Chasing EGFR Mutations in the Plasma of Patients With Resected NSCLC: Lessons in the ADAURA Era.

After decades of stillness, the (neo)adjuvant space of NSCLC treatment is being revolutionized by the advent of immunotherapy and targeted agents. Dealing with early-stage, EGFR-driven NSCLC, the results of the ADAURA study sustain the use of osimertinib after curative resection of stage IB-IIIA EGFR-mutant NSCLC.1Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (834) Google Scholar,2Tsuboi M. Herbst R.S. John T. et al.Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.N Engl J Med. 2023; 389: 137-147https://doi.org/10.1056/NEJMoa2304594Crossref PubMed Scopus (12) Google Scholar Sharing the enthusiasm for this unprecedented achievement, open questions are still present on the use of osimertinib in the adjuvant setting.3Passaro A. Mok T.S.K. Attili I. et al.Adjuvant Treatments for Surgically Resected Non-Small Cell Lung Cancer Harboring EGFR Mutations: A Review [published online ahead of print, 2023 May 11].JAMA Oncol. 2023; https://doi.org/10.1001/jamaoncol.2023.0459Crossref PubMed Scopus (1) Google Scholar The identification of additional prognostic biomarkers for treatment intensification or deintensification represents the next step for improving patient selection and subsequent outcomes. In the latest issue of the Journal of Thoracic Oncology, Jung et al.4Jung H.A. Ku B.M. Kim Y.J. et al.Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage I-IIIA EGFR mutant-non-small cell lung cancer.J Thorac Oncol. 2023; 18: 1199-1208Abstract Full Text Full Text PDF Scopus (1) Google Scholar provide a large prospective study on circulating tumor DNA (ctDNA) monitoring in surgically resected stage IA-IIIA (seventh American Joint Committee on Cancer staging) EGFR-driven NSCLC.4Jung H.A. Ku B.M. Kim Y.J. et al.Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage I-IIIA EGFR mutant-non-small cell lung cancer.J Thorac Oncol. 2023; 18: 1199-1208Abstract Full Text Full Text PDF Scopus (1) Google Scholar Aside from being valuable per se, the relevance of the study is increased by the almost concomitant report of the overall survival data from ADAURA,2Tsuboi M. Herbst R.S. John T. et al.Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.N Engl J Med. 2023; 389: 137-147https://doi.org/10.1056/NEJMoa2304594Crossref PubMed Scopus (12) Google Scholar from which the contribution of Jung et al. will inevitably be assessed in this editorial. With 278 patients enrolled, the work of Jung et al.4Jung H.A. Ku B.M. Kim Y.J. et al.Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage I-IIIA EGFR mutant-non-small cell lung cancer.J Thorac Oncol. 2023; 18: 1199-1208Abstract Full Text Full Text PDF Scopus (1) Google Scholar represents the second-largest study to date in the setting of ctDNA monitoring in resected NSCLC.5Verzè M. Pluchino M. Leonetti A. et al.Role of ctDNA for the detection of minimal residual disease in resected non-small cell lung cancer: a systematic review.Transl Lung Cancer Res. 2022; 11: 2588-2600Crossref PubMed Scopus (6) Google Scholar More importantly, the uniqueness of the present work relies on the exclusive inclusion of patients with EGFR mutations (limited to the classical exon 19 deletion, del19, and L858R). Considering the enrollment took place between 2015 and 2017, no patient received adjuvant treatment with osimertinib or other EGFR inhibitors in clinical trials. The authors assessed the presence of the EGFR mutation (previously identified on tumor tissue) in ctDNA within two windows of dynamic monitoring. The first was in the perioperative moment (baseline before surgery and at 4 weeks after the operation), prompting the prognostic evaluation through the correlation of the results with disease-free survival (DFS). The authors distributed the patients into three groups according to ctDNA behavior: (1) group A, negative baseline ctDNA; (2) group B, positive baseline ctDNA and negative postoperative ctDNA; and (3) group C, positive baseline ctDNA persisting after surgery. The second window occurred during the follow-up period, integrating the routine clinicoradiologic workup. The precise definition of the