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3 results on '"Bhagawati-Prasad, V."'

1. Entrectinib in ROS1-positive advanced non-small cell lung cancer: the phase 2/3 BFAST trial.

Author

Peters S, Gadgeel SM, Mok T, Nadal E, Kilickap S, Swalduz A, Cadranel J, Sugawara S, Chiu CH, Yu CJ, Moskovitz M, Tanaka T, Nersesian R, Shagan SM, Maclennan M, Mathisen M, Bhagawati-Prasad V, Diarra C, Assaf ZJ, Archer V, and Dziadziuszko R

Subjects
Humans, Female, Male, Middle Aged, Aged, Adult, Aged, 80 and over, Liquid Biopsy, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Indazoles therapeutic use, Indazoles adverse effects, Benzamides therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases genetics
Abstract

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 ., (© 2024. The Author(s).)

Published
2024
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2. High-dose alectinib for RET fusion-positive non-small cell lung cancer in the Blood First Assay Screening Trial.

Author

Dziadziuszko R, Peled N, Mok T, Peters S, Aix SP, Alatorre-Alexander J, Vicuna BD, Maclennan M, Bhagawati-Prasad V, Shagan SM, Schleifman E, Ruf T, Mathisen MS, and Gadgeel SM

Abstract

Introduction: This paper presents results from Cohort B (rearranged during transfection [ RET ], fusion-positive) of the Blood First Assay Screening Trial in patients with advanced non-small cell lung cancer (NSCLC) screened for genetic alterations using blood-based next-generation sequencing., Material and Methods: Adults with advanced RET fusion-positive NSCLC received alectinib 900 mg twice daily (BID) in Phase I. Enrolment closed prematurely with Phase II uninitiated., Results: Among eight treated patients, confirmed best overall responses in evaluable patients were stable disease (4/5) and progressive disease (1/5). One dose-limiting toxicity (death, unknown cause) was considered by the investigator to be related to treatment and underlying disease. Serious adverse events (SAEs) occurred in five patients, and SAEs that may be related to treatment occurred in two patients., Conclusions: Alectinib showed limited activity in advanced RET fusion-positive NSCLC, and further investigation was not conducted due to the development of selective RET inhibitors pralsetinib and selpercatinib. No new safety signals were observed, and the safety profile of alectinib was in line with previous reports at the 600 mg BID dose., Competing Interests: R.D: Advisory/consultancy fees from F. Hoffmann- La Roche, Ltd, Foundation Medicine, Pfizer, AstraZeneca, Novartis, Merck Sharp & Dohme, Karyopharm, and Boehringer Ingelheim. Honoraria from F. Hoffmann-La Roche, Ltd, AstraZeneca, and Amgen. Participated in data safety monitoring boards/advisory boards for F. Hoffmann-La Roche, Ltd, AstraZeneca, Amgen, and Merck Sharp & Dohme. N.P: Advisor and honorarium from, and research with, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Foundation Medicine, Gaurdant Health, Merck, MSD, Novartis, NovellusDx, Pfizer, Roche, and Takeda. IP held for Volatile Organic Compounds for Detecting Cell Dysplasia and Genetic Alterations Associated With Lung Cancer; WO/2012/023138. T.M: Received fees for serving on advisory boards and consulting, and speakers fees and institutional grants and research support from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pfizer. Fees for serving on advisory boards and consulting and speakers fees from ACEA Pharma, Amgen, Boehringer lngelheim, Daiichi Sankyo, Fishawack Facilitate, Ltd., Eli Lilly, OrigiMed Co. Ltd., Sanofi- Aventis; owns stock and has received fees for serving on advisory boards and board of directors/leadership roles from HutchMed; institutional grants and research support and fees for serving on advisory boards and consulting from Merck Serono and SFJ Pharmaceutical Ltd.; fees for serving on advisory boards, board of directors/leadership roles and consulting from Lunit, Inc.; fees for serving on advisory boards and for consulting from AbbVie, BerryOncology, Blueprint Medicines Corporation, C4 Therapeutics, CStone Pharmaceuticals, Curio Science, Eisai, Gilead Sciences, Inc., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., IQVIA, Janssen, lgnyta, Inc., lncyte Corporation, lnivata, Loxo Oncology Inc., Mirati Therapeutics Inc., Puma Biotechnology Inc., Vertex Pharmaceuticals, Yuhan Corporation; speakers fees and fees for consulting from Alpha Biopharma Co., Ltd., Amoy Diagnostics Co., Ltd., AstraZeneca (before 1 January 2019), BeiGene; fees for serving on advisory boards and institutional grants and research support from AstraZeneca, Gl Therapeutics, Inc., Takeda; institutional grants and research support from Roche, XCovery; speakers fees from Daz Group, InMed Medical Communication, Janssen, Liangyihui Network Technology Co., Ltd., Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostic/Foundation Medicine, Shanghai BeBirds Translation and Consulting Co., Ltd., Taiho, Takeda Oncology, touchIME; fees for consulting from Elevation Oncology, MoreHealth, Qiming Development (HK) Ltd., Roche Pharmaceuticals, Takeda Pharmaceuticals HK Ltd.; fees for serving on advisory boards for Roche/Genentech and Virtus Medical Group; fees for a board of directors/leadership role with AstraZeneca PLC; discloses serving on advisory boards (uncompensated) for geneDecode Co., Ltd.; owns stock from Act Genomics-Sanomics Group and Aurora Tele-Oncology Ltd.; declares uncompensated board of directors/leadership roles with the American Society of Clinical Oncology, Asian Thoracic Oncology Research Group, Chinese Lung Cancer Research Foundation Limited, Chinese Society of Clinical Oncology, Hong Kong Cancer Fund, Hong Kong Cancer Therapy Society, International Association for the Study of Lung Cancer (ending 30 April 2019), St. Stephen’s College and Preparatory School. S.P: Received institutional support for consulting or advising from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, eCancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, IQVIA, Incyte, Janssen, Medscape, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Oncology Education, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics and Takeda; institutional fees for speaking at company-sponsored public events for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, eCancer, Eli Lilly, Illumina, Imedex, Medscape, Merck Sharp & Dohme, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi and Takeda; and institutional grants and research support for the conduct of clinical trials from Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, GlaxoSmithKline, Illumina, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Mirati Therapeutics Inc., Novartis, Pfizer, Phosplatin Therapeutics, and Roche/Genentech. S.P.A: Nothing to disclose. J.A: Received consulting fees from F. Hoffmann-La Roche, Ltd, AstraZeneca, Takeda, and Pfizer; honorarium from F. Hoffmann-La Roche, Ltd, AstraZeneca, Takeda; and meetings and/or travel support from F. Hoffmann- La Roche, Ltd, AstraZeneca, and MSD. B.D.V: Nothing to disclose. M.M: Employment at Syneos Health and works as a Study Statistician in FSP model for F. Hoffmann- La Roche, Ltd on a full-time basis. V.B: Roche employee and shareholder. Breath Analysis of Pulmonary Nodules. US20130150261 A1; Apparatus for treating a target site of a body; WO/2015/059646. S.M.S: Genentech employee and Roche shareholder. E.S: Genentech employee and Roche shareholder. T.R: Roche employee and shareholder. M.S.M: Genentech employee and Roche shareholder. S.M.G: Received fees for consulting from Genentech/Roche, Takeda, AstraZeneca, Pfizer, Daiichi Sankyo and Eli Lilly; served on an independent data monitoring committee for AstraZeneca., (Copyright © 2023 Termedia.)

Published
2023
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3. First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE 2 -receptor E-type 4 (EP4), in patients with advanced cancers.

Author

Hong DS, Parikh A, Shapiro GI, Varga A, Naing A, Meric-Bernstam F, Ataman Ö, Reyderman L, Binder TA, Ren M, Liu M, Dayal S, Siu AY, Sachdev P, Xu L, Bhagawati-Prasad V, Tchakov I, Ooi CE, Bao X, and Marabelle A

Subjects
Administration, Oral, Adult, Aged, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Staging, Neoplasms diagnosis, Neoplasms pathology, Response Evaluation Criteria in Solid Tumors, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Young Adult, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Agents, Immunological pharmacokinetics, Benzoates administration & dosage, Benzoates adverse effects, Benzoates pharmacokinetics, Neoplasms drug therapy, Pyrazoles administration & dosage, Pyrazoles adverse effects, Pyrazoles pharmacokinetics, Receptors, Prostaglandin E, EP4 Subtype antagonists & inhibitors
Abstract

Background: E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046., Methods: This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment., Results: No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t 1/2 ) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses., Conclusions: In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting., Trial Registration Number: NCT02540291., Competing Interests: Competing interests: DSH has received research grant funding from AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, and Takeda; DSH received travel, accommodations, and expenses from LOXO and MiRNA; DSH held a consulting or advisory role for the following: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer (advisory boards and Speakers’ Bureaux), Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, and Trieza Therapeutics. DSH discloses the following other ownership interests: Molecular Match (Advisor), OncoResponse (founder), and Presagia (Advisor). AN has received research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and the Immune Deficiency Foundation (spouse); AN has served on an advisory board for CytomX Therapeutics and Novartis; AN has received travel and accommodation expenses paid for by ARMO BioSciences. GIS has received research funding from EL, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology. GIS has served on advisory boards for Pfizer, EL, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, and Daiichi Sankyo. The Dana-Farber Cancer Institute has received funding from Pfizer and Array BioPharma for the conduct of investigator-initiated clinical trials of palbociclib led by GIS. GIS holds Patent 9872874, entitled, “Dosage regimen for sapacitabine and seliciclib,” and also has a pending patent related to his work on CDK4/6 inhibition entitled, ‘‘Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition.’’ FMB has no conflicts of interest to disclose. AP is a consultant/advisory board member for Puretech, Driver, Foundation Medicine, and Eisai; AP has institutional research funding from Array, Plexxikon, Guardant, BMS, MacroGenics, Genentech, Novartis, OncoMed, and Tolero; AP has received travel support from Eisai. AM has received honoraria and consulting fees from Eisai. XB is an employee of H3 Biomedicine, a subsidiary of Eisai. LR, TAB, MR, SD, PS, LX, IT, ViB-P, and CEO are employees of Eisai or Eisai Ltd. ML, ÖA, and AYS were employees of Eisai at the time the study was conducted., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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