Regulatory implications of ctDNA in immuno-oncology for solid tumors

Paz J Vellanki, Soma Ghosh, Anand Pathak, Michael J Fusco, Erik W Bloomquist, Shenghui Tang, Harpreet Singh, Reena Philip, Richard Pazdur, Julia A Beaver, Paz J Vellanki, Soma Ghosh, Anand Pathak, Michael J Fusco, Erik W Bloomquist, Shenghui Tang, Harpreet Singh, Reena Philip, Richard Pazdur, Julia A Beaver

Abstract

In the era of precision oncology, use of circulating tumor DNA (ctDNA) is emerging as a minimally invasive approach for the diagnosis and management of patients with cancer and as an enrichment tool in clinical trials. In recent years, the US Food and Drug Administration has approved multiple ctDNA-based companion diagnostic assays for the safe and effective use of targeted therapies and ctDNA-based assays are also being developed for use with immuno-oncology-based therapies. For early-stage solid tumor cancers, ctDNA may be particularly important to detect molecular residual disease (MRD) to support early implementation of adjuvant or escalated therapy to prevent development of metastatic disease. Clinical trials are also increasingly using ctDNA MRD for patient selection and stratification, with an ultimate goal of improving trial efficiency through use of an enriched patient population. Standardization and harmonization of ctDNA assays and methodologies, along with further clinical validation of ctDNA as a prognostic and predictive biomarker, are necessary before ctDNA may be considered as an efficacy-response biomarker to support regulatory decision making.

Keywords: Clinical Trials as Topic; Immunotherapy; Review.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Use of ctDNA molecular residual disease as an enrichment tool in clinical trials. (A) ctDNA status after surgery can be used as a stratification factor, enrolling patients both negative and positive for ctDNA. (B) An enrichment strategy is to only enroll patients who are positive for ctDNA and may have higher risk disease. (C) An adaptive enrichment strategy is to include a ctDNA-negative arm that may be closed at an interim analysis for futility. (D) Patients with ctDNA-positive disease after curative-intent surgery and standard adjuvant systemic therapy may be randomized to an investigational therapy or observation. (E) Patients who are negative for ctDNA after curative-intent surgery may be randomized to standard-of-care (SoC) adjuvant therapy versus a de-escalated regimen. ctDNA, circulating tumor DNA; DFS, disease-free survival; OS, overall survival.

References

    1. Rossi G, Ignatiadis M. Promises and pitfalls of using liquid biopsy for precision medicine. Cancer Res 2019;79:2798–804. 10.1158/0008-5472.CAN-18-3402
    1. Wan JCM, Massie C, Garcia-Corbacho J, et al. . Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 2017;17:223–38. 10.1038/nrc.2017.7
    1. Narayan P, Ghosh S, Philip R, et al. . State of the science and future directions for liquid biopsies in drug development. Oncologist 2020;25:730–2. 10.1634/theoncologist.2020-0246
    1. FDA draft guidance for industry: use of circulating tumor DNA for early stage solid tumor drug development. Available: [Accessed 31 May 2022].
    1. Beaver JA, Pazdur R. The Wild West of checkpoint inhibitor development. N Engl J Med 2022;386:1297–301. 10.1056/NEJMp2116863
    1. U.S. Food and Drug Administration, Merck Sharp Dohme, KEYTRUDA (pembrolizumab) [package insert]. Available: [Accessed 31 May 2022].
    1. U.S. Food and Drug Administration, Bristol-Myers Squibb Company, OPDIVO (nivolumab) [package insert]. Available: [Accessed 31 May 2022].
    1. U.S. Food and Drug Administration, Genentech Inc, TECENTRIQ (atezolizumab) [package insert]. Available: [Accessed 31 May 2022].
