Early Noninvasive Detection of Response to Targeted Therapy in Non-Small Cell Lung Cancer

With the advent of precision oncology, there is an urgent need to develop improved methods for rapidly detecting responses to targeted therapies. Here we have developed an ultrasensitive measure of cell-free tumor load using targeted and whole genome sequencing approaches to assess responses to tyrosine kinase inhibitors in advanced lung cancer patients. Analyses of 28 patients treated with anti-EGFR or HER2 therapies revealed a bimodal distribution of cell-free circulating tumor DNA (ctDNA) after therapy initiation, with molecular responders having nearly complete elimination of ctDNA (>98%). Molecular non-responders displayed limited changes in ctDNA levels post-treatment and experienced significantly shorter progression-free survival (median 1.6 vs. 13.7 months, P < 0.0001, HR = 66.6, 95% CI: 13.0 to 341.7) which was detected on average four weeks earlier than CT imaging. ctDNA analyses of patients with radiographic stable or non-measurable disease improved prediction of clinical outcome compared to CT imaging. These analyses provide a rapid approach for evaluating therapeutic response to targeted therapies and have important implications for the management of cancer patients and the development of new therapeutics.

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