On November 17, 2022 GRAIL, LLC, a healthcare company whose mission is to detect cancer early when it can be cured, reported findings from a fundamental substudy of the Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study, demonstrating that methylation had the most promising combination of cancer detection and prediction of cancer signal origin when compared with other evaluated approaches (Press release, Grail, NOV 17, 2022, View Source [SID1234624218]). This is the first rigorous and systematic comparison of various genomic measures from circulating cell-free DNA (cfDNA) for multi-cancer early detection (MCED) testing, and the largest comprehensive genome-wide comparison of cfDNA approaches. Findings were published online in Cancer Cell in a manuscript titled "Evaluation of Cell-Free DNA Approaches for Multi-Cancer Early Detection."

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"Results from the CCGA study formed the basis for how we developed and refined the Galleri test—it’s our origin story and the foundation of our work to transform cancer care with a simple blood test," said Amoolya Singh, Ph.D., Senior Vice President of Data Science and Chief Scientific Officer at GRAIL. "This defining study made it possible to carefully design a population screening test with a high specificity and low false-positive rate for cancer detection. When combined with standard screenings, this test has the potential to improve detection of cancer in asymptomatic individuals."

The CCGA Discovery Substudy, the first of three pre-planned substudies of the case-controlled CCGA study, evaluated multiple potential approaches to blood-based multi-cancer early detection (MCED) in a cohort of 2,800 individuals. These approaches included whole-genome sequencing, whole-genome methylation sequencing, and ultra deep targeted sequencing. Together this covered eight classifiers including methylation, somatic copy number alterations, somatic mutations, and a ninth pan-feature classifier. Criteria for evaluation included sensitivity (a test’s ability to correctly identify people with cancer) at high (98%) specificity (a test’s ability to correctly identify people without cancer) and cancer signal origin prediction (a test’s ability to predict the anatomical localization or cell of origin of the detected cancer signal).

The CCGA Discovery Substudy showed that among the evaluated classifiers, those using whole-genome methylation had one of the highest cancer signal detection sensitivities at 98% specificity. Additionally, out of the evaluated approaches, whole-genome methylation had the best predicted cancer signal origin.

Findings from CCGA Discovery, along with the other substudies, were instrumental in developing, refining and validating the targeted methylation platform used in the Galleri MCED test, which applies next-generation genomic sequencing, advanced data science and machine learning to detect a shared cancer signal across more than 50 types of cancer at 99.5% specificity and accurately predict where the signal originated in the body through a simple blood draw. Test performance was consistent in the interventional PATHFINDER study, which was recently presented at the European Society for Medical Oncology Congress 2022.

CCGA Discovery evaluated various cfDNA measures in three prototype assays and nine prototype machine learning classifiers to determine the most promising approach for an MCED test with a low false-positive rate and sufficient sensitivity to improve outcomes for individuals who undergo screening. The substudy included 2,800 participants—1,628 with cancer and 1,172 without cancer (non-cancer). Blood samples from individuals with cancer were demographically matched to non-cancer individuals to reduce statistical uncertainty. Patients with cancer diagnosed by screening or by clinical presentation were enrolled before starting definitive therapy.

The substudy implemented innovations in cancer detection evaluation, including study design, custom distributed and cloud computing, and the introduction of a novel measure: circulating tumor DNA allele fraction, defined as the fraction of tumor-distinguishing methylation marks in a cfDNA sample (i.e., the available signal). Furthermore, it introduced the metric of clinical limit of detection (cLOD) to measure cancer detection as a function of cfDNA tumor fraction—a more robust performance metric than sensitivity, which is highly dependent on study cancer type and stage composition.

"To be able to meaningfully compare ct-DNA assays in the future, the clinical limit of detection must be assessed," added Singh. "The CCGA Discovery analysis is the first direct head-to-head comparison of multiple approaches that we are aware of. Notably, CCGA Discovery identified methylation features in ct-DNA as having the leading combination of cancer detection and cancer signal origin performance. This motivated the development of an improved targeted methylation platform that underlies Galleri today with substantially improved performance."

