Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI-Treated Patients with EGFR-Mutant NSCLC (SWOG S1403)

Philip C Mack, Jieling Miao, Mary W Redman, James Moon, Sarah B Goldberg, Roy S Herbst, Mary Ann Melnick, Zenta Walther, Fred R Hirsch, Katerina Politi, Karen Kelly, David R Gandara, Philip C Mack, Jieling Miao, Mary W Redman, James Moon, Sarah B Goldberg, Roy S Herbst, Mary Ann Melnick, Zenta Walther, Fred R Hirsch, Katerina Politi, Karen Kelly, David R Gandara

Abstract

Purpose: Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome.

Experimental design: Serial plasma ctDNA (baseline, 8 weeks, and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib ± cetuximab in tyrosine kinase inhibitor-naïve, EGFR mutation tissue-positive non-small cell lung cancer.

Results: EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared with those with persistent ctDNA at Cycle 3 Day 1 [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; P < 0.0001], with a median progression-free survival (PFS) of 15.1 (95% CI, 10.6-17.5) months in the group with clearance of ctDNA versus 4.6 (1.7-7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR, 0.44; 95% CI, 0.21-0.90), P = 0.02; median overall survival (OS): 32.6 (23.5-not estimable) versus 15.6 (4.9-28.3) months.

Conclusions: Plasma clearance of mutant EGFR ctDNA at 8 weeks was highly and significantly predictive of PFS and OS, outperforming RECIST response for predicting long-term benefit.

Conflict of interest statement

Conflict of Interest Disclosures

PCM: Honorarium Guardant, Amgen

JielingM MWR, JamesM: No reported disclosures

SBG: Research funds and honorarium from AstraZeneca and Boehringer Ingelheim, and honorarium from Bristol-Myers Squibb, Genentech, Amgen, Blueprint Medicine, Sanofi Genzyme, Daiichi-Sankyo, Regeneron, Takeda, and Janssen.

RSH: see attachment

MAM: No reported disclosures

ZW: No reported disclosures

FRH: Scientific advisory boards (compensated): AstraZeneca/Daiichi, Genentech, Sanofi/Regeneron, Merck, Bristol-Myers Squibb, Novartis, Amgen, OncoCyte, Nectin Therapeutics. Institutional Research grants (University of Colorado): Amgen, Biodesix, Rain Therapeutics

KP: co-inventor on a patent licensed to Molecular MD for EGFR(T790M) mutation testing (through MSKCC). K.P. has received Honoraria/Consulting fees from Takeda, NCCN, Novartis, Merck, AstraZeneca, Tocagen, Maverick Therapeutics, Dynamo Therapeutics, Halda and research support from AstraZeneca, Kolltan, Roche, Boehringer Ingelheim and Symphogen.

KK: Consultant or advisory role: AstraZeneca, Regeneron, Novartis, Takeda, Lilly, Amgen, EMD Serono,Genmab, Targeted Oncology, Genentech, Debiopharm Group, Abbvie, Daiichi Sanko, Janssen, Eisai, Sanofi; institutional research grants: Company: EMD Serono, Genentech, Abbvie, Regeneron, Astellas Pharma, Tizona Therapeutics, Inc., Lilly, Novartis, Amgen, Bristol-Meyers Squibb, Five Prime Therapeutics, Jounce Therapeutics, Seattle Genetics; Author Royalties for UpToDate, an evidence based, peer reviewed information resource, available via the web, desktop, and PDA. Travel or accommodations: Lilly, EMD Serono, Novartis, Takeda

DRG: Institutional Research Grants: Amgen, Astex, Genentech; Consultant/Advisory Board: Adagene, AstraZeneca (institutional), Boehringer Ingelheim, Guardant Health (institutional), IO Biotech (institutional), Merck, Novartis, Oncocyte (institutional), Oceans Genomics (institutional), Regeneron, Roche-Genentech, Sanofi

RSH: Board of Directors: Immunocore, Junshi Pharmaceuticals, Consulting: AstraZeneca, Bolt Biotherapeutics , Bristol-Myers Squibb, Candel Therapeutics, Inc., Checkpoint Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology LLC, eFFECTOR Therapeutics Inc., Eli Lilly and Company, EMD Serono, Genentech, Gilead, HiberCell Inc., I-Mab Biopharma, Immune-Onc Therapeutics Inc., Immunocore, Janssen, Johnson and Johnson, Loxo Oncology, Mirati Therapeutics, NextCure, Novartis, Ocean Biomedical Inc., Oncocyte Corp, Oncternal Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revelar Biotherapeutics Inc, Ribbon Therapeutics, Roche, Sanofi, WindMIL Therapeutics, Xencor Inc; Research Support: AstraZeneca, Eli Lilly and Company Genentech/Roche Merck and Company. Leadership roles: American Association for Cancer Research (Board Member/ Committee Chair), International Association for the Study of Lung Cancer (Board Member/ Committee Chair), Society for Immunotherapy of Cancer (Committee Chair), Southwest Oncology Group (Committee Chair/ Principal Investigator)

