ctDNA Response Can Identify Poor Clinical Outcomes with Immunotherapy

Liquid biopsies are gaining popularity as a minimally invasive way to rapidly and accurately determine clinical response. Current predictive biomarkers for guiding treatment decision in patients with non–small cell lung cancer (NSCLC) do not accurately predict therapeutic response, highlighting real-time minimally invasive molecular analyses that can guide treatment decisions as an unmet clinical need. To establish circulating tumor DNA (ctDNA) molecular responses in clinical decision-making, Anagnostou and colleagues conducted a two-stage ctDNA-directed molecular response adaptive phase II clinical trial (BR.36) and reported here on the first stage where 50 patients with advanced/metastatic NSCLC received standard-of-care single-agent pembrolizumab. The primary endpoint of the study was to establish the concordance between ctDNA molecular response (mR), defined as the maximal mutant allele fraction (maxMAF) clearance after two cycles of pembrolizumab, and radiologic response evaluation criteria in solid tumors (RECIST) response, as well as to define the ctDNA molecular response optimal time point. Secondary endpoints included evaluation of time to ctDNA response and correlation with progression-free survival (PFS) and overall survival (OS). The primary endpoint of the trial was met with a sensitivity of ctDNA mR for RECIST response of 82% and a specificity of 75%. Median time to ctDNA mR was 2.1 months with a concordance between ctDNA and radiographic response being largely observed. Further correlation of ctDNA mR with PFS and OS revealed that patients with mR had longer PFS (5.03 versus 2.6 months) and OS (not reached versus 7.23 months) than patients with molecular disease progression (mPD), defined as persistence of maxMAF. In summary, the results of this trial show that ctDNA response and radiographic response were mostly agreeable and informative in OS prediction which suggests that ctDNA mR can aid in identifying patients with metastatic NSCLC that are less likely to have favorable clinical outcomes after single agent immunotherapy. These findings were implemented in the second stage of this trial in which patients at high risk of progression will be randomized to treatment intensification or continuation of therapy.

Anagnostou V, Ho C, Nicholas G, Juergens RA, Sacher A, Fung AS, et al. ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results. Nat Med 2023;29:2559-69.

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