On May 15, 2019 GRAIL, Inc., a healthcare company focused on the early detection of cancer, reported that new findings from its Circulating Cell-free Genome Atlas (CCGA) study will be presented in four poster presentations at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place May 31 – June 4 in Chicago (Press release, Grail, MAY 15, 2019, View Source [SID1234536355]).

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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).1 An abstract posted online today ahead of the 2019 ASCO (Free ASCO Whitepaper) Annual Meeting reports data from an analysis from the first CCGA sub-study showing GRAIL’s prototype methylation technology detected the tumor tissue of origin (where the cancer originated in the body) with high accuracy (Abstract 3049). This analysis evaluated blood samples from 166 participants who had a cancer diagnosis at the time of enrollment, and whose cancer was detected using the methylation technology. Results showed the technology correctly identified the tumor’s tissue of origin in 87 percent of the blood samples evaluated (n=144/166), including 96 percent of breast cancer cases (n=22/23); 88 percent of lung cancer cases (n=29/33); 90 percent of liver cancer cases (n=9/10); and 100 percent of pancreatic cancer cases (n=17/17).

GRAIL has since selected methylation as its preferred approach and is now evaluating its refined methylation blood test in the second pre-planned sub-study of CCGA. Initial data from the second CCGA sub-study will be presented at ASCO (Free ASCO Whitepaper), reporting the ability of GRAIL’s methylation test to detect multiple cancer types and identify the tumor tissue of origin.

"Identifying the tumor tissue of origin will be a critical feature of our multi-cancer early detection test to enable doctors to appropriately direct next steps for diagnosis and care," said Alexander Aravanis, MD, PhD, Chief Scientific Officer at GRAIL. "Our unique test is designed to combine our methylation technology, a proprietary database of methylation signatures, and GRAIL’s machine-learning algorithms to both detect the presence of cancer and determine where in the body the cancer originated. We look forward to presenting initial results from our next CCGA sub-study at ASCO (Free ASCO Whitepaper)."

Survival Data (Abstract 1545)

Data presented last year showed GRAIL’s technology detected the strongest signals for the deadliest cancer types, while signal for indolent cancer types was low.1 A new analysis evaluated survival of 1,289 CCGA participants in the first CCGA sub-study with at least one year of clinical follow-up. Results showed people in the study whose cancer was detected by the methylation technology were three times more likely to die from their cancer compared to participants whose cancer was not detected by the technology, independent of clinical stage (HR=3.0, p<0.001). By comparison, participants with stage IV cancers were three times more likely to die than those with stage I-III cancers (HR=3.3, p<0.001). These data suggest detection with GRAIL’s methylation technology could have a similar ability to predict survival as clinical stage.

"Overdiagnosis of some cancer types that are slow-growing can be a concern with current screening tests," said Geoffrey Oxnard, MD, Associate Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School. "These initial follow-up data are encouraging and add to the evidence from the CCGA study suggesting this blood test may detect the types of cancers more in need of immediate treatment, rather than contributing to the overdiagnosis of indolent cancers."

Follow-up of participants in CCGA is ongoing and outcomes will be collected for five years. These long-term data are important for determining the potential clinical impact of detecting deadly cancers in the blood before a person presents with symptoms.

Details for Posters Featuring GRAIL’s Data at ASCO (Free ASCO Whitepaper)

Abstract 3049
Minetta C. Liu, et al. Genome-wide cell-free DNA (cfDNA) methylation signatures and effect on tissue of origin (TOO) performance
Poster Session: June 1, 2019: 8:00-11:00AM CDT, Hall A, Poster Board #41

Abstract 3103
Darya Filippova, et al. The Circulating Cell-free Genome Atlas (CCGA) study: Size selection of cell-free DNA (cfDNA) fragments
Poster Session: June 1, 2019: 8:00-11:00AM CDT, Hall A, Poster Board #95

Abstract 5574
Allen Cohn, et al. The Circulating Cell-free Genome Atlas (CCGA) study: Follow-up (F/U) on non-cancer participants with cancer-like cell-free DNA signals
Poster Session: June 1, 2019: 1:15-4:15PM CDT, Hall A, Poster Board #397

Abstract 1545
Geoffrey R. Oxnard, et al. Prognostic significance of blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating risk of overdiagnosis
Poster Session: June 3, 2019: 1:15-4:15PM CDT, Hall A, Poster Board #39

About the Circulating Cell-free Genome Atlas (CCGA) Study

The CCGA study is a prospective, observational, longitudinal study that has completed enrollment of approximately 15,000 people with and without cancer across 142 sites in the United States and Canada. GRAIL is conducting three pre-planned sub-studies within CCGA to discover, train, and validate its multi-cancer early detection test.