patient population and the clinical question was accompanied by the utilization of the most sensitive method to detect EGFR mutations, the droplet digital PCR (ddPCR). Used in the era of EGFR T790M research in ctDNA, in the context of progression to first-second generation EGFR inhibitors, ddPCR progressively gave ground in favor of wider next-generation sequencing gene panels. Nevertheless, ddPCR could be a method of choice if looking for traces of known mutations in blood, especially in cases of disease limited to the thorax, and even more so in the absence of clinical/radiologic macroscopic disease, such as in the postoperative setting and during follow-up. In line with this, whereas the absolute quantification of EGFR mutations in ctDNA as “copies/mL” seems a bit archaic in the era of “allelic fraction,” it is rather appropriate. The main difference from the “ADAURA dimension” is represented by the inclusion of stage IA disease in this study, numerically preponderant as representing 60% of the population. Patients with stage IA disease are considered cured and do not require adjuvant treatment. Nevertheless, the 5-year overall survival after surgical resection varies from 92% (stage pIA1) to 81% (stage pIA3) in molecularly unselected NSCLC according to the eighth TNM classification.6Rami-Porta R. Bolejack V. Crowley J. et al.The IASLC Lung Cancer Staging Project: Proposals for the Revisions of the T Descriptors in the Forthcoming. 8th ed of the TNM Classification for Lung Cancer.J Thorac Oncol. 2015; 10: 990-1003Abstract Full Text Full Text PDF PubMed Scopus (538) Google Scholar In a large, retrospective study by Saw et al.7Saw S.P.L. Zhou S. Chen J. et al.Association of clinicopathologic and molecular tumor features with recurrence in resected early-stage epidermal growth factor receptor-positive non-small cell lung cancer.JAMA Netw Open. 2021; 4e2131892Crossref PubMed Scopus (18) Google Scholar including 162 stage IA (seventh American Joint Committee on Cancer staging) EGFR-mutant NSCLC, 2-year and 5-year DFS was 81% and 78%, respectively. In the work by Jung et al.,4Jung H.A. Ku B.M. Kim Y.J. et al.Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage I-IIIA EGFR mutant-non-small cell lung cancer.J Thorac Oncol. 2023; 18: 1199-1208Abstract Full Text Full Text PDF Scopus (1) Google Scholar relevant insights emerged by breaking down the stage IA patient population according to the three groups of perioperative ctDNA behavior. Among the 167 patients with stage IA, 128 belonged to group A (baseline ctDNA negative), 31 to group B (baseline ctDNA positive, postoperative negative), and 8 to group C, (baseline ctDNA positive remaining positive after surgery). It is already impressive that, in 23% (groups B + C) of pIA NSCLC (i.e., pT < 3 cm, pN0), the EGFR mutation was detected in plasma by ddPCR before surgery. Despite the lack of statistical significance (p = 0.17), the 3-year DFS in stage IA was 96% to 97% for groups A and B, dropping to 75% in group C. Trying to interpret these data and visualizing the detection of ctDNA shedding as a sign of micrometastatic (or minimal residual) disease, in groups A and B, no tumor cell is left. On the other hand, the lack of complete clearance in group C means that, even if the residual resected lung parenchyma and (more importantly) the thoracic nodes are free from malignant cells, some of them are still present in the body and will potentially evolve in relapsing disease. In this space of “very-early” EGFR-positive NSCLC, the data of Jung et al.4Jung H.A. Ku B.M. Kim Y.J. et al.Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage I-IIIA EGFR mutant-non-small cell lung cancer.J Thorac Oncol. 2023; 18: 1199-1208Abstract Full Text Full Text PDF Scopus (1) Google Scholar suggest the potential contribution of a “very sensitive” approach to track traces of tumor in plasma—negatively affecting the prognosis and potentially representing the true target population for adjuvant osimertinib. Of note, the ADAURA 2 trial is currently ongoing, randomizing patients with stage IA2-IA3 EGFR-mutant NSCLC to osimertinib or placebo (ClinicalTrials.gov identifier: NCT05120349).8Tsutani Y. Goldman J.W. Dacic S. et al.Adjuvant Osimertinib vs. placebo in Completely Resected Stage IA2-IA3 EGFR-Mutated NSCLC: ADAURA2.Clin Lung Cancer. 