©2022 American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
A) Flow diagram of patient plasma availability and EGFR mutation positivity in ctDNA. Time course showing treatment-induced changes in EGFR MAF for B) all patients with a positive BL EGFR MAF and a C3D1 timepoint (n = 62), and C) for all patients with both C3D1 and PRG timepoints (right side, n = 46). Red lines indicate cases with residual ctDNA at C3D1; blue lines indicate cases with complete clearance at C3D1. The graph is log-transformed to highlight differences at low MAFs.
Figure 2.
Figure 2.
Kaplan-Meier analysis of A) PFS and B) OS for patients with EGFR MAF clearance (blue lines) or residual (red lines) ctDNA at C3D1 (8 weeks). All patients here were BL positive for mutant EGFR ctDNA.
Figure 3.
Figure 3.
EGFR Copy number Gain. A) Dot plot showing EGFR MAF (Y-axis) categories by positivity or negativity for EGFR copy number gain. B) PFS and C) OS for patients dichotomized by CNG.

References

    1. Rolfo C, et al., Liquid Biopsy for Advanced Non-Small Cell Lung Cancer: A Consensus Statement from The International Association for the Study of Lung Cancer (IASLC). J Thorac Oncol, 2021.
    1. Leighl NB, et al., Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clin Cancer Res, 2019. 25(15): p. 4691–4700.
    1. Diehl F, et al., Circulating mutant DNA to assess tumor dynamics. Nat Med, 2008. 14(9): p. 985–90.
    1. Mok T, et al., Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy. Clin Cancer Res, 2015. 21(14): p. 3196–203.
    1. Goldberg SB, et al., Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA. Clin Cancer Res, 2018. 24(8): p. 1872–1880.
    1. Hellmann MD, et al., Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC. Clin Cancer Res, 2020. 26(12): p. 2849–2858.
    1. Anagnostou V, et al., Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer Res, 2019. 79(6): p. 1214–1225.
    1. Thompson JC, et al., Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy. JCO Precis Oncol, 2021. 5.
    1. Zhang Q, et al., Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov, 2020. 10(12): p. 1842–1853.
    1. Zou W, et al., ctDNA Predicts Overall Survival in Patients With NSCLC Treated With PD-L1 Blockade or With Chemotherapy. JCO Precis Oncol, 2021. 5: p. 827–838.
    1. Janjigian YY, et al., Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov, 2014. 4(9): p. 1036–45.
    1. Pirazzoli V, et al., Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naive EGFR L858R-Induced Lung Adenocarcinoma. Clin Cancer Res, 2016. 22(2): p. 426–35.
    1. Goldberg SB, et al., Randomized Trial of Afatinib Plus Cetuximab Versus Afatinib Alone for First-Line Treatment of EGFR-Mutant Non-Small-Cell Lung Cancer: Final Results From SWOG S1403. J Clin Oncol, 2020. 38(34): p. 4076–4085.
    1. Mack PC, et al., Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases. Cancer, 2020. 126(14): p. 3219–3228.
    1. Lanman RB, et al., Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PLoS One, 2015. 10(10): p. e0140712.
    1. Zill OA, et al., The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients. Clin Cancer Res, 2018. 24(15): p. 3528–3538.
    1. Odegaard JI, et al., Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies. Clin Cancer Res, 2018. 24(15): p. 3539–3549.
    1. Reungwetwattana T, et al., Longitudinal circulating tumour DNA (ctDNA) monitoring for early detection of disease progression and resistance in advanced NSCLC in FLAURA. Annals of Oncology, 2019. 30.
    1. Buder A, et al., EGFR mutation tracking predicts survival in advanced EGFR- mutated non-small cell lung cancer patients treated with osimertinib. Translational Lung Cancer Research, 2020. 9(2): p. 239–245.
    1. Cho MS, et al., Clinicopathological parameters for circulating tumor DNA shedding in surgically resected non-small cell lung cancer with EGFR or KRAS mutation. PLoS One, 2020. 15(3): p. e0230622.
    1. Chabon JJ, et al., Integrating genomic features for non-invasive early lung cancer detection. Nature, 2020. 580(7802): p. 245–251.
    1. Lam VK, et al., Genotype-Specific Differences in Circulating Tumor DNA Levels in Advanced NSCLC. J Thorac Oncol, 2021. 16(4): p. 601–609.
    1. Abbosh C, et al., Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature, 2017. 545(7655): p. 446–451.
    1. Gray JE, et al., Tissue and Plasma EGFR Mutation Analysis in the FLAURA Trial: Osimertinib versus Comparator EGFR Tyrosine Kinase Inhibitor as First-Line Treatment in Patients with EGFR-Mutated Advanced Non-Small Cell Lung Cancer. Clin Cancer Res, 2019. 25(22): p. 6644–6652.
    1. Aggarwal C, et al., Clinical Implications of Plasma-Based Genotyping With the Delivery of Personalized Therapy in Metastatic Non-Small Cell Lung Cancer. JAMA Oncol, 2019. 5(2): p. 173–180.
    1. Ruiz-Patino A, et al., EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP). Target Oncol, 2018. 13(5): p. 621–629.

Source: PubMed

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