Association between circulating tumor DNA (ctDNA) and recurrence-free survival (RFS) in patients (pts) with resected stage III melanoma: An exploratory analysis of SWOG S1404.
Authors: LaPelusa Michael Brian , Marcano David , Othus Megan , Grossmann Allie , Aushev Vasily N. , Sridhar Bharat , Renner Derrick , Sethi Himanshu , Liu Minetta C. , Tarhini Ahmad A. , Kirkwood John M. , Grossmann Kenneth F. , Moon James , Li Hongli , Mashru Sandeep H. , Khushalani Nikhil I. , Sharon Elad , Korde Larissa A. , Ribas Antoni , Patel Sapna Pradyuman 
Published: July 2024

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Background: Our exploratory study aimed to understand the association between the presence of ctDNA after definitive surgical resection and RFS in pts with stage III melanoma treated with adjuvant immunotherapy. Methods: This study included 92 pts with resected stage III melanoma enrolled in a phase 3 trial (NCT02506153) that evaluated the efficacy of adjuvant pembrolizumab compared to interferon alfa-2b or ipilimumab in pts with stage IIIA(N2a)-IV resected melanoma. Personalized, tumor-informed ctDNA assays (Signatera) were run on banked plasma samples (median: 3.8 mL) collected at up to 5 time points after resection: pre-adjuvant treatment (pre-Tx), 1, 3, 6, or 12 months after Tx initiation and at recurrence. RFS was measured from randomization (pre-Tx) to first recurrence or death. A case-control design was used: 50% with recurrence within 2 yrs of randomization and 50% alive without recurrence for > 2 yrs. Conditional logistic regression compared the presence of ctDNA at pre-Tx between case-control groups. Results: Of the 92 pts, samples from 10 did not pass quality control. This study analyzed a total of 245 plasma samples from 82 pts. No significant differences in demographics, including stage, number of + lymph nodes, and BRAF status, existed between pts who were ctDNA+ or ctDNA- pre-Tx. 7 of 10 pts (70.0%) who were ctDNA+ pre-Tx had disease recurrence within 2 yrs compared to 33 of 72 pts (45.8%) who were ctDNA- (p = 0.19). 2-yr RFS was 30% in pts who were ctDNA+ pre-Tx and 54% in pts who were ctDNA- (HR 1.75; 95% CI: 0.78, 3.94; p = 0.18). Of the 7 pts who were ctDNA+ pre-Tx and had disease recurrence within 2 yrs, 5 were ctDNA+ at all time points assessed. The other 2 pts transiently cleared ctDNA during Tx, turning back ctDNA+ prior to recurrence. Of the 3 pts who were ctDNA+ pre-Tx and did not recur within 2 yrs, 2 cleared ctDNA during immunotherapy and remained ctDNA- at later time points. All 39 pts who were ctDNA- pre-Tx and did not recur within 2 yrs remained ctDNA- at later time points. Among 29 pts having ctDNA timepoints available for analysis near the time of recurrence (end-of-Tx or on-progression timepoints), 22 (75.9%) were ctDNA+. Conclusions: In this study, pre-Tx incidence of ctDNA+ after surgical resection was low, potentially related to limited plasma yield. However, the ctDNA positivity rate increased in subsequent serial testing. ctDNA might help identify early disease recurrence in patients with melanoma in the adjuvant setting, but further studies of larger cohorts accounting for treatment effect with more uniform pre-analytic collection are needed.