About GRAIL’s Methylation Technology

GRAIL is developing a next-generation sequencing (NGS) blood test for the early detection of multiple deadly cancer types. 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. More than 20 cancer types across stages are represented within the database.

DNA methylation is a natural process used by cells to regulate gene expression. It is a chemical modification to DNA and a well-studied epigenomic feature of the genome. In cancer, abnormal methylation patterns and the resulting changes in gene expression can contribute to tumor growth. For example, hypermethylation can cause tumor-suppressor genes to be inactivated.

On May 15, 2019 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported mature data from the FORWARD II expansion cohort evaluating mirvetuximab soravtansine in combination with Avastin (bevacizumab) in patients with folate receptor alpha (FRα)-positive platinum-resistant ovarian cancer (Press release, ImmunoGen, MAY 15, 2019, View Source [SID1234536354]). These findings will be presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held May 31 – June 4 in Chicago, IL.

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"We are pleased that the combination of mirvetuximab plus Avastin has generated significant anti-tumor activity in patients with platinum-resistant disease, with trends toward deeper, more durable responses seen in individuals with higher FRα expression and a favorable tolerability profile. The outcomes observed in patients with medium or high FRα expression are encouraging with respect to those reported in similar patient populations for Avastin plus chemotherapy," said Anna Berkenblit, M.D., Vice President and Chief Medical Officer of ImmunoGen. "Our goal remains to establish mirvetuximab as the combination agent of choice in ovarian cancer, supporting its use in earlier lines of therapy. These mature data support further exploration of this doublet, as well as the ongoing expansion study evaluating a triplet combination of mirvetuximab with Avastin and carboplatin in patients with platinum-sensitive disease."

DATA FROM FORWARD II EXPANSION COHORT WITH AVASTIN

Mirvetuximab soravtansine in combination with Avastin in patients with FRα-positive platinum-resistant ovarian cancer continues to demonstrate anti-tumor activity with durable responses and a favorable tolerability profile, particularly among the subset of patients who have received up to two prior lines of therapy and have medium or high levels of FRα expression.

Key findings in 66 patients with platinum-resistant disease include:

In the subset of 16 Avastin-naïve patients with medium or high FRα expression who have received up to two prior lines of therapy, the confirmed overall response rate (ORR) was 56 percent (95% CI 30,80), with a median progression-free survival (PFS) of 9.9 months (95% CI 4.1,15.9) and a median duration of response (DOR) of 12 months (95% CI 6,14.9).
In the overall patient population, the confirmed ORR was 39 percent (95% CI 28,52), with a median PFS of 6.9 months (95% CI 4.9,8.6) and a median DOR of 8.6 months (95% CI 4.9, 14.9).
The combination continues to display a safety profile in-line with the known profiles of each agent, with no new safety signals identified.
"Current treatment options for patients with platinum-resistant ovarian cancer have, unfortunately, exhibited limited efficacy with challenging side effects," stated David O’Malley, M.D., Professor, Director of Gynecology Clinical Trials and Phase 1 Program, James Cancer Center and The Ohio State University Wexner Medical Center, and FORWARD II Principal Investigator. "Final results from the combination of mirvetuximab soravtansine and Avastin expansion cohort demonstrate very encouraging activity and good tolerability in platinum-resistant ovarian cancer patients, especially those with medium or high FRα expression levels. I look forward to further evaluating mirvetuximab in combination with Avastin as well as in the triplet with carboplatin."

ASCO PRESENTATION DETAILS

Title: "Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-resistant ovarian cancer: Final findings from the FORWARD II study"
Day/Time: Saturday, June 1, 1:15pm – 4:15pm CDT and discussed at the Poster Discussion Session, 4:30pm-6pm CDT in S406
Lead Author: David M. O’Malley, M.D., The Ohio State University College of Medicine
Location: Hall A
Abstract: 5520
Initial data from an investigator-sponsored trial through the National Comprehensive Cancer Network evaluating mirvetuximab in combination with gemcitabine in patients with FRα-positive recurrent epithelial ovarian, endometrial, or triple negative breast cancer will also be presented. Full dose mirvetuximab appears to combine well with gemcitabine, with a safety profile as expected for these agents and with encouraging anti-tumor activity seen in all three tumor types.