    1. Schmid P, Cortes J, Pusztai L, et al. . Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810–21. 10.1056/NEJMoa1910549
    1. Kelly RJ, Ajani JA, Kuzdzal J, et al. . Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 2021;384:1191–203. 10.1056/NEJMoa2032125
    1. Bajorin DF, Witjes JA, Gschwend JE, et al. . Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 2021;384:2102–14. 10.1056/NEJMoa2034442
    1. Choueiri TK, Tomczak P, Park SH, et al. . Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 2021;385:683–94. 10.1056/NEJMoa2106391
    1. Felip E, Altorki N, Zhou C, et al. . Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021;398:1344-1357. 10.1016/S0140-6736(21)02098-5
    1. Forde PM, Spicer J, Lu S, et al. . Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 2022;386:1973–85. 10.1056/NEJMoa2202170
    1. Garcia-Murillas I, Schiavon G, Weigelt B, et al. . Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 2015;7:302ra133. 10.1126/scitranslmed.aab0021
    1. Tie J, Wang Y, Tomasetti C, et al. . Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med 2016;8:346ra92. 10.1126/scitranslmed.aaf6219
    1. Abbosh C, Birkbak NJ, Wilson GA, et al. . Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 2017;545:446–51. 10.1038/nature22364
    1. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. . Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov 2017;7:1394–403. 10.1158/-17-0716
    1. Tan L, Sandhu S, Lee RJ, et al. . Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA. Ann Oncol 2019;30:804–14. 10.1093/annonc/mdz048
    1. Reinert T, Henriksen TV, Christensen E, et al. . Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol 2019;5:1124-1131. 10.1001/jamaoncol.2019.0528
    1. Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. . Early detection of metastatic relapse and monitoring of therapeutic efficacy by Ultra-Deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol 2019;37:1547–57. 10.1200/JCO.18.02052
    1. Coombes RC, Page K, Salari R, et al. . Personalized detection of circulating tumor DNA Antedates breast cancer metastatic recurrence. Clin Cancer Res 2019;25:4255–63. 10.1158/1078-0432.CCR-18-3663
    1. Garcia-Murillas I, Chopra N, Comino-Méndez I, et al. . Assessment of molecular relapse detection in early-stage breast cancer. JAMA Oncol 2019;5:1473-1478. 10.1001/jamaoncol.2019.1838
    1. Yang J, Gong Y, Lam VK, et al. . Deep sequencing of circulating tumor DNA detects molecular residual disease and predicts recurrence in gastric cancer. Cell Death Dis 2020;11:346. 10.1038/s41419-020-2531-z
    1. Azad TD, Chaudhuri AA, Fang P, et al. . Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer. Gastroenterology 2020;158:494–505. 10.1053/j.gastro.2019.10.039
    1. Lee JH, Long GV, Menzies AM, et al. . Association between circulating tumor DNA and pseudoprogression in patients with metastatic melanoma treated with Anti-Programmed cell death 1 antibodies. JAMA Oncol 2018;4:717–21. 10.1001/jamaoncol.2017.5332
    1. Aravanis AM, Lee M, Klausner RD. Next-Generation sequencing of circulating tumor DNA for early cancer detection. Cell 2017;168:571–4. 10.1016/j.cell.2017.01.030
    1. Reinert T, Schøler LV, Thomsen R, et al. . Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery. Gut 2016;65:625–34. 10.1136/gutjnl-2014-308859
    1. Schøler LV, Reinert T, Ørntoft M-BW, et al. . Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer. Clin Cancer Res 2017;23:5437–45. 10.1158/1078-0432.CCR-17-0510
    1. Tarazona N, Gimeno-Valiente F, Gambardella V, et al. . Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer. Ann Oncol 2019;30:1804–12. 10.1093/annonc/mdz390
