Early reduction in ctDNA predicts survival in lung and bladder cancer patients treated with durvalumab

Purpose: Immunotherapy has transformed the treatment of many solid tumors, with some patients deriving long-term benefit, but how to identify such patients remains unclear. Somatic mutations detected in circulating tumor DNA (ctDNA) from plasma can be an indicator of disease progression, response to therapy and clonality of primary and metastatic lesions. Hence, ctDNA analysis can provide a valuable noninvasive and tumor-specific marker for longitudinal monitoring of tumor burden. We explored the use of ctDNA to predict survival on durvalumab, an anti-PD-L1 therapy. Experimental design: Variant allele frequencies (VAF) of somatic mutations in 73 genes were assessed in ctDNA using targeted sequencing in a discovery cohort consisting of 28 non-small cell lung cancer (NSCLC) patients and two validation NSCLC and urothelial cancer (UC) cohorts of 72 and 29 patients respectively, to correlate ctDNA changes with clinical outcomes. Results: Somatic variants were detected in 96% of patients. Changes in VAF preceded radiographic responses, and patients with reduction in VAF at 6 weeks had significantly greater reduction in tumor volume, with longer progression-free and overall survival. Conclusions: ctDNA VAF changes are strongly correlated with duration of treatment, antitumor activity and clinical outcomes in NSCLC and UC. Early on-treatment reduction in ctDNA VAF may be a useful predictor of long-term benefit from immunotherapy. Prospective studies should validate these findings and the value of utilizing early changes in ctDNA for therapeutic decision-making by identifying non-responders to checkpoint inhibitor monotherapies and guiding combination therapies.

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