Title: "A phase 1 study of mirvetuximab soravtansine (IMGN853) and gemcitabine (G) in patients with FOLR1-positive recurrent epithelial ovarian (EOC), endometrial cancer (EC), or triple-negative breast cancer (TNBC)"
Day/Time: Saturday, June 1, 8:00am – 11:00am CDT and discussed at the Poster Discussion Session, 3:00pm-4:30pm CDT in E450
Lead Author: Mihaela C. Cristea, MD, City of Hope
Location: Hall A
Abstract: 3009
Additional information can be found at www.asco.org.

ABOUT FORWARD II

FORWARD II is a Phase 1b/2 study of mirvetuximab in combination with Avastin (bevacizumab), carboplatin or Keytruda (pembrolizumab) in patients with FRα-positive platinum-resistant or platinum-agnostic ovarian cancer, primary peritoneal, or fallopian tube tumors, as well as a triplet combination of mirvetuximab plus carboplatin and Avastin in patients with platinum-sensitive ovarian cancer.

ABOUT MIRVETUXIMAB SORAVTANSINE

Mirvetuximab soravtansine (IMGN853) is the first folate receptor alpha (FRα)-targeting ADC. It uses a humanized FRα-binding antibody to target the ADC specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells.

On May 15, 2019 Kite, a Gilead Company (Nasdaq: GILD), reported that new data from its cell therapy programs will be presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held in Chicago from May 31 – June 4, 2019 (Press release, Kite Pharma, MAY 15, 2019, View Source [SID1234536353]). Six abstracts highlighting updated Yescarta (axicabtagene ciloleucel) efficacy and safety results, and ongoing research from the company’s chimeric antigen receptor T (CAR T) cell therapy development program in hematologic malignancies will be presented at the meeting.

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"Our CAR T research program is progressing at a rapid pace and we are excited to share the latest data at ASCO (Free ASCO Whitepaper)," said John McHutchison, AO, MD, Chief Scientific Officer and Head of Research and Development, Gilead Sciences. "Our data at this year’s meeting will include new analyses from the pivotal ZUMA-1 trial of Yescarta, early results from a novel approach to improve the Yescarta safety profile and results from the ZUMA-3 trial of our investigational CAR T therapy KTE-X19 in adults with acute lymphoblastic leukemia. These findings will help physicians better assess the potential role of CAR T in patients with high unmet need and continue to build upon our understanding of cell therapy."

Kite, a Gilead Company (Nasdaq: GILD), reported that new data from its cell therapy programs will be presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) being held in Chicago from May 31 – June 4, 2019. Six abstracts highlighting updated Yescarta (axicabtagene ciloleucel) efficacy and safety results, and ongoing research from the company’s chimeric antigen receptor T (CAR T) cell therapy development program in hematologic malignancies will be presented at the meeting.

"Our CAR T research program is progressing at a rapid pace and we are excited to share the latest data at ASCO (Free ASCO Whitepaper)," said John McHutchison, AO, MD, Chief Scientific Officer and Head of Research and Development, Gilead Sciences. "Our data at this year’s meeting will include new analyses from the pivotal ZUMA-1 trial of Yescarta, early results from a novel approach to improve the Yescarta safety profile and results from the ZUMA-3 trial of our investigational CAR T therapy KTE-X19 in adults with acute lymphoblastic leukemia. These findings will help physicians better assess the potential role of CAR T in patients with high unmet need and continue to build upon our understanding of cell therapy."

Area of Focus, Presentation
Number and Date/Time
(CDT)

Abstract Title
Presentations
Acute Lymphoblastic Leukemia
Abstract #7006 (Oral)
Saturday, June 1 (5:00-5:12 pm)

End of Phase 1 Results of ZUMA-3, a Phase 1/2 Study of KTE-X19, Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
Large B-Cell Lymphoma
Abstract #7555 (Poster)
Monday, June 3 (8:00-11:00 am)

Outcomes of Patients ≥ 65 Years of Age in ZUMA-1, a Pivotal Phase 1/2 Study of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma
Large B-Cell Lymphoma
Abstract #7558 (Poster)
Monday, June 3 (8:00-11:00 am)

Preliminary Results of Earlier Steroid Use with Axicabtagene Ciloleucel in Patients with Relapsed/Refractory Large B-Cell Lymphoma
Large B-Cell Lymphoma
Abstract #7545 (Poster)
Monday, June 3 (8:00-11:00 am)

Hematopoietic Recovery and Immune Reconstitution After Axicabtagene Ciloleucel Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed/Refractory Large B-cell Lymphoma
Trials-In-Progress

Chronic Lymphocytic Leukemia
Abstract #TPS7566 (Poster)
Monday, June 3 (8:00-11:00 am)

ZUMA-8: A Phase 1/2 Multicenter Study Evaluating KTE-X19 in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia
Large B-Cell Lymphoma
Abstract #TPS7574 (Poster)
Monday, June 3 (8:00-11:00 am)

ZUMA-12: A Phase 2 Multicenter Study of Axicabtagene Ciloleucel as a First-Line Therapy in Patients with High-Risk Large B-Cell Lymphoma

For more information, including a complete list of abstract titles at the meeting, please visit: View Source

Yescarta was the first CAR T cell therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, and high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of cytokine release syndrome and neurologic toxicities; see below for Important Safety Information.

KTE-X19 is an investigational agent that has not been approved by the U.S. Food and Drug Administration or any regulatory authority for any uses. Efficacy and safety have not yet been established.

U.S. Important Safety Information for Yescarta

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed.
Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS.
CYTOKINE RELEASE SYNDROME (CRS): CRS occurred in 94% of patients, including 13% with ≥ Grade 3. Among patients who died after receiving Yescarta, 4 had ongoing CRS at death. The median time to onset was 2 days (range: 1-12 days) and median duration was 7 days (range: 2-58 days). Key manifestations include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Ensure that 2 doses of tocilizumab are available prior to infusion of Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES: Neurologic toxicities occurred in 87% of patients. Ninety-eight percent of all neurologic toxicities occurred within the first 8 weeks, with a median time to onset of 4 days (range: 1-43 days) and a median duration of 17 days. Grade 3 or higher occurred in 31% of patients. The most common neurologic toxicities included encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta. Monitor patients at least daily for 7 days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for 4 weeks after infusion and treat promptly.

YESCARTA REMS: Because of the risk of CRS and neurologic toxicities, Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. The required components of the Yescarta REMS are: Healthcare facilities that dispense and administer Yescarta must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after Yescarta infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Yescarta are trained about the management of CRS and neurologic toxicities. Further information is available at www.YESCARTAREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS: Allergic reactions may occur. Serious hypersensitivity reactions including anaphylaxis may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

SERIOUS INFECTIONS: Severe or life-threatening infections occurred. Infections (all grades) occurred in 38% of patients, and in 23% with ≥ Grade 3. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections in 9%, and viral infections in 4%. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines. Febrile neutropenia was observed in 36% of patients and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Yescarta infusion occurred in 28% of patients and included thrombocytopenia (18%), neutropenia (15%), and anemia (3%). Monitor blood counts after Yescarta infusion.

HYPOGAMMAGLOBULINEMIA: B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia occurred in 15% of patients. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Yescarta treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Yescarta treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS: The most common adverse reactions (incidence ≥ 20%) include CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections-pathogen unpecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

On May 15, 2019 AVEO Oncology (NASDAQ: AVEO) reported two poster presentations at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held May 31-June 4, 2019 in Chicago, Illinois (Press release, AVEO, MAY 15, 2019, View Source [SID1234536352]).

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Presentation Details

Title: Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer
First Author: Wendy M. Swetzig, PhD, Northwestern University Feinberg School of Medicine
Abstract Number: 5538
Poster Session: Gynecologic Cancer
Poster Board: 361
Date and Time: Saturday, June 1, 2019, 1:15-4:15 PM CT
Location: Hall A

Title: TIVO-3: Subgroup analysis of progression-free survival of tivozanib compared to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC)
First Author: Camillo Porta, MD, Associate Professor, Department of Internal Medicine, University of Pavia and Division of Translational Oncology, IRCCS Maugeri, Italy
Abstract Number: 4572
Poster Session: Genitourinary (Nonprostate) Cancer
Poster Board: 398
Date and Time: Monday, June 3, 2019, 1:15-4:15 PM CT
Location: Hall A

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models3 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 1/2 study in RCC. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal and breast cancers. In addition, a new formulation of tivozanib is in pre-clinical development for the treatment of age-related macular degeneration.

On May 15, 2019 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported positive data from the Phase I/II STARTRK-NG study, evaluating the investigational medicine entrectinib in children and adolescents with recurrent or refractory solid tumors with and without neurotrophic tyrosine receptor kinase (NTRK), ROS1 or anaplastic lymphoma kinase (ALK) gene fusions (Press release, Genentech, MAY 15, 2019, View Source [SID1234536351]). The study showed entrectinib shrank tumors (objective response rate; ORR) in all children and adolescents who had NTRK, ROS1 or ALK fusion-positive solid tumors (11 of 11 patients), including two patients achieving a complete response. Of the 11 patients, five patients with primary high-grade tumors in the central nervous system (CNS) had an objective response, including one patient with a complete response. The safety profile of entrectinib was consistent with that seen in previous analyses. Data will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Sunday, June 2, 2019, from 8:00 – 8:12 a.m. CDT (Abstract 10009), and was part of today’s official ASCO (Free ASCO Whitepaper) presscast.

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"We are encouraged by the results we have seen with entrectinib in children with pediatric and adolescent cancers, including those with tumors in the brain," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "The STARTRK-NG study underscores the importance of combining comprehensive genomic profiling with targeted therapies and supports our approach to providing people with personalized medicines developed specifically for their type of cancer."

Additional data for entrectinib across different tumor types and patient populations will also be presented at ASCO (Free ASCO Whitepaper), highlighting the company’s unique approach to personalized healthcare through advances in targeted therapies, diagnostics and data analytics:

Initial results from an integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials evaluating the efficacy of entrectinib in adults with solid tumors and CNS metastases will be presented on Saturday, June 1, 2019, in a poster session from 3:00 – 4:30 p.m. CDT (Abstract 3017).

Results from a real-world data study evaluating time-to-treatment discontinuation and progression-free survival as endpoints for comparative efficacy analysis of clinical trials of entrectinib and crizotinib for the treatment of people with ROS1-positive non-small cell lung cancer (NSCLC) will be presented during a poster session on Sunday, June 2, 2019, from 8:00 – 11:00 a.m. CDT (Abstract 9070).

The FDA recently granted Priority Review for entrectinib for both the treatment of pediatric and adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors who have either progressed following prior therapies or as an initial therapy when there are no acceptable standard therapies, and for the treatment of people with metastatic ROS1-positive NSCLC. These NDAs are based on results from the integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the STARTRK-NG study. The FDA is expected to make a decision on approval by August 18, 2019.

About the STARTRK-NG study

STARTRK-NG is a Phase I/II open-label dose-escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without NTRK, ROS1 or ALK fusions. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using Response Assessment in Neuro-Oncology (RANO) for CNS tumors, Response Evaluation Criteria in Solid Tumors (RECIST), and Curie score (CS) for neuroblastoma. The study enrolled 29 children and adolescents aged 4.9 months through 20 years (median age of 7 years) who had recurrent or refractory solid tumors, and 28 were evaluated for response. Of the 28 children and adolescents evaluated, 11 children were identified to have tumors with NTRK, ROS1 or ALK fusions and one with ALK F1174L-mutated neuroblastoma. A summary of the results are included below.

Complete responses were observed in two patients with tumors harboring NTRK and ALK fusions: one with an NTRK fusion-positive primary CNS tumor and one with an ALK fusion-positive inflammatory myofibroblastic tumor. Another complete response was observed in one neuroblastoma patient with an ALK F1174L mutation.
Partial responses were observed in nine patients, three unconfirmed at the time of the clinical cut-off date, across NTRK, ROS1 and ALK fusion-positive primary CNS (n=4) and extracranial (n=5) solid tumors.
Median duration of therapy for confirmed fusion-positive responders was 10.51 months (3.8 to 17.7 months), and median time to response was 1.89 months (1 to 1.9 months).
The safety profile of entrectinib was consistent with that seen in previous analyses. Treatment-related adverse events were most frequently National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2, leading to discontinuation in 6.9 percent of patients.

About NTRK fusion-positive cancer

Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signaling pathways involved in proliferation of certain types of cancer. NTRK gene fusions are tumor-agnostic, meaning they are present in tumors irrespective of site of origin. These fusions have been identified in a broad range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About entrectinib

Entrectinib (RXDX-101) is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions. Entrectinib is being investigated across a range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.