    1. Wang Y, Li L, Cohen JD, et al. . Prognostic potential of circulating tumor DNA measurement in postoperative surveillance of nonmetastatic colorectal cancer. JAMA Oncol 2019;5:1118–23. 10.1001/jamaoncol.2019.0512
    1. Olsson E, Winter C, George A, et al. . Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 2015;7:1034–47. 10.15252/emmm.201404913
    1. Groot VP, Mosier S, Javed AA, et al. . Circulating tumor DNA as a clinical test in resected pancreatic cancer. Clin Cancer Res 2019;25:4973–84. 10.1158/1078-0432.CCR-19-0197
    1. Tie J, Cohen JD, Wang Y, et al. . Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol 2019;5:1710-1717. 10.1001/jamaoncol.2019.3616
    1. Henriksen TV, Tarazona N, Frydendahl A, et al. . Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, toward assessment of adjuvant therapy efficacy and clinical behavior of recurrences. Clin Cancer Res 2022;28:507–17. 10.1158/1078-0432.CCR-21-2404
    1. Parsons HA, Rhoades J, Reed SC, et al. . Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer. Clin Cancer Res 2020;26:2556–64. 10.1158/1078-0432.CCR-19-3005
    1. Lin J-C, Wang W-Y, Chen KY, et al. . Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 2004;350:2461–70. 10.1056/NEJMoa032260
    1. Chera BS, Kumar S, Beaty BT, et al. . Rapid clearance profile of plasma circulating tumor HPV type 16 DNA during chemoradiotherapy correlates with disease control in HPV-associated oropharyngeal cancer. Clin Cancer Res 2019;25:4682–90. 10.1158/1078-0432.CCR-19-0211
    1. Bellmunt J, Hussain M, Gschwend JE, et al. . Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:525–37. 10.1016/S1470-2045(21)00004-8
    1. Powles T, Assaf ZJ, Davarpanah N, et al. . ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021;595:432–7. 10.1038/s41586-021-03642-9
    1. Bellmunt J. Adjuvant immunotherapy in muscle-invasive urothelial carcinoma - Author's reply. Lancet Oncol 2021;22:e238. 10.1016/S1470-2045(21)00298-9
    1. Powles TB, Gschwend JE, Bracarda S, et al. . 716TiP IMvigor011: A global, double-blind, randomised phase III study of atezolizumab (atezo; anti–PD-L1) vs placebo (pbo) as adjuvant therapy in patients (pts) with high-risk muscle-invasive bladder cancer (MIBC) who are circulating tumour (ct)DNA+ post cystectomy. Ann Oncol 2021;32:S721–4. 10.1016/j.annonc.2021.08.112
    1. Turner N, Swift C, Jenkins B, et al. . Abstract GS3-06: primary results of the cTRAK Tn trial: a clinical trial utilising ctDNA mutation tracking to detect minimal residual disease and trigger intervention in patients with moderate and high risk early stage triple negative breast cancer. Cancer Res 2022;82:GS3-06. 10.1158/1538-7445.SABCS21-GS3-06
    1. Peters S, Spigel D, Ahn M, et al. . P03.03 MERMAID-1: a phase III study of adjuvant Durvalumab plus chemotherapy in resected NSCLC patients with MRD+ post-surgery. Journal of Thoracic Oncology 2021;16:S258–9. 10.1016/j.jtho.2021.01.376
    1. Spigel DR, Peters S, Ahn M-J, et al. . 93TiP MERMAID-2: phase III study of durvalumab in patients with resected, stage II-III NSCLC who become MRD+ after curative-intent therapy. Journal of Thoracic Oncology 2021;16:S745–6. 10.1016/S1556-0864(21)01935-3
    1. The Christie NHS Foundation Trust . Circulating tumour DNA guidEd therapy for stage IIB/C mElanoma after surgiCal resecTION (detection). identifier: NCT04901988, 2021. Available: [Accessed 6 Jun 2022].
    1. University of British Columbia . A study of Durvalumab and stereotactic radiotherapy for stage I non-small cell lung cancer (SCION). identifier: NCT04944173, 2021. Available: [Accessed 6 Jun 2022].
