ctDNA Monitoring May Predict Immune Checkpoint Blocker Therapy Response

Circulating tumour DNA levels after 8 weeks of checkpoint blocker therapy correlates with patient response to treatment

medwireNews: Quantitative circulating tumour (ct)DNA could be used to monitor patient response to anti-programmed cell death protein 1 (PD-1) therapy and predict survival outcomes, the findings of a proof-of-concept study suggest.

“As inefficient PD-1 blockade could possibly be deleterious, ctDNA monitoring could play a critical role in treatment decisions, especially when the synchronous radiological evaluation is difficult or equivocal”, the authors hypothesize in the Annals of Oncology.                                  

The team assessed ctDNA levels from 15 patients with non-small-cell lung cancer, uveal melanoma or microsatellite-unstable colorectal cancer as they began treatment with nivolumab or pembrolizumab.

ctDNA was identified in samples from 10 of the 15 patients using bidirectional pyrophosphorolysis-activated polymerisation, droplet digital polymerase chain reaction, or next-generation sequencing, report Francois-Clement Bidard, from the Institut Curie in Paris, France, and co-workers.

ctDNA levels at baseline were not significantly associated with patient factors such as age, gender, performance status, tumour type, number of metastatic sites, or the number of prior treatments, they observe.

Patient ctDNA levels were then reassessed at week 8 of treatment, alongside radiological assessment for immune-related response criteria.

This revealed a significant correlation between changes in ctDNA levels and tumour size. Specifically, two patients who had complete clearance of ctDNA at week 8 showed a “marked and lasting response to therapy”, the researchers say, whereas eight patients with a small decrease or an increase in ctDNA at week 8 had stable or progressive disease.

The patients received a median of 4.7 months of treatment and were followed-up for a median of 10.8 months. Week 8 ctDNA levels were found to be significantly associated with progression-free survival (hazard ratio [HR]=10.2) and overall survival (HR=15.0).

“Notwithstanding this long-term prognostic impact, ctDNA detection at baseline is not a predictive factor of response to therapy,” the authors caution.

They reiterate that two patients with ctDNA at baseline had undetectable levels at week 8 and an “extremely good tumor response and outcomes,” while others without ctDNA detected at either timepoint had “prolonged progression-free survival”.

Thus, the researchers comment: “Our results therefore suggest that only patients with ctDNA levels below the limit of sensitivity of ctDNA detection techniques at [week] 8 benefit from anti-PD-1 therapy.”

The team concludes: “To complement this proof-of-concept study, confirmatory observational cohorts are needed to define the ctDNA cut-offs to be used as a real-time ‘companion’ biomarker and the medical and economic benefits of this type of monitoring.

“Earlier time-points for ctDNA monitoring (e.g. four weeks after initiation of therapy) could also be investigated, allowing early selection of patients likely to benefit from [immune checkpoint blocker] therapy.”

Reference

Cabel L, Riva F, Servois V, et al. Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study. Ann Oncol; Advance online publication 29 April 2017. https://doi.org/10.1093/annonc/mdx212

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