ctDNA Reductions Associated With Improved Clinical Outcomes in NSCLC Treated With IO

Findings from a pooled analysis indicated that a decrease in circulating tumor DNA was associated with improved clinical benefit in patients with non–small cell lung cancer treated with immune checkpoint inhibitors.

Patients with non–small cell lung cancer who were treated with immune checkpoint inhibitors and experienced reductions in circulating tumor DNA (ctDNA) were associated with durable clinical benefit across various end points, according to results from a pooled analysis of 5 independent clinical trials published in the Journal of Clinical Oncology Precision Medicine.

Improved overall survival (OS) appeared to be associated with a reduction in ctDNA levels from on-treatment liquid biopsies (HR, 2.28; 95% CI, 1.62-3.20; P <.001). Decreases in ctDNA were also associated with improved progression-free survival (PFS; HR, 1.76; 95% CI, 1.31-2.36; P <.001).

Of 254 potential patients, a total of 200 were included in the analysis. Patient characteristics were widely different with regard to age, sex, stage at enrollment, histology, PD-L1 expression, and previous lines of therapy. Investigators found that smoking history was univariately associated with ctDNA changes. Investigators noted these findings were similar from previous studies, which suggested that cancers resulting from accumulation of tobacco-related mutations may have increased tumor burden, and thus may be more responsive to immunotherapeutics.

Investigators used a variety of next-generation sequencing assays to analyze ctDNA such as targeted panels and whole genome sequencing. Investigators noted that there was variety in terms of the variants that were detected across the multiple cohorts, the magnitude of the variant allele frequencies (VAF), and the range of baseline VAF values. Investigators used a 3-level Max VAF Percent Change Group to account for potential differences in data due to the different assays that were used.

Consistent results were observed with OS, PFS, and durable clinical benefit. Overall, 32% of patients had a decrease, 51% had intermediate change, and 17% had an increase in ctDNA levels from baseline while on treatment with an immunotherapeutic.

Unadjusted and adjusted Cox models found a relationship between reduction in ctDNA levels and OS results. The 1-year survival change show statistically significant differences with 75% of patients having a decreased risk, 58% having intermediate change, and 32% having an increase in Max VAF. Similar results were found in regard to PFS; each increase across the categories of 3-level Max VAF Percent Change Group variable appeared to be associated with an increased risk of progression or death (HR, 1.76; 95% CI, 1.31-2.36; P <.001).

Improved tumor response was associated with a reduction in ctDNA via the RECIST classification of partial response (PR) or complete response. Investigators used logistic regression models to identify an odds ratio (OR) of 0.19 for those who had an intermediate vs decrease (95% CI, 0.08-0.45; P <.001) and 0.11 (95% CI, 0.03-0.38) for increase vs decrease. This suggested that every strata increase in the 3-level Max VAF Percent Change Group was associated with a decreased likelihood in achieving a PR or better. At baseline, the ctDNA values were not univariately associated with achieving a PR or better.

A decrease in ctDNA was associated with a median PFS of 6 months or more, according to logistic regression models with cohort stratification and adjustment of baseline clinical covariates. The OR for intermediate vs decrease was 0.13 (95% CI, 0.05-0.34; P <.001) and increase vs decrease was 0.06 (95% CI, 0.02-0.22); this highlighted a decreasing likelihood in achieving a median PFS of 6monther or more with each ctDNA increase.


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. Published Online August 6, 2022. doi:10.1200/PO.21.00372