Clinical, pathological and molecular characteristics of patients with disease recurrence despite pathologic response to neoadjuvant ipilimumab plus nivolumab in stage III melanoma.

Background: Pathologic response has been shown to be strongly associated with long-term event-free survival after neoadjuvant ipilimumab plus nivolumab in stage III melanoma. Only a small proportion of patients developed disease recurrence after initial pathologic response, making conclusions with statistically significant data challenging. However, the homogeneity of population of patients with stage III melanoma might augment the ability to identify immune resistance mechanisms.

Methods: To test if recurrence could be due to true tumor immune evasion or due to insufficient persistence of the immune pressure, 10/140 patients with pathologic response after neoadjuvant ipilimumab plus nivolumab with disease recurