Dr Sullivan on Pseudoprogression as a Potential Explanation for Outcomes With Tebentafusp in Uveal Melanoma

Ryan J. Sullivan, MD, associate professor, medicine, Harvard Medical School; associate professor, hematology/oncology, Massachusetts General Hospital, explains the prolongation of survival with tebentafusp-tebn (Kimmtrak) despite apparent initial radiographic tumor progression in patients with uveal melanoma.

According to previous research, increased circulating tumor DNA (ctDNA) levels are generally reflective of a higher tumor burden, Sullivan begins. However, patients receiving immunotherapy agents, such as immune checkpoint inhibitors, can often experience pseudoprogression, he explains. In this phenomenon, an initial increase in tumor size is observed at the same time that ctDNA levels decrease. Due to the apparent radiographic progression, this phenomenon often leads to premature treatment discontinuation. Later radiographic scans will eventually align with the reduction in tumor burden, Sullivan adds.

A study of ctDNA levels in patients with metastatic uveal melanoma receiving the bispecific T-cell engager tebentafusp showed that 88% of patients with previously untreated disease had reduced ctDNA levels after treatment with this agent. Patients with a higher degree of ctDNA reduction were shown to experience improved overall survival (OS), Sullivan continues. However, these patients did show a low overall response rate of 10% according to RECIST v1.1 criteria. Notably, tebentafusp is associated with OS benefit but not response benefit, Sullivan notes. These findings show that some patients benefit from continued treatment despite apparent disease progression.

Although this pattern appears to be consistent with the phenomenon of pseudoprogression, it cannot be definitively stated as an explanation due to a lack of biopsies and other data, Sullivan states. Regardless, the study shows that ctDNA is another marker of tumor burden in uveal melanoma, Sullivan reports. The use of ctDNA assays could help identify patients that may experience continued benefit from tebentafusp, who might be otherwise missed with traditional imaging alone, Sullivan concludes.

Disclosures: Dr Sullivan reports working as an independent contractor for Novartis, Pfizer, Bristol Myers Squibb, Merck; he also reports a grant/contract with Merck.