    1. Tie J, Cohen JD, Lahouel K, et al. . Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med 2022;386:2261–72. 10.1056/NEJMoa2200075
    1. Baxter NN, Kennedy EB, Bergsland E, et al. . Adjuvant therapy for stage II colon cancer: ASCO guideline update. J Clin Oncol 2022;40:892–910. 10.1200/JCO.21.02538
    1. Blumenthal GM, Bunn PA, Chaft JE, et al. . Current status and future perspectives on neoadjuvant therapy in lung cancer. J Thorac Oncol 2018;13:1818-1831. 10.1016/j.jtho.2018.09.017
    1. Korn EL, Sachs MC, McShane LM. Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer. Ann Oncol 2016;27:10–15. 10.1093/annonc/mdv507
    1. Korn EL, Freidlin B. Surrogate and intermediate endpoints in randomized trials: what's the goal? Clin Cancer Res 2018;24:2239–40. 10.1158/1078-0432.CCR-18-0183
    1. Vega DM, Nishimura KK, Zariffa N, et al. . Changes in circulating tumor DNA reflect clinical benefit across multiple studies of patients with non-small-cell lung cancer treated with immune checkpoint inhibitors. JCO Precis Oncol 2022;6:e2100372. 10.1200/PO.21.00372
    1. Cortazar P, Zhang L, Untch M, et al. . Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164–72. 10.1016/S0140-6736(13)62422-8
    1. Amiri-Kordestani L, Wedam S, Zhang L, et al. . First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab for the treatment of patients with HER2-positive breast cancer. Clin Cancer Res 2014;20:5359–64. 10.1158/1078-0432.CCR-14-1268
    1. FDA guidance for industry: pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval, 2020. Available: [Accessed 6 Jun 2022].
    1. Prowell TM, Beaver JA, Pazdur R. Residual Disease after Neoadjuvant Therapy - Developing Drugs for High-Risk Early Breast Cancer. N Engl J Med 2019;380:612–5. 10.1056/NEJMp1900079
    1. Stadler J-C, Belloum Y, Deitert B, et al. . Current and future clinical applications of ctDNA in Immuno-Oncology. Cancer Res 2022;82:349–58. 10.1158/0008-5472.CAN-21-1718
    1. Anagnostou V, Forde PM, White JR, et al. . Dynamics of tumor and immune responses during immune checkpoint blockade in non-small cell lung cancer. Cancer Res 2019;79:1214–25. 10.1158/0008-5472.CAN-18-1127
    1. Herbreteau G, Langlais A, Greillier L, et al. . Circulating tumor DNA as a prognostic determinant in small cell lung cancer patients receiving Atezolizumab. J Clin Med 2020;9:3861. 10.3390/jcm9123861
    1. Goldberg SB, Narayan A, Kole AJ, et al. . Early assessment of lung cancer immunotherapy response via circulating tumor DNA. Clin Cancer Res 2018;24:1872–80. 10.1158/1078-0432.CCR-17-1341
    1. Váraljai R, Wistuba-Hamprecht K, Seremet T, et al. . Application of circulating cell-free tumor DNA profiles for therapeutic monitoring and outcome prediction in genetically heterogeneous metastatic melanoma. JCO Precis Oncol 2020;310.1200/PO.18.00229. [Epub ahead of print: 15 02 2019].
    1. Guibert N, Jones G, Beeler JF, et al. . Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer. Lung Cancer 2019;137:1–6. 10.1016/j.lungcan.2019.09.005
    1. Jin Y, Chen D-L, Wang F, et al. . The predicting role of circulating tumor DNA landscape in gastric cancer patients treated with immune checkpoint inhibitors. Mol Cancer 2020;19:154. 10.1186/s12943-020-01274-7
    1. Wang F, Zhao Q, Wang Y-N, et al. . Evaluation of pole and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. JAMA Oncol 2019;5:1504. 10.1001/jamaoncol.2019.2963