About the CCGA Study

The CCGA study is a prospective, multi-center, case-controlled, longitudinal study designed to characterize the landscape of genomic cancer signals in the blood of people with and without cancer.

The study is collecting de-identified biospecimens and clinical data from more than 15,000 participants across 142 sites in the U.S. and Canada, including both people who had cancer at the time of enrollment (newly diagnosed, and not yet received treatment) and people who did not have a known cancer diagnosis. Participants will be followed annually for up to five years. A separate pre-specified substudy from CCGA involving 4,077 participants was previously published in the Annals of Oncology in September, 2021.

About GRAIL’s MCED Clinical Development Program

The Galleri clinical development program consists of studies that collectively include more than 335,000 participants together with what is believed to be the largest linked datasets of genomic and clinical data in the field of cancer research. GRAIL’s program includes the foundational CCGA development and validation study, the interventional PATHFINDER and PATHFINDER 2 studies, the NHS-Galleri randomized, controlled clinical study, the STRIVE and SUMMIT observational studies, and the REFLECTION real-world registry. The largest of these, the NHS-Galleri trial, has enrolled 140,000 participants with the primary objective of a reduction in late-stage cancer diagnoses, thought to be a necessary prerequisite for ascertaining a mortality reduction.

On November 17, 2022 Castle Biosciences, Inc. (Nasdaq: CSTL), a company improving health through innovative tests that guide patient care, reported the publication of a study completed in collaboration with the Melanoma Research Foundation (MRF) in which most patients diagnosed with uveal melanoma (UM) indicated their desire for prognostic testing at diagnosis, reported finding value in their test result and experienced lower decision regret, regardless of whether their test result indicated that their UM tumor was at a high or low risk of metastasis (Press release, Castle Biosciences, NOV 17, 2022, View Source [SID1234624217]). The study, titled "Uveal melanoma patient attitudes towards prognostic testing using gene expression profiling," was published in Melanoma Management and can be viewed on Castle’s website.

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"We were excited to embark on this collaboration with Castle Biosciences, a leader in prognostic testing for uveal melanoma, as few studies have explored patients’ perspectives towards prognostic testing and the value patients can gain by having personalized prognostic information," said Kyleigh LiPira, M.B.A., chief executive officer of the MRF. "The more information patients can have in advance of making treatment decisions is critical to having successful outcomes. This data further reinforces the need for patients to understand their options so they can be active participants in their care."

The study aimed to assess patient experiences with DecisionDx-UM testing and other prognostic methods through an online questionnaire that was distributed by the MRF’s CURE OM initiative. CURE OM (the Community United for Research and Education of Ocular Melanoma) is the MRF’s initiative to increase awareness, education and research funding for ocular melanoma, while improving the lives of people affected by this disease. The questionnaire captured anonymized information regarding patients’ experiences with prognostic testing following a diagnosis of UM; 177 patients completed the survey.

Highlights from the study include the following:

90% of respondents reported wanting prognostic information at the time of diagnosis.
99% of respondents who had prognostic testing performed with DecisionDx-UM and shared their test results (80 out of 81 respondents) reported gaining value from their test result.
Patients reported gaining value from their prognostic test results, including:
More personalized treatment options
Increased knowledge and understanding of their disease
Relief from uncertainty about the future
Information relevant to life planning
Patients who received a low-risk (Class 1A) DecisionDx-UM result were 10 times more likely than those who received a high-risk (Class 2) result to report gaining a "sense of relief from uncertainty about the future." (X2=11, df=1, p=0.0009). Conversely, a majority of patients who received a high-risk (Class 2) result reported that their test result provided them "increased knowledge and understanding" about their disease (X2=17.48, df=3, p=0.0006).
There was no significant difference in decision regret levels among those receiving a low- (Class 1A), intermediate- (Class 1B) or high-risk (Class 2) DecisionDx-UM test result (Kruskal-Wallis rank sum test, X2=4.1, p=0.13).
Patients who chose to have some kind of prognostic testing experienced less decision regret than patients who opted out of testing, reinforcing the overall value that prognostic testing can bring to a patient’s care, regardless of whether they receive a low- or high-risk result.
About DecisionDx-UM

