Dr Kelly on ctDNA Dynamics Following Neoadjuvant Immunotherapy in GEJ Cancer

Ronan J. Kelly, MD, MBA, FASCO, director, Charles A. Sammons Cancer Center, W.W. Caruth Jr. Endowed Chair of Immunology, Baylor University Medical Center; chief, Oncology, Baylor Scott & White Health System; clinical professor,Texas A&M University College of Medicine; adjunct associate professor, oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University; professor, Clinical Sciences Division, the Translational Genomics Research Institute, discusses the use of circulating tumor DNA (ctDNA) as an early predictor of response following treatment with neoadjuvant immune checkpoint inhibitors in resectable esophageal and gastroesophageal junction (GEJ) cancer.

Kelly and colleagues conducted a phase 1b trial of 32 patients with resectable stage II or III esophageal and gastroesophageal junction cancer. Patients received 2 cycles of induction nivolumab (Opdivo) and either 3 cycles of neoadjuvant nivolumab (arm A; n = 16) or nivolumab plus relatlimab-rmbw (Opdualag; arm B; n = 16) in combination with chemoradiotherapy, followed by surgery. ctDNA samples were collected at baseline, during and after induction therapy, prior to surgical resection, and after surgery.

Findings published in Nature Medicine showed that the study met its primary end point of safety in arm A, although modifications to mitigate toxicities were required in arm B. Exploratory ctDNA analyses provided notable insights into the temporal dynamics of tumor shrinkage. A total of 12 patients were categorized as having undetectable ctDNA and 20 had detectable ctDNA 1 month following checkpoint inhibitor induction therapy or by the time of surgery. Patients showing an immediate decrease in ctDNA levels after 1 dose of immune checkpoint inhibitors achieved favorable pathologic complete responses and did not experience recurrence over a 4-year follow-up period. This finding suggests that patients responding within the neoadjuvant treatment window may benefit from de-escalated treatment approaches and are being overtreated with chemoradiation and surgery; conversely, patients without decreasing ctDNA levels may benefit from treatment escalation.

Furthermore, patients with undetectable ctDNA, either from baseline or following immune checkpoint inhibitor induction, demonstrated significantly longer recurrence-free survival compared with those who had detectable ctDNA. Moreover, individuals with minimal residual disease (MRD) had a median recurrence-free survival (RFS) of 7.8 months despite receiving comprehensive treatment, including chemoradiation, surgery, and immune checkpoint inhibitors. However, the median RFS was not reached during the study period for patients with MRD-negative tumors.

Overall, this study contributes valuable insights into the potential clinical utility of ctDNA monitoring for dynamically assess systemic tumor burden and predicting outcomes during treatment with neoadjuvant immune checkpoint inhibitor therapy. Further research is needed to validate ctDNA as a predictive biomarker in this setting.