    1. Yang G, Huang J, Zu Y. Abstract: analysis of mutation detection of POLD1/pole in pan-cancer. J Clin Oncol. 2020.
    1. Marcus L, Lemery SJ, Keegan P, et al. . Fda approval summary: pembrolizumab for the treatment of microsatellite Instability-High solid tumors. Clin Cancer Res 2019;25:3753–8. 10.1158/1078-0432.CCR-18-4070
    1. Willis J, Lefterova MI, Artyomenko A, et al. . Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel. Clin Cancer Res 2019;25:7035–45. 10.1158/1078-0432.CCR-19-1324
    1. Wang Z, Zhao X, Gao C, et al. . Plasma-Based microsatellite instability detection strategy to guide immune checkpoint blockade treatment. J Immunother Cancer 2020;8:e001297. 10.1136/jitc-2020-001297
    1. Cabel L, Proudhon C, Romano E, et al. . Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy. Nat Rev Clin Oncol 2018;15:639–50. 10.1038/s41571-018-0074-3
    1. Goodman AM, Kato S, Bazhenova L, et al. . Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 2017;16:2598–608. 10.1158/1535-7163.MCT-17-0386
    1. Rizvi H, Sanchez-Vega F, La K, et al. . Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. J Clin Oncol 2018;36:633–41. 10.1200/JCO.2017.75.3384
    1. Gandara DR, Paul SM, Kowanetz M, et al. . Blood-Based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 2018;24:1441–8. 10.1038/s41591-018-0134-3
    1. Khagi Y, Goodman AM, Daniels GA, et al. . Hypermutated circulating tumor DNA: correlation with response to checkpoint inhibitor-based immunotherapy. Clin Cancer Res 2017;23:5729–36. 10.1158/1078-0432.CCR-17-1439
    1. Forschner A, Battke F, Hadaschik D, et al. . Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma - results of a prospective biomarker study. J Immunother Cancer 2019;7:180. 10.1186/s40425-019-0659-0
    1. Marcus L, Fashoyin-Aje LA, Donoghue M, et al. . Fda approval summary: pembrolizumab for the treatment of tumor mutational Burden-High solid tumors. Clin Cancer Res 2021;27:4685–9. 10.1158/1078-0432.CCR-21-0327
    1. Sturgill EG, Misch A, Jones CC, et al. . Discordance in tumor mutation burden from blood and tissue affects association with response to immune checkpoint inhibition in real-world settings. Oncologist 2022;27:175–82. 10.1093/oncolo/oyab064
    1. Zhang Y, Chang L, Yang Y, et al. . The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer. J Immunother Cancer 2019;7:98. 10.1186/s40425-019-0581-5
    1. Chae YK, Davis AA, Agte S, et al. . Clinical implications of circulating tumor DNA tumor mutational burden (ctDNA TMB) in non-small cell lung cancer. Oncologist 2019;24:820–8. 10.1634/theoncologist.2018-0433
    1. Chen X, Wu X, Wu H, et al. . Camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary tract cancer: a single-arm, open-label, phase II trial. J Immunother Cancer 2020;8:e001240. 10.1136/jitc-2020-001240
    1. Kasi PM, Fehringer G, Taniguchi H, et al. . Impact of circulating tumor DNA-based detection of molecular residual disease on the conduct and design of clinical trials for solid tumors. JCO Precis Oncol 2022;6:e2100181. 10.1200/PO.21.00181
    1. Dawson S-J. Characterizing the cancer genome in blood. Cold Spring Harb Perspect Med 2019;9:a026880. 10.1101/cshperspect.a026880
    1. Locke WJ, Guanzon D, Ma C, et al. . Dna methylation cancer biomarkers: translation to the clinic. Front Genet 2019;10:1150. 10.3389/fgene.2019.01150
    1. Luo H, Zhao Q, Wei W, et al. . Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer. Sci Transl Med 2020;12. 10.1126/scitranslmed.aax7533
    1. Liu Y. At the dawn: cell-free DNA fragmentomics and gene regulation. Br J Cancer 2022;126:379–90. 10.1038/s41416-021-01635-z
    1. Febbo PG, Martin A-M, Scher HI, et al. . Minimum technical data elements for liquid biopsy data submitted to public databases. Clin Pharmacol Ther 2020;107:730–4. 10.1002/cpt.1747
    1. FDA draft guidance for industry and FDA staff: biomarker qualification: Evidentiary framework; December 2018. Available: [Accessed 7 Jun 2022].
    1. Godsey JH, Silvestro A, Barrett JC, et al. . Generic protocols for the analytical validation of next-generation sequencing-based ctDNA assays: a joint consensus recommendation of the BloodPAC's Analytical Variables Working Group. Clin Chem 2020;66:1156–66. 10.1093/clinchem/hvaa164

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