DecisionDx-UM is Castle Biosciences’ 15-gene expression profile (GEP) test that uses an individual patient’s tumor biology to predict individual risk of metastasis in patients with uveal melanoma. DecisionDx-UM is the standard of care in the management of newly diagnosed uveal melanoma in the majority of ocular oncology practices in the United States. Since 2009, the American Joint Committee on Cancer (AJCC; v7 and v8) Staging Manual for UM has specifically identified the GEP test as a prognostic factor that is recommended for collection as a part of clinical care. Further, the National Comprehensive Cancer Network (NCCN) guidelines for uveal melanoma include the DecisionDx-UM test result as a prognostic method for determining risk of metastasis and recommended differential surveillance regimens based on a Class 1A, 1B, and 2 result. DecisionDx-UM is the only prognostic test for uveal melanoma that has been validated in prospective, multi-center studies, and it has been shown to be a superior predictor of metastasis compared to other prognostic factors, such as chromosome 3 status, mutational status, AJCC stage and cell type. It is estimated that nearly 8 in 10 patients diagnosed with uveal melanoma in the U.S. receive the DecisionDx-UM test as part of their diagnostic workup. More information about the test and disease can be found at www.CastleTestInfo.com.

On November 17, 2022 Takeda (TSE:4502/NYSE:TAK) reported that the randomized, Phase 3 PhALLCON trial met its primary endpoint, demonstrating that adult patients with newly-diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) treated with ICLUSIG (ponatinib) plus reduced-intensity chemotherapy achieved higher rates of minimal residual disease (MRD)-negative complete remission (CR) compared to imatinib (Press release, Takeda, NOV 17, 2022, View Source [SID1234624216]). MRD-negativity is associated with improvement in long-term outcomes for patients, as reported in literature. ICLUSIG is the only pan-mutational and third-generation tyrosine kinase inhibitor (TKI), targeting BCR::ABL1 and all known single, treatment-resistant mutations, including the most resistant T315I mutation.

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"Ph+ ALL is a fast-progressing disease with no targeted treatments currently approved in the frontline for patients in the U.S. There is an urgent need for an effective treatment that can suppress the development of difficult-to-treat mutations, which are associated with poor long-term outcomes," said Awny Farajallah, MD, Head of Global Medical Affairs Oncology at Takeda. "We are excited to see how ICLUSIG may be able to address this gap in care for these patients and look forward to sharing the results."

The PhALLCON study is a Phase 3 randomized, international, open-label multicenter trial evaluating the efficacy and safety of ICLUSIG versus imatinib in combination with reduced-intensity chemotherapy as a frontline therapy for adult patients with newly diagnosed Ph+ ALL. In the trial, no new safety signals were observed. Data from this trial will be discussed with regulatory agencies and shared with the scientific community in the future.

About Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR::ABL1 and is associated with Ph+ ALL.

About ICLUSIG (ponatinib) tablets
ICLUSIG is a kinase inhibitor targeting BCR::ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR::ABL1 and its mutations. ICLUSIG inhibits native BCR::ABL1, as well as all BCR::ABL1 treatment-resistant mutations, including the most resistant T315I mutation. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is indicated for the treatment of adult patients with chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated-phase (AP) or blast-phase (BP) CML or Ph+ ALL for whom no other kinase inhibitor is indicated, and T315I+ CML (CP, AP or BP) or T315I-positive Ph+ ALL. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

IMPORTANT SAFETY INFORMATION

WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning.

Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG.
Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity.
Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity.

