Early ctDNA response to chemotherapy. A potential surrogate marker for overall survival. (May 2021) - Jakobsen, Anders
Abstract: Aim: The aim of the study was to compare ctDNA response rate and objective response rate as surrogate markers for overall survival (OS) in patients with metastatic cancer treated with chemotherapy. Methods: The study included 420 patients distributed in five cohorts with colorectal, ovarian, and non–small cell lung cancer. It represents a retrospective analysis of patients enrolled in prospective biomarker studies and clinical trials. All patients had ctDNA measured before start of treatment and at the first evaluation of objective response. ctDNA response rate was defined as the fraction of patients converting from a measurable level at baseline to an unmeasurable level at the first evaluation of objective response. Aberrant, tumour specific, methylated DNA was measured in plasma. The method involves DNA isolation, bisulphite conversion and droplet digital PCR. The primary outcome measure was the correlation between ctDNA response rate, overall response rate (ORR) and median survival. Results: There was moderate correlation between ctDNA response rate and objective response at first evaluation (R 2 = 0.68). The same applied to ctDNA response rate and ORR (R 2 = 0.57). ctDNA held prognostic information in all the investigated tumour types (p < 0.05). There was a high correlation between ctDNA response and median survival across the included tumour types and treatments (R 2 = 0.99) clearly outperforming both response at first evaluation and ORR (R 2 = 0.70 and 0.57, respectively). Conclusion: The results suggest that ctDNA response might serve as a surrogate marker for OS. If validated, it may have great implications on the approval of new drugs. Highlights: ctDNA response rate is superior to overall response rate as a surrogate end-point. Results indicated high correlation between ctDNA response rate and median survival. ctDNA response rate might be a relevant surrogate end-point in drug introduction.