Circulating Tumor DNA–Guided Therapy of Advanced NSCLC with Immune Checkpoint Inhibitor–Based Regimens

Immune checkpoint inhibitors (ICIs) have emerged as effective treatment options for patients with advanced non–small-cell lung cancer (NSCLC) due to their durable clinical benefit and manageable toxicity. However, resistance and early progression have been reported, even in patients with tumors that express biomarkers associated with ICI response.1 Resistance to ICIs has led to an interest in combining ICIs with chemotherapy to improve patient outcomes.2 This study investigated the hypothesis that a circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients at risk of early progression following treatment with ICIs, which may guide treatment with regimens that combine ICIs and chemotherapy in the first-line setting.2 TF is a measure of the proportion of ctDNA that is derived from tumor cells in blood samples and has been shown to correlate with tumor growth and metastasis.3

This study used the nationwide (US-based) deidentified Flatiron Health-Foundation Medicine NSCLC clinico-genomic database. The deidentified data were obtained from approximately 280 US cancer clinics. Real-world overall survival (rwOS) and real-world progression-free survival (rwPFS) were estimated using Kaplan-Meier analysis. Hazard ratios (HRs) were calculated using multivariate Cox proportional hazard models adjusting for relevant covariates. TF, which reflects the proportion of ctDNA that is derived from tumor cells,3 was measured using an aneuploidy-based assay plus variant-based estimate and was categorized as follows: ≥10%: elevated; 1%-10%: intermediate; <1%: low. Early progression was defined as real-world progression within 8 weeks of starting therapy.2

The trial included 426 patients with advanced NSCLC who initiated first- or second-line ICI therapy (128 ICI, 298 ICI plus chemotherapy) within 60 days of testing with a liquid biopsy. Of these patients, 88 (21%) had elevated TF, 193 (45%) had intermediate TF, and 145 (34%) had low TF. Patients with elevated TF had a higher frequency of liver involvement (elevated: 27%; intermediate: 12%; low: 8%) and had worse Eastern Cooperative Oncology Group performance status scores of >2 at baseline (elevated: 33%; intermediate: 22%; low: 17%). Among the 100 patients with elevated TF, 44% had an unknown PD-L1 status, 23% had high PD-L1 expression, 19% had low PD-L1 expression, and 14% were negative for PD-L1. In addition, early progression was more frequent among patients with elevated TF (elevated: 26%; intermediate: 22%; low: 15%).

Patients with low TF treated with either an ICI with or without chemotherapy had better median rwPFS (low: 6.7 months; intermediate: 5.1 months, HR: 1.39 [1.11-1.74]; elevated: 3.4 months, HR: 1.74 [1.31-2.31]). In addition, patients with low TF had better median rwOS (low: 14.2 months; intermediate: 8.4 months, HR: 1.52 [1.10-2.09]; elevated: 4.6 months, HR: 2.17 [1.47-3.21]). Combining chemotherapy to ICI in patients with elevated TF improved rwPFS and rwOS compared with patients who received an ICI alone.2 Among patients with elevated TF, those treated with the combination regimen had rwPFS and rwOS of 4.3 months and 7.2 months, respectively, compared with rwPFS and rwOS of 1.9 months for those treated with ICI monotherapy.

In summary, evaluation of ctDNA may identify patients with advanced NSCLC who are at high risk for early progression following initiation of ICI therapy and who may benefit from the combination of ICI plus chemotherapy in the first-line setting.


  1. Onoi K, Chihara Y, Uchino J, et al. Immune checkpoint inhibitors for lung cancer treatment: a review. J Clin Med. 2020;9:1362.
  2. Besse B, Madison R, Cho-Phan CD, et al. CtDNA shed as a tool to select immune checkpoint inhibitors (ICPI) with or without chemotherapy for patients (pts) with advanced non–small cell lung cancer (aNSCLC). Presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract 9045.
  3. Bredno J, Lipson J, Venn O, et al. Clinical correlates of circulating cell-free DNA tumor fraction. PLoS One. 2021;16:e0256436.

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