WARNINGS AND PRECAUTIONS

Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG in OPTIC and PACE. These included cardiovascular, cerebrovascular, and peripheral vascular events. The incidence of AOEs in OPTIC (45 mg->15 mg) was 14% of 94 patients; 6% experienced Grade 3 or 4. In PACE, the incidence of AOEs was 26% of 449 patients; 14% experienced Grade 3 or 4. Fatal AOEs occurred in 2.1% of patients in OPTIC, and in 2% of patients in PACE. Some patients in PACE experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed with these events in PACE were history of hypertension, hypercholesterolemia, and non-ischemic cardiac disease. In OPTIC and PACE, AOEs were more frequent with increasing age.

In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within the 3 months prior to the first dose of ICLUSIG were excluded. Consider whether the benefits of ICLUSIG are expected to exceed the risks.

Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk to guide a decision to restart ICLUSIG.

Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG. In PACE, VTEs occurred in 6% of 449 patients including serious or severe (Grade 3 or 4) VTEs in 5.8% of patients. VTEs included deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. The incidence was higher in patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients). One of 94 patients in OPTIC experienced a VTE (Grade 1 retinal vein occlusion). Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity.

Heart Failure: Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PACE, heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher). Heart failure occurred in 13% of 94 patients in OPTIC; 1.1% experienced serious or severe (Grade 3 or 4). In PACE, the most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). In OPTIC, the most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and BNP increased (3.2%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure.

Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL. Hepatotoxicity occurred in 28% of 94 patients in OPTIC and 32% of 449 patients in PACE. Grade 3 or 4 hepatotoxicity occurred in OPTIC (6% of 94 patients) and PACE (13% of 449 patients). The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose or discontinue ICLUSIG based on recurrence/severity.

Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis.

Pancreatitis: Serious or severe pancreatitis has occurred in patients who received ICLUSIG. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Neuropathy: Peripheral and cranial neuropathy occurred in patients in OPTIC and PACE. Some of these events in PACE were Grade 3 or 4. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Ocular Toxicity: Serious or severe ocular toxicity leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. The most frequent ocular toxicities occurring in OPTIC and PACE were dry eye, blurred vision, and eye pain. Retinal toxicities included age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. Fatal hemorrhages occurred in PACE and serious hemorrhages occurred in OPTIC and PACE. In PACE, the incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages. Events often occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Fluid Retention: Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PACE, one instance of brain edema was fatal and serious events included pleural effusion, pericardial effusion, and angioedema. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular and atrial arrhythmias, occurred in patients in OPTIC and PACE. For some patients, events were serious or severe (Grade 3 or 4) and led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Myelosuppression: Grade 3 or 4 events of neutropenia, thrombocytopenia, and anemia occurred in patients in OPTIC and PACE. The incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 x 109/L or platelets less than 50 x 109/L, interrupt ICLUSIG until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose.

Tumor Lysis Syndrome (TLS): Serious TLS was reported in ICLUSIG-treated patients in OPTIC and PACE. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Patients may present with neurological signs and symptoms, visual disturbances, and hypertension. Diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown.

Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.

ADVERSE REACTIONS
The most common (>20%) adverse reactions are rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided.
Strong CYP3A Inducers: Avoid coadministration.

USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 6 days following last dose

Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.
Ponatinib may impair fertility in females, and it is not known if these effects are reversible.

Pre-existing Hepatic Impairment: Reduce the starting dose of ICLUSIG to 30mg orally once daily for patients with pre-existing hepatic impairment as these patients are more likely to experience adverse reactions compared to patients with normal hepatic function.

Takeda’s Commitment to Oncology
Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it’s with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need. For more information, visit www.takedaoncology.com.

On November 17, 2022 Novocure (NASDAQ: NVCR) reported 25 abstracts on Tumor Treating Fields (TTFields) therapy will be featured at the Society for Neuro-Oncology (SNO) 2022 Annual Meeting from Nov. 16 to Nov. 20 in Tampa (Press release, NovoCure, NOV 17, 2022, View Source [SID1234624215]). The presentations cover a broad range of topics, including TTFields’ multimodal mechanism of action, safety and tolerability, and health economics and outcomes research (HEOR).

