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

Abstract

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.