2023; 24: 376-380Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar These considerations can be then applied to the global cohort of patients and to the one with stage IB to IIIA disease (n = 111), here representing the “minority” compared with the stage IA. The preoperative detection of ctDNA rose from approximately 20% in stage IA/IB/IIA to 40% in stage IIB to IIIA, accompanied by an increasing amount of ctDNA (copies/mL), mirroring the increasing disease burden. On the other hand, with the limitation of low patient numbers, no clear difference in ctDNA clearance after surgery emerged across pathologic stages. More importantly, the behavior of ctDNA (groups A, B, and C) remained together with the stage itself—the only prognostic factors for disease recurrence in the multivariate analysis. In stage IB to IIIA, a double-drop in the 3-year DFS was observed from 65% of group A to 50% of group B and 25% of group C, meaning that in these stages, different from stage IA, the preoperative detection of ctDNA harbors a prognostic role, stronger in the case of a lack of postoperative clearance. It is worth mentioning that only 61% (68/111) of the patients who were virtual candidates for perioperative chemotherapy underwent systemic treatment (n = 16 neoadjuvant chemoradiotherapy, n = 47 adjuvant chemotherapy, and n = 5 adjuvant chemo-radiotherapy)—a proportion overlapping with ADAURA,1Wu Y.L. Tsuboi M. He J. et al.Osimertinib in resected EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2020; 383: 1711-1723Crossref PubMed Scopus (834) Google Scholar and for which the latter study had been questioned.9Gyawali B. West H.J. Lessons from ADAURA on adjuvant cancer drug trials: evidence, ethics, and economics.J Clin Oncol. 2021; 39: 175-177Crossref PubMed Scopus (17) Google Scholar Baseline ctDNA presence and, even more, the lack of its clearance after surgery could vouch for an intensification of the adjuvant treatment, evoking the scenario of FLAURA 2 in the advanced disease space (combining chemotherapy and osimertinib).10Tagrisso plus chemotherapy demonstrated strong improvement in progression-free survival for patients with EGFR-mutated advanced lung cancer in FLAURA2 Phase III trial.https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemo-improved-pfs-in-lung-cancer.htmlDate accessed: June 19, 2023Google Scholar In the last part of their work, Jung et al.4Jung H.A. Ku B.M. Kim Y.J. et al.Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage I-IIIA EGFR mutant-non-small cell lung cancer.J Thorac Oncol. 2023; 18: 1199-1208Abstract Full Text Full Text PDF Scopus (1) Google Scholar focused on the truly longitudinal monitoring of EGFR mutations in ctDNA during follow-up. Because of the granular nature of the evidence, these data can be more challenging to interpret, especially in the light of a potential clinical application. Nevertheless, ddPCR captured EGFR mutations in ctDNA before radiologic relapse in 54% and 11% of the cases with EGFR del19 and L858, respectively—the discrepancy attributed to the lower sensitivity of ddPCR for single-base substitutions. Among the several insights that could be driven by looking at the individual patient data in the swimmer plot, it is worth noticing that, in seven cases with positive EGFR del19 by ddPCR in the follow-up phase, a subsequent plasma sampling did not detect the mutation, underlying the intrinsic variabilities of a very sensitive dynamic marker.11Tsui D.W.Y. Cheng M.L. Shady M. et al.Tumor fraction-guided cell-free DNA profiling in metastatic solid tumor patients.Genome Med. 2021; 13: 96Crossref PubMed Scopus (17) Google Scholar,12Risberg B. Tsui D.W.Y. Biggs H. et al.Effects of collection and processing procedures on plasma circulating cell-free DNA from cancer patients.J Mol Diagn. 2018; 20: 883-892Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar The early interception of disease progression by means of liquid biopsy in the setting of advanced, EGFR-driven NSCLC has been recently proposed in the APPLE trial.13Remon J. Besse B. Aix S.P. et al.Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small-cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial.Ann Oncol. 2023; 34: 468-476Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar The clinical and pragmatic potential of the anticipation of disease recurrence in resected EGFR-mutant NSCLC is less straightforward, as it would question the start of systemic treatment with a lack of macroscopic disease (potentially suitable of locoregional treatments once manifested thereafter). On the other hand, the detection and increase of EGFR mutations in ctDNA during adjuvant osimertinib, in line with the ADAURA trial, would suggest a lack of efficacy of the inhibitor against emerging disease. As acknowledged by the authors, their work has limitations. We mention here the lack of a precise report of staging procedures, both clinically and surgically. No notion of preoperative positron emission tomography or brain magnetic resonance imaging assessment and completeness of nodal sampling is provided, and a suboptimal evaluation could have led to a global downstaging of patients in the study. The relative abundance of stage IA patients, despite providing the discussed insights in this population, is at the detriment of stage IB and IIIA ones, whose underrepresentation could mitigate the strength of the relative data. Indeed, the limited patient number in some of the groups, according to both the pathologic staging and the perioperative ctDNA groups, precludes generalization and requires further analysis in larger populations. The relatively short follow-up period does not allow us to envisage the magnitude of disease relapses beyond the 3-year landmark DFS according to perioperative ctDNA groups. This long-term analysis would be of particular interest as the 3-year duration of adjuvant osimertinib is discussed3Passaro A. Mok T.S.K. Attili I. et al.Adjuvant Treatments for Surgically Resected Non-Small Cell Lung Cancer Harboring EGFR Mutations: A Review [published online ahead of print, 2023 May 11].JAMA Oncol. 2023; https://doi.org/10.1001/jamaoncol.2023.0459Crossref PubMed Scopus (1) Google Scholar; the 5-year treatment duration is currently the object of a phase 2 study (TARGET; ClinicalTrials.gov identifier: NCT05526755). In conclusion, in addition to its prospective nature and sharp, rigorous design, we think the major strength of this study in the space of perioperative ctDNA evaluation is represented by its focus on the EGFR-driven patient population. In this precise setting, ddPCR allows the detection of traces of the true target of adjuvant therapy— that is, undetectable micrometastatic disease. In the era of ADAURA (and its potential declination), the work of Jung et al.4Jung H.A. Ku B.M. Kim Y.J. et al.Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stage I-IIIA EGFR mutant-non-small cell lung cancer.J Thorac Oncol. 2023; 18: 1199-1208Abstract Full Text Full Text PDF Scopus (1) Google Scholar could serve not only as a proof-of-concept but suggests potential patient stratification for adjuvant treatment (de)intensification, pushing the limits of precision medicine for patients with resected EGFR-driven NSCLC. Francesco Facchinetti: Conceptualization; Writing - original draft preparation. Pasi A Jänne: Supervision; Validation; Writing - review & editing. Marcello Tiseo: Supervision; Validation; Writing - review & editing. This work is partially supported by a grant from the ARC Foundation for cancer research–Fondation ARC. Longitudinal Monitoring of Circulating Tumor DNA From Plasma in Patients With Curative Resected Stages I to IIIA EGFR-Mutant Non–Small Cell Lung CancerJournal of Thoracic OncologyVol. 18Issue 9PreviewFor patients with early stage EGFR-mutant–positive (EGFR-M+) NSCLC, curative surgery followed by adjuvant chemotherapy is considered the standard of care. This study evaluated the feasibility and efficacy of longitudinal monitoring of circulating tumor DNA (ctDNA) as a valuable biomarker for early detection of minimal residual disease (MRD) and provides identification of the group at high risk for recurrence in resected stages I to IIIA EGFR-M+ NSCLC. Full-Text PDF