ctDNA May Predict ICI Response in NSCLC, Pooled Analysis Results Show

Circulating tumor DNA (ctDNA) is associated with outcomes in patients with non–small cell lung cancer (NSCLC) treated with an immune checkpoint inhibitor (ICI), according to the results of a pooled analysis of 5 studies.

“Our study provides supporting evidence that ctDNA may serve as an early predictor of treatment response,” the study authors, led by Diana Merino Vega, PhD, formerly of Friends of Cancer Research, wrote. Findings from the pooled analysis were published in JCO Precision Oncology.¹ “Given the multitude of recent studies investigating the use of ctDNA as a minimally invasive way to measure treatment outcome, these results are timely by confi rming observations seen across multiple, independent studies and by outlining harmonization strategies to support future studies and meta-analyses to validate ctDNA as an end point in drug development.”

Many studies’ results have suggested that the use of ctDNA for monitoring responses to treatment could be a significant tool for clinical research as well as a predictive biomarker. The study authors pulled together data from independent studies to determine the role of ctDNA in monitoring ICI responses in NSCLC.

Currently, the use of ctDNA for monitoring response to ICIs has been suggested but not well defined and is of great interest to physicians.

The analysis was a pilot project, ctDNA for Monitoring Treatment Response (ctMoniTR), conducted by Friends of Cancer Research. It involved the pooling and harmonization of data from 5 independent studies on PD-1/ PD-L1 ICI use in patients with NSCLC.

The studies pooled included a total of 254 patients who were treated with anti–PD-1/PD-L1 therapy as either monotherapy or in combination with chemotherapy in any line of treatment, although 54 did not meet study criteria of baseline and peritreatment ctDNA samples. Various next-generation sequencing–based ctDNA assays were used in the 5 studies, and variant allele frequency (VAF) was reported in 4 of the 5 studies.

Overall, the majority of patients (53%) were younger than 66 years, male (61%), White (65%), and smokers (85.9%). Most patients also had nonsquamous histology (74%), advanced disease (89%), and an ECOG performance status of 1 or higher (63%). In addition, 67% of patients had received at least 1 prior line of systemic treatment, and 79% were positive for PD-L1 expression.

As there was variability between the timing and frequency of samples collected in the 5 studies, the researchers calculated a 3-level Max VAF Percent Change Group, which showed that from baseline 32% of patients had a decrease in ctDNA levels with ICI treatment, 51% had a mild change, and 17% had an increase.

Association was observed between reductions in ctDNA levels and improved overall survival (OS). Patients with reductions in ctDNA levels had a 1-year OS rate of 75%. Each step up in category of the 3-level Max VAF Percent Change Group was associated with an increased risk of death (adjusted HR, 2.28; 95% CI, 1.62-3.20; P < .001). Those with intermediate changes and increased levels of ctDNA had 1-year OS rates of 58% and 32%, respectively.

For progression-free survival (PFS), the risk of disease progression or death with each step up in category level was associated with an adjusted hazard ratio of 1.76 (95% CI, 1.31-2.36; P < .001). The 1-year PFS rates were 54% in those with decreased ctDNA levels, 34% in those with intermediate changes, and 24% in those with increased levels.

When PFS was analyzed by factors, an improvement in PFS was noted for ever smokers (HR, 0.37; 95% CI, 0.20-0.68; P = .001) and those with advanced disease (HR, 0.35; 95% CI, 0.16-0.76; P = .008). No association was noted with PD-L1 positivity (HR, 1.10; 95% CI, 0.79-1.53; P = .583).

Durable clinical benefi t of PFS lasting at least 6 months showed an odds ratio of 0.13 (95% CI, 0.05-0.34; P = .001) for intermediate change in ctDNA levels vs decreased levels, and 0.06 (95% CI, 0.02-0.22) for increased vs decreased levels.

Logistic regression models showed an odds ratio for tumor response of 0.19 (95% CI, 0.08-0.45; P < .001) for a step down from intermediate change to decreased ctDNA levels, and 0.11 (95% CI, 0.03-0.38) for increased vs decreased ctDNA levels.

“Our data suggest that ctDNA measurements may help guide treatment decisions, either independently or in conjunction with radiographic evaluation, especially in tumors that are challenging to assess,” Vega et al wrote.

The study authors did note limitations in their analysis, including the sample sizes and inconsistencies in ctDNA assays used.

The project will continue to look at the use of ctDNA monitoring in other tumor types, stages, and drug classes.

_REFERENCES:

_{1. Vega DM, Nishimura KK, Zariff a N, et al. Changes in circulating tumor DNA reflect clinical benefi t across multiple studies of patients with non–small-cell lung cancer treated with immune checkpoint inhibitors. JCO Precision Oncol. Published online August 11, 2022. doi:10.1200/PO.21.00372}