Brief Communication: Personalized Circulating Tumor DNA as a Predictor of Pathologic Response in Neoadjuvant Treatment of Resectable Melanoma

Patients with resectable stage III-IV melanoma are at high risk of recurrence following surgical excision. Neoadjuvant therapy (NEO) with immune checkpoint inhibition (ICI) improves event-free survival and may allow for pathologic treatment response assessment with potential adjuvant therapy de-escalation. Identification of a biomarker correlated with tumor response could facilitate individualized therapeutic decision-making. This study investigates the utility of circulating tumor DNA (ctDNA) as a predictive biomarker of pathologic response in melanoma treated with NEO ICI. We identified melanoma patients treated with NEO ICI at Dana-Farber Cancer Institute and measured personalized ctDNA plasma levels pretreatment, before each NEO ICI cycle, and postoperatively. We evaluated whether ctDNA levels during the NEO course correlated with graded pathologic response. Of 18 patients who underwent NEO ICI, there were 10 pathologic complete responses (pCR; 0% viable tumor), 1 pathologic near-complete response (near pCR; >0% but ≤10% viable tumor), 1 partial response (pPR; >10%-≤50% viable tumor), and 6 nonresponses (pNR; >50% viable tumor). Responders (pCR, near pCR, or pPR) were more likely to have negative presurgical ctDNA levels (100% (12/12) vs. 33% (2/6), P=0.005). In addition to absolute levels, ctDNA kinetics during NEO ICI were also predictive of pathologic response, with nonresponders more likely to show an increase in ctDNA levels between the first and final ICI cycles compared with responders (mean change ctDNA (SD), 0.09 (0.15) vs. -1.16 (3.31), P=0.004). These findings underscore the potential of ctDNA as a dynamic biomarker to inform response-driven, personalized treatment strategies following NEO ICI.