Ultrasensitive ctDNA profiling to identify long-term survivors in phase I immunotherapy trials.

2560 Background: Patients (pts) included in early clinical trials (ECT) typically show a median overall survival of 8-10 months (PMID: 18042834 and 21975023), with long-term survivors (LTS) rarely encountered. While prognostic scores have been developed to identify short-term survivors (STS) in ECT, predictors of LTS remain largely unexplored. Ultrasensitive circulating tumor DNA (uctDNA) serves as a reliable surrogate for tumor burden (Toledo R et al , ASCO 2024), and may provide insights into LTS. This study aims to identify key determinants of LTS. Methods: A case-control study was conducted on pts treated at VHIO’s phase I unit between 2013 and 2023, as part of the institutional translational study RIO360. Pts with an overall survival (OS) > 3 years after C1D1 were classified as LTS and compared to STS with OS < 1 year, matched for age, sex, stage, prior immunotherapy (IO), and ECOG. Clinical, histopathological, uctDNA, and treatment outcomes were collected. uctDNA analysis was performed prior to C1D1 and throughout treatment (every 3 to 4 weeks) in the subset of patients treated with IO. Comparisons between LTS and STS were performed using univariate binomial generalized linear models. Results: Of 1282 pts, a total of 117 pts (9.1%) were classified as LTS (median OS 5.2 years) and compared with 117 matched STS pts (median OS 0.6 year). The most common tumor types among LTS were HNSCC (18%), melanoma (10%), and breast (9.1%), while in STS were colorectal (27%), breast (12%), and melanoma (11%). Treatment with 3+ prior lines was more common in STS (45%) than LTS (24%) (p = 0.002). Visceral metastases were present in 59% LTS and 77% STS (p = 0.010). Higher neutrophil count and dNLR were associated with STS (p < 0.05). LTS had lower mean uctDNA at baseline (7.5 vs 10.9 ppm; p < 0.001). Two consecutive uctDNA decreases were observed in 92% of LTS pts, while 80% of STS pts showed two consecutive uctDNA increases (p < 0.001). Conclusions: In ECT, predictors of long-term survival include the absence of visceral metastasis, less prior treatment exposure, low baseline uctDNA levels, and early decreases in uctDNA. This study further explores uctDNA dynamics during treatment, with detailed findings to be presented.