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Serial monitoring of circulating tumor DNA as a marker of response to immune checkpoint blockade in MSI-H gastrointestinal tumors.

2025; Lippincott Williams & Wilkins; Volume: 43; Issue: 4_suppl Linguagem: Inglês

10.1200/jco.2025.43.4_suppl.273

1527-7755

Victoria Serpas Higbie, Michael LaPelusa, Preksha Shah, Merrida Childress, Amaya Gascó, Amy An, Alisha Bent, Bryan K. Kee, Scott Kopetz, Phat H. Le, Van K. Morris, S. Pant, Christine M. Parseghian, John Paul Shen, Robert A. Wolff, Michael J. Overman,

Gastric Cancer Management and Outcomes

273 Background: Microsatellite instability- high (MSI-H) tumors have high rates of response to immune checkpoint blockade (ICB) with prolonged durability of response. However, predicting who will have a response is difficult and there are limitations to radiographic evaluation of response. As circulating tumor DNA (ctDNA) offers a noninvasive approach to monitoring response and therapeutic efficacy, we sought to correlate ctDNA change with response to ICB in MSI-H gastrointestinal (GI) tumors. Methods: We conducted a retrospective study of MSI-H GI patients receiving ICB who underwent serial ctDNA sequencing. Tissue-informed ctDNA monitoring utilized comprehensive genomic profiling results of pre-treatment tumor tissue from a clinical trial assay based on FoundationOne CDx, a variant selection algorithm to exclude non-tumor variants, and multiplex PCR of up to 16 patient-specific variants to detect and quantify ctDNA. ctDNA changes were correlated with radiographic response. Results: A total of 20 patients with MSI-H tumors were evaluated including 17 colon, 2 small bowel, and 1 pancreatic. For 12 patients, it was the first exposure to ICB whereas 8 had previously progressed and were being rechallenged with ICB. Response was seen in 9 patients with a best overall response (BOR) of complete response (CR) in 4 and partial response (PR) in 5 while 5 showed stable disease (SD) and progression (PD) in 6. All patients had baseline ctDNA samples and at least 1 serial ctDNA after ICB initiation (median number of samples was 3). The mean time from baseline to first on-treatment sample was 30 days (range 13-64 days). 4 patients had undetectable ctDNA levels at baseline and remained undetectable on treatment. Of the 16 that had detectable ctDNA at baseline, 11 had a decrease in ctDNA levels at 1st on-treatment sample and 5 had an increase. The mean percent change of ctDNA at 1st on-treatment for those who had a response (CR + PR) was a 76% decrease while the mean percent change for those with SD was a 7% increase and for those with PD a 72% increase (p=0.05). Of the 6 patients with BOR of PD, 5 had an increase in ctDNA and 1 had undetectable levels at baseline. Of the 5 patients with BOR of SD, 2 had a decrease, 1 had an increase, and 2 were undetectable at baseline. Duration of SD did not correlate with initial ctDNA response. Conclusions: Early ctDNA change correlated with response in MSI-H GI tumors suggesting that serial ctDNA monitoring may provide early indication of response even prior to radiographic evaluation.