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Cited by 161Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsLung Cancer Diagnosis and Treatment

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Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non–small cell lung cancer (NSCLC)

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Ricciuti, Biagio, Jones, Greg, Severgnini, Mariano, Alessi, Joao V, Recondo, Gonzalo, Lawrence, Marissa, Forshew, Tim, Lydon, Christine, Nishino, Mizuki, Cheng, Michael, Awad, Mark·2021·Journal for ImmunoTherapy of Cancer
DOI 10.1136/jitc-2020-001504PMC PMC7996662
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Abstract

Background: Currently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment. Methods: Plasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes. Results: Among 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was −90.1% (range −100% to +65%) among patients who subsequently had a radiologic response (n=18), –19.9% (range: −100% to +1884%) among stable disease cases (n=15), and +28.8% (range: −100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase. Conclusion: In patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.

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Figure 1 Study flow chart. ctDNA, circulating tumor DNA.
Figure 1 Study flow chart. ctDNA, circulating tumor DNA.CC BY-NC · PubMed Central
Figure 2 (A) Agreement between ctDNA decrease at the first follow-up blood sampling and radiographic best objective response (BOR) to immunotherapy. The waterfall plot shows the percent change in target lesions from baseline. Red bars indicate cases where there was a ctDNA decrease, while blue bars indicate cases with a ctDNA increase. (B) Linear correlation between BOR by RECIST V.1.1 and percent of change in ctDNA at the first follow-up blood sampling. Y-axis is truncated at 100%. Two patients (not shown) with ctDNA increase had non-measurable disease and experienced disease progression as best response to treatment. ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria In Solid Tumors.
Figure 2 (A) Agreement between ctDNA decrease at the first follow-up blood sampling and radiographic best objective response (BOR) to immunotherapy. The waterfall plot shows the percent change in target lesions from baseline. Red bars indicate cases where there was a ctDNA decrease, while blue bars indicate cases with a ctDNA increase. (B) Linear correlation between BOR by RECIST V.1.1 and percent of change in ctDNA at the first follow-up blood sampling. Y-axis is truncated at 100%. Two patients (not shown) with ctDNA increase had non-measurable disease and experienced disease progression as best response to treatment. ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria In Solid Tumors.CC BY-NC · PubMed Central
Figure 3 (A) Plasma ctDNA change at the first follow-up blood sampling according to the response to pembrolizumab±chemotherapy. (B) Plasma ctDNA change at the first follow-up according to whether the progression-free survival (PFS) was ≥6 months or <6 months to pembrolizumab±chemotherapy. Y-axis is truncated at 100%. AF, allele fraction; ctDNA, circulating tumor DNA.
Figure 3 (A) Plasma ctDNA change at the first follow-up blood sampling according to the response to pembrolizumab±chemotherapy. (B) Plasma ctDNA change at the first follow-up according to whether the progression-free survival (PFS) was ≥6 months or <6 months to pembrolizumab±chemotherapy. Y-axis is truncated at 100%. AF, allele fraction; ctDNA, circulating tumor DNA.CC BY-NC · PubMed Central
Figure 4 ctDNA change over time in patients with (A) partial or complete response (PR/CR), (B) stable disease (SD), and (C) progressive disease (PD) to immunotherapy±chemotherapy by RECIST V.1.1. ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria In Solid Tumors.
Figure 4 ctDNA change over time in patients with (A) partial or complete response (PR/CR), (B) stable disease (SD), and (C) progressive disease (PD) to immunotherapy±chemotherapy by RECIST V.1.1. ctDNA, circulating tumor DNA; RECIST, Response Evaluation Criteria In Solid Tumors.CC BY-NC · PubMed Central
Figure 5 (A) Overall response rate to pembrolizumab±chemotherapy in patients with decrease versus increase in plasma ctDNA at the first follow-up. (B) Progression-free survival (PFS) and (C) overall survival (OS) to pembrolizumab±chemotherapy in patients with decrease versus increase in plasma ctDNA at the first follow-up blood sampling. ctDNA, circulating tumor DNA.
Figure 5 (A) Overall response rate to pembrolizumab±chemotherapy in patients with decrease versus increase in plasma ctDNA at the first follow-up. (B) Progression-free survival (PFS) and (C) overall survival (OS) to pembrolizumab±chemotherapy in patients with decrease versus increase in plasma ctDNA at the first follow-up blood sampling. ctDNA, circulating tumor DNA.CC BY-NC · PubMed Central

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Metadata

Authors
Ricciuti, B., Jones, G., Severgnini, M., Alessi, J. V., Recondo, G., Lawrence, M., Forshew, T., Lydon, C., Nishino, M., Cheng, M., & Awad, M.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • Inivata, Research Triangle Park, North Carolina, USA
  • Brigham and Women's Hospital (US)
Corresponding author
Awad, Mark
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2021-03
Volume
9
Issue
3
Pages
e001504
ISSN
2051-1426 (ISSN-L)
DOI
10.1136/jitc-2020-001504
PMC
PMC7996662
OpenAlex
W3139130539
Cited by
161
References
30
Citations by year
2026: 24 · 2025: 33 · 2024: 32 · 2023: 36 · 2022: 27 · 2021: 9
FWCI
16.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Cancer Institute (R01CA203636)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords
circulating tumor DNA, liquid biopsy, pembrolizumab, non-small cell lung cancer, first-line immunotherapy, predictive biomarkers, pharmacodynamic biomarkers, treatment response prediction, platinum-based chemotherapy, pemetrexed, progression-free survival, overall survival, treatment resistance, immune checkpoint inhibitors, tumor mutational burden, PD-L1
MeSH terms
Circulating Tumor DNA, Progression-Free Survival, Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Predictive Value of Tests, Retrospective Studies, Time Factors, Biomarkers, Tumor, Disease Progression, Early Diagnosis, Antibodies, Monoclonal, Humanized

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