between the National Cancer Institute and the National Human Genome Research Institute. This program began in 2006 and has molecularly characterized over 20,000 primary cancers and matched normal samples, across 33 different cancer types. After 12 years and contributions from over 11,000 patients, TCGA has deepened our understanding of the molecular basis of cancer, changed the way cancer patients are managed in the clinic, established a rich genomics data resource for the research community and helped advance health and science technologies.
The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, observational study and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection, based on cell-free DNA (cfDNA). This study completed enrollment of approximately 15,000 participants with and without cancer (56% with 20 tumor types and all clinical stages), across 142 sites in the US and Canada. The principal goal is to develop a noninvasive cancer detection assay and the CCGA was designed to characterize the landscape of genomic cancer signals in the blood and to detect and validate GRAIL’s multi-cancer early detection blood test through three pre-planned sub-studies. The authors in 2018 previously reported that it is possible to detect early-stage lung cancer, with a high degree of specificity, from a simple blood test, using targeted sequencing and whole-genome sequencing. In this substudy, liquid biopsy could accurately detect over 40% of early-stage lung cancers (Stage I-IIIA), with 98% specificity. It was determined that whole-genome bisulfite sequencing for DNA methylation was the most effective approach for early cancer detection. 
DNA methylation is a natural epigenetic mechanism used by cells to regulate gene expression with some regions of hypermethylation and some regions of hypomethylation, and is a chemical modification to DNA. In cancer, abnormal methylation patterns and the resulting changes in gene expression can contribute to tumor growth (hypermethylation can cause tumor-suppressor genes to be inactivated). Methylation patterns, are unique to the tumor DNA, enabling tumor detection and localization but are not of value when it comes to precision therapies. This is unlike mutations and copy number changes, which can be detected in white blood cells in individuals without cancer as well, leading to false-positives.
In two separate presentations, the authors in this present sub-study reported the results for patients with more than 20 cancer subtypes across all stages and evaluated the prognostic significance of detecting abnormal patterns of cfDNA methylation by whole-genome bisulfite sequencing (WGBS) assay. The goal of targeted methylation assay was to detect both early and advanced disease cancers, and improve clinical outcomes
Liu, MC, et al. reported outcomes for 2,301 participants (1422 had cancer and 879 did not) with more than 20 cancer types (12 prespecified and high-risk cancers included Lung, HR negative Breast, Colorectal, Anorectal, Esophageal, Gastric, Liver, Pancreatic, Head and Neck, Ovary, Myeloma and Lymphoid neoplasms) across all stages. The 12 prespecified cancers account for two thirds of all cancer deaths in the US. At 99% specificity, the sensitivity for these 12 high-risk cancers ranged from 59-86% at early stages (stages I–III). For all 20 cancer types, the overall detection rate across all stages was 55%. Additionally, a Tissue of Origin result was provided for 94% of all cancers detected and of these, the assay correctly identified the Tissue of Origin in 90% of cases, which the authors commented is critical for guiding efficient downstream workup for a positive signal.
Oxnard GR, et al. performed an exploratory longitudinal analysis and reported the results of the Overall Survival of 1,320 participants with more than 20 cancer types in this substudy, thereby evaluating the prognostic significance of detection by this assay. Across all stages of disease, cancers detected by cfDNA whole-genome bisulfite sequencing for DNA methylation were associated with significantly worse survival than those not detected by the blood test. The 2-year Overall Survival was less than 50% among patients whose cancers were detected by the assay compared with 2-year OS of over 90% for those whose cancers were not detected by this assay. The poor prognostic ability of this assay was seen in both cancers that presented with symptoms and those found via screening suggesting that DNA–based detection with this methylation assay may be an indicator of prognosis. In multivariate analysis, cancers detected by this assay had double the risk of death (HR=2.6; P< 0.001) when accounting for clinical stage, cancer type, histologic grade, age, sex, and method of diagnosis and also had comparable prognostic significance to clinical stage (P <0.001).
It was concluded from these two presentations that cfDNA test based on the presence of DNA methylation is highly specific at detecting high-risk malignancies, with very high accuracy for identifying the tissue of origin, and may also have prognostic value.
Genome-wide Cell-free DNA (cfDNA) Methylation Signatures and Effect on Tissue of Origin (TOO) Performance. Liu MC, Jamshidi A, Venn O, et al. 2019 ASCO Annual Meeting. Abstract 3049. Presented June 1, 2019.
Prognostic significance of blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating risk of overdiagnosis. Oxnard GR, Chen X, Fung ET, et al. 2019 ASCO Annual Meeting. Abstract 1545. Presented June 3, 2019.
FDA Approves ROZLYTREK® for NTRK Positive tumors and ROS1 Positive Non Small Cell Lung Cancer
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.
Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer
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 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for Hormone Receptor positive, HER negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.
Oncotype Dx assay categorizes patients on the basis of Recurrence Scores into Low risk (less than 18), Intermediate risk (18-30), and High risk (31 or more). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer. In this study, the Intermediate risk Recurrent Score (18-30) was changed to 11-25, to account for exclusion of higher-risk patients with HER2-positive disease and to minimize the potential for under treatment.
TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. Patients were followed up for 9 years. The Primary endpoint was invasive Disease Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause. Results reported in June 2018 showed that while most women with an Intermediate Recurrence Score of 11-25 did not benefit from chemotherapy, women 50 years or younger with a Recurrence Score of 16-25 did indeed benefit from adjuvant chemotherapy.
The authors in this publication provided additional results from the same data set showing that adding “Clinical Risk” provides additional prognostic information. The investigators used a binary classification system from the MINDACT trial (Microarray in Node-Negative Disease May Avoid Chemotherapy), which used a 70-gene assay, and divided patients into high or low “Clinical Risk” based on tumor size and histologic grade. Clinical Risk was defined as low if the tumor was 3 cm or less in diameter and had a low histologic grade, 2 cm or less and had an intermediate histologic grade, or 1 cm or less in diameter and had a high grade. The Clinical Risk was defined as high if the low-risk criteria were not met. This additional reporting provided prognostic information about recurrent risk, but not benefits of chemotherapy particularly in the Intermediate Recurrence Score group.
Among women who were 50 years of age or younger with a low Recurrence Score, the distant recurrence rate at 9 years was less than 5%, irrespective of Clinical Risk, and about 5% among those with an intermediate Recurrence Score with low Clinical Risk. However in sharp contrast, among women 50 years of age or younger, with high Clinical Risk and an intermediate Recurrence Score who had received endocrine therapy alone, the rate of distant recurrence at 9 years was 12.3%, compared with 6.1% among women who had received adjuvant chemotherapy. It is possible that younger women with a Recurrence Score of 11-25 and high Clinical Risk, receiving endocrine therapy alone, may have been undertreated with Tamoxifen, and the authors speculated that based on previously published studies, adding Ovarian Suppression and an Aromatase Inhibitor might result in risk reduction, equivalent to that observed using adjuvant chemotherapy.
The authors concluded that these new findings complement the original, definitive TAILORx conclusion and integration of genomic (Recurrence Score) and Clinical Risk may provide a more accurate estimate of prognosis for individual patients, than could be provided by either the genomic or clinical information alone. They added that this Clinical Risk stratification facilitates more refined estimates of absolute chemotherapy benefit for women 50 years of age or younger, with a Recurrence Score 16-25. Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. Sparano JA, Gray RJ, Ravdin PM, et al. N Engl J Med 2019;380:2395-2405