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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. Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial.

Author

Peters S, Dziadziuszko R, Morabito A, Felip E, Gadgeel SM, Cheema P, Cobo M, Andric Z, Barrios CH, Yamaguchi M, Dansin E, Danchaivijitr P, Johnson M, Novello S, Mathisen MS, Shagan SM, Schleifman E, Wang J, Yan M, Mocci S, Voong D, Fabrizio DA, Shames DS, Riehl T, Gandara DR, and Mok T

Subjects
Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor genetics, Humans, Immunotherapy, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics
Abstract

Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted., (© 2022. The Author(s).)

Published
2022
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4. Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial.

Author

Kim ES, Velcheti V, Mekhail T, Yun C, Shagan SM, Hu S, Chae YK, Leal TA, Dowell JE, Tsai ML, Dakhil CSR, Stella P, Jin Y, Shames DS, Schleifman E, Fabrizio DA, Phan S, and Socinski MA

Subjects
Antibodies, Monoclonal, Humanized, Biomarkers, Tumor genetics, Humans, Immune Checkpoint Inhibitors, Mutation genetics, Retrospective Studies, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Circulating Tumor DNA genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology
Abstract

Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers., (© 2022. The Author(s).)

Published
2022
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