Abstract
Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45–8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43–0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41–0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal–squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 432-437 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 595 |
| Issue number | 7867 |
| DOIs | |
| State | Published - Jul 15 2021 |
Funding
All patients provided written informed consent, which included the exploratory biomarker end points described here. The study was approved by the relevant institutional review board and ethics committee for each participating centre and was conducted in accordance with the principles of Good Clinical Practice, the provisions of the Declaration of Helsinki and other applicable local regulations (NCT02662309). The study was sponsored by Queen Mary University of London. The Barts Experimental Cancer Centre Clinical Trials Group had overall responsibility for trial management and day-to-day running of the trial, and the trial was overseen by an independent data monitoring committee (IDMC). Emerging safety data were reviewed regularly by the IDMC. Acknowledgements The study was sponsored by F. Hoffmann-La Roche Ltd/Genentech, Inc. We thank the patients who participated in the trial and the clinical site investigators, the Barts Health Experimental Cancer Medicine Centre (CRUK), A. Yiu and M. Ravasz from Fios Genomics for additional help with transcriptomic analysis, S. Flynn, K. Zvonar and D. Rishipathak of the Genentech Biomarker Operations Team for providing support in the generation and analysis of the data, and E. E. Kadel III from the Genentech Biomarker Development team for data integration. Medical writing assistance for this manuscript was provided by H. Grewal and Z. Augur of Anshin Biosolutions, M. Malhotra of Natera and A. J. Pratt of Health Interactions, Inc., and was funded by F. Hoffmann-La Roche Ltd. M. Jacobson and J. Ball contributed to research funding for the ABACUS cohort. Competing interests T.P. received honoraria from advisory/consultancy roles with AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono (EMD Serono), Astellas, Johnson & Johnson, Eisai and Roche; institutional research funding support from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono (EMD Serono), Astellas and Johnson & Johnson; and travel, accommodation and expenses support from Roche, Pfizer, MSD, AstraZeneca and Ipsen. Z.J.A. discloses employment with Genentech, previous employment with Natera and stock and other ownership interests with Roche. N.D., D.S.S., V.D. and K.C.Y. disclose employment with Genentech and stock and other ownership interests with Roche. R.B. and X.S. disclose employment with and own stock or other ownership interests in Genentech. B.E.S. discloses honoraria from Merck, Roche, Pfizer and Ellipses; advisory/ consulting fees from Merck, Ellipses and Onc; expert testimony or speakers’ bureau fees from Merck and Pfizer; travel, accommodation or expenses support from Roche and Pfizer. P.G. received consulting fees from AstraZeneca, Bayer, BMS, Clovis Oncology, Driver, Dyania Health, EMD Serono, Exelixis, Foundation Medicine, GlaxoSmithKline, Genentech, Genzyme, Heron Therapeutics, Immunomedics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics and QED Therapeutics; and institutional research funding support from AstraZeneca, Bavarian Nordic, Bayer, BMS, Clovis Oncology, Debiopharm, Genentech, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck, Mirati Therapeutics, OncogeneX, Pfizer and QED Therapeutics. M.H. received honoraria or advisory fees from Pfizer, AstraZeneca, Bayer, Genentech, PER, Projects in Knowledge, Astellas Pharma, Sanofi/ Genzyme, Research to Practice, BMS and Daiichi Sankyo; research funding support from AstraZeneca, Genentech, Pfizer and Bayer; and travel, accommodation or expenses support from Pfizer, Bayer, Astellas Pharma and Genentech/Roche; and also has two pending patents and one licensed patent with Imbio. S.O. received advisory/consulting fees and honorarium from Astellas, Bayer, BMS, Eisai, Janssen, MSD, Novartis, Pfizer and Sanofi; research funding support from Ipsen and Sanofi; and travel, accommodation or expenses support from Bayer, BMS, Eisai, MSD, Novartis and Pfizer. J.E.G. received consulting fees or honoraria from Amgen, AstraZeneca, Bayer, Janssen-Cilag, Merck, MSD, Pfizer, Roche and BMS. P.A. received advisory/consulting fees and honoraria from MSD Oncology, Sanofi and Roche/Genentech. D.C. received consulting fees from Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Ipsen, Janssen Oncology, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech and Sanofi; research funding support from Janssen Oncology; and travel, accommodation or expenses support from AstraZeneca Spain, BMS, Pfizer and Roche. H.N. received research funding support from Ono and Chugai; consulting fees from Bayer, Chugai, BMS, Astellas, MSD, Janssen and AstraZeneca; and participated in speakers’ bureaus for Chugai, MSD, Astellas and AstraZeneca. S.D. received honoraria from Ferring, Olympus, Pacific Edge, Photocure, QED, MDxHealth and Spectrum Pharmaceuticals; advisory fees from Ferring, Photocure, QED and Taris; and research funding, travel, accommodation or expenses support from Photocure. S.S., H.S. and A.A disclose employment with Natera. B.G.Z. discloses employment with and owns stock or other ownership interests in Natera. M.P. discloses employment with F. Hoffmann-La Roche. J.Z. discloses employment with Hoffmann-La Roche. C.C., C.B. and S.M. disclose employment with Genentech. J.B. received advisory/consulting fees from Astellas Pharma, AstraZeneca/MedImmune, BMS, Genentech, Merck, Novartis, Pfizer and Pierre Fabre; honoraria from UpToDate; research funding support from Millennium, Sanofi and Pfizer/EMD Serono; owns stock or other ownership interests in Rainer; and travel, accommodation or expenses support from Pfizer, MSD Oncology and Ipsen.
ASJC Scopus subject areas
- General