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"We are honored and proud of the volume and depth of TTFields research featured at the SNO 2022 Annual Meeting"

New research in HEOR includes an analysis by a coalition of researchers at Central Brain Tumor Registry of the United States (CBTRUS), Duke University and the National Cancer Institute that utilized commercial claims and population-based datasets to better understand potential treatment factors associated with improved survival for glioblastoma (GBM) (Corey Neff, M.P.H., Department of Neurosurgery, Duke University School of Medicine in Durham, North Carolina, et al.) The presentation, "Improvements in survival for glioblastoma in the post-Stupp protocol era," showed that survival in GBM has continued to improve over time in the post-Stupp protocol era, which may be due to developments of new therapeutic approaches. The analysis showed post-Stupp therapeutic developments, including TTFields, significantly increase overall survival in the commercially insured population. Of the 19,414 identified adult patients with GBM, 3,061 used TTFields therapy. These patients experienced an extended median overall survival compared to patients who were not treated with TTFields (17.6 months versus 13.1 months, respectively; hazard ratio: 0.77; P<0.001).

A presentation by Maciej M. Mrugala, M.D., Ph.D., M.P.H., Director of the Neuro-Oncology Program at the Mayo Clinic College of Medicine and Science in Phoenix, analyzed post-market safety data from more than 23,000 high-grade glioma patients who received TTFields therapy in the last decade, representing the largest safety dataset to date. These global real-world data reinforced the findings from our EF-14 phase 3 pivotal study that TTFields therapy is well-tolerated in GBM patients, with no new safety signals identified. There were no observed differences by type of GBM diagnoses and by age subgroups. These data are consistent with previous findings in that TTFields therapy is not associated with added systemic toxicity; localized skin irritation is the most common adverse event and can be managed with appropriate prophylaxis and treatment strategies.

A presentation highlighting TTFields therapy as a treatment for newly diagnosed GBM includes the first results of the PriCoTTF phase 1/2 study, which met its primary endpoint demonstrating the safety and tolerability of TTFields concomitant with radiotherapy, presented by Sied Kebir, M.D., Deputy Head of the Division of Clinical Neurooncology at University Medicine Essen in Germany.

Josef Vymazal, M.D., Deputy Director of Na Homolce Hospital in Prague, will present data from 18 years of clinical practice experience with newly diagnosed GBM patients. Patients who received TTFields therapy demonstrated improvements in progression free survival and overall survival compared to controls (hazard ratio: 0.55, P=0.006; and 0.61, P=0.027 respectively). This is one of several extensive studies assessing survival outcomes in newly diagnosed GBM patients treated with TTFields therapy conducted at a single center to date.

"We are honored and proud of the volume and depth of TTFields research featured at the SNO 2022 Annual Meeting," said Frank Leonard, President of Novocure’s U.S. CNS (central nervous system) Cancers Franchise. "Over the last 15 years, SNO has been an important meeting for Novocure as Tumor Treating Fields therapy has become ingrained within the neuro-oncology community and as our science continues to evolve. We look forward to gathering and participating in this essential scientific exchange for the advancement of neuro-oncology."

ABSTRACTS

All poster presentations will occur from 7:30 p.m. to 9:30 p.m. EST Friday, Nov. 18, in West/Central Hall.

CLINICAL STUDIES

(INNV-10) Overcoming challenges and optimizing patient outcomes with Tumor Treating Fields (TTFields) therapy. Lead author and presenter: P. Gage Gwyn.

(INNV-07) Tumor Treating Fields (TTFields; 200 kHz) post-marketing safety data from patients with glioblastoma treated between 2011–2022. Lead author and presenter: Maciej M. Mrugala.

(INNV-11) Eighteen Years of Experience with Treatment of Glioblastoma Using Tumor Treating Fields (TTFields) in Newly Diagnosed Glioblastoma (ndGBM) in a single center. Lead author and presenter: Josef Vymazal.

(NCOG-22) TIGER PRO-Active Study: Investigating daily activity, sleep and neurocognitive functioning in glioblastoma patients applying TTFields therapy in Germany in Routine Clinical Care. Lead author: Martin Glas. Presenter: Sied Kebir.

(RADT-17) A case of recurrent glioblastoma effectively treated with tumor-treating-fields. Lead author and presenter: Xin Geng.

(INNV-22) A case report of multiple lesions disappearing after TMZ+TTFields+ Darafenib and trametinib in a patient with GBM. Lead author and presenter: Boning Cai.

(INNV-30) Retrospective analysis of TTFields in patients with HGG based on the criteria of 2021 WHO CNS5. Lead author: Xiaoyan Yang. Presenter: Feng Wang.

(RADT-18) Particle Beam Radiation Therapy plus Tumor Treating Fields in the Treatment of Newly Diagnosed WHO Grade 4 Gliomas: An Early Result of Phase 2 Single-arm Trial. Lead author and presenter: Xianxin Qiu.

(CTNI-47) Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients. Lead author: Chunjui Chen. Presenter: Zhiyong Qin.

(CTIM-05) Final results of 2-THE-TOP: a pilot phase 2 study of TTFields (Optune) plus pembrolizumab plus maintenance temozolomide (TMZ) in patients with newly diagnosed glioblastoma (ndGBM). Lead author and presenter: David D. Tran. (Abstract only)

(CTNI-29) Investigating safety and efficacy of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma – first results of the PriCoTTF phase I/II trial. Lead author: Martin Glas. Presenter: Sied Kebir.

(INNV-09) Impact of Molecular markers on treatment outcome of Glioblastoma patients treated with concurrent Tumor-Treating Fields (TTF) and chemoradiation: secondary analysis of SPARE trial. Lead author and presenter: Louis Cappelli.

(RADT-19) Chemoradiation (CRT) treatment with or without concurrent Tumor-Treating Fields (TTFields) in patients with newly diagnosed glioblastoma (GBM). Lead author and presenter: Louis Cappelli.

PRECLINICAL STUDIES

(CSIG-41) Sensitizing cancer cells to Tumor Treating Fields (TTFields) by Inhibition of PI3K. Lead author: Anat Klein-Goldberg. Presenter: Moshe Giladi.

(DNAR-10) The efficacy of temozolomide and lomustine in glioblastoma cell lines may be enhanced by concomitant treatment with Tumor Treating Fields (TTFields). Lead author: Hila Fishman. Presenter: Moshe Giladi.

(EXTH-72) TTFields enhance the antineoplastic activity of the drug-repurposing approach CUSP9v3 in glioblastoma in vitro. Lead author: Qiyu Cao. (Abstract only)

(CCRG-04) Targeting the cell-cycle effects of Tumor Treating Fields (TTFields) to increase its efficacy. Lead author: Paul L.G. Slangen. Presenter: Gerben R. Borst.

(DNAR-12) Combining Tumour Treating Fields with therapeutic DNA damage response inhibitors to increase potency in high-grade glioblastomas using clinically relevant ex-vivo glioma stem cell models. Lead author: Aurelie Vanderlinden. Presenter: Ola Rominiyi.

INNOVATION

(MODL-07) Sensitivity of Tumor Treating Fields (TTFields) treatment planning to tumor segmentation errors. Lead author: Oshrit Ze’evi. Presenter: Eyal Abend.

(MODL-13) Sensitivity of Tumor Treating Fields (TTFields) treatment planning to healthy tissue segmentation inaccuracies. Lead author: Oshrit Ze’evi. (Abstract only)

(MODL-21) Efficacy of different layouts in treating infratentorial tumors with Tumor Treating Fields (TTFields). Lead author: Ariel Naveh. (Abstract only)

(EXTH-05) Toward 100% clinical efficacy for tumor-treating fields. Lead author and presenter: Kristen W. Carlson.

(NIMG-69) Prediction of Progression-Free Survival in Patients with Primary Glioblastoma: MRI T2 Relaxivity and Deep Learning. Lead author and presenter: Aaron Rulseh

HEALTH ECONOMICS AND OUTCOMES RESEARCH

(QOL-21) Real-world quality-of-life and health utilities for patients with CNS cancers on the XCELSIOR platform. Lead author: Sarah Ginn. Presenter: Gordon V. Chavez.

(EPID-06) Improvements in survival for glioblastoma in the post-Stupp protocol era. Lead author: Corey Neff. Presenter: Quinn T. Ostrom.

On November 17, 2022 Universal Diagnostics (Universal DX), a bioinformatics and multi-omics company on a mission to transform cancer into a curable disease, reported the results of a study evaluating putative methylation markers in biological context of early colorectal cancer (CRC) development (Press release, Universal Diagnostics, NOV 17, 2022, View Source [SID1234624214]).

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Universal DX has previously shown that non-invasive blood testing can be used to detect CRC and pre-cancerous advanced adenomas (AA) through both analysis of cell-free circulating tumor DNA (ctDNA) methylation, fragmentation and microbiome patterns with single targeted sequencing analysis and combining it with advanced computational biology and machine learning algorithms.

Today’s news is the latest in a series of findings from Universal DX, extending early-stage colorectal cancer detection to prognostics and stratification, which could lead to better outcomes and improved survival rates.

"This newest study underscores the robustness and validity of our previous results, by adding more biological value to the individual methylation marker regions," said Christian Hense, COO at Universal DX. "Investigating their impact on gene expression and putting these biomarkers in the context of biological pathways allows for better understanding of the behavior of early cancer. Extending early detection potential of the markers to further prognostics and stratification could lead to improved survival outcomes of the patients as well as potentially serve as interesting new treatment targets in the future. Every step in our research gets us closer to a day where cancer is a curable disease and we can save more lives."

Study results:

Differential signal was observed between AA and NAT and CRC and adjacent normal tissue, indicating biological signal change with adenoma progression to cancer.
Hierarchical clustering identified 3 distinct classes of patients based on methylation levels.
KEGG pathway analysis revealed that the top pathways involved were axonal guidance, ephrin receptor signaling, epithelial-mesenchymal transition and FGF signaling, all which play a significant role in the context of cancer development and progression.
Correlation of methylation signal to transcriptomics data from The Cancer Genome Atlas (TCGA) COAD and READ cohorts showed significant correlation to dysregulation of the gene expression, indicating the functional relevance of the gene methylation.
Targeted methylation sequencing on plasma samples of patients with early stage (I-IIA) colorectal cancer (26 patients from Ukraine and Germany) and age and gender matching colonoscopy-verified controls (from same cohort), showed high individual marker accuracy with AUC > 0.73.
Kaplan-Meier analysis showed significant correlation to patients’ 5- year survival prediction linked to 3 genes: FGF14 (p=0.025, HR = 1.75), DPY19L2P1 (p=0.012, HR = 1.86), PTPRO (p=0.046, HR = 1.63).
Universal DX leverages proprietary, state-of-the-art computational biology tools combined with a targeted next generation sequencing assay platform that allows for simultaneous detection of methylation, fragmentation and microbiome signals for highly-sensitive cancer signal scoring of cell-free DNA regions linked to cancer of interest.

Hense continued: "CRC is one of the deadliest cancers in the United States. The current methods of biomarker-based tests to screen for CRC are still extremely limited. At Universal DX, we are on a mission to find new and better methods. We know early detection is one of the most powerful tools for improving survival rates, so identifying these markers could be the next step towards earlier – and easier – detection."

Universal DX will present its findings live at the AACR (Free AACR Whitepaper) special conference on Precisions, Prevention, Early Detection, and Interception of Cancer in Austin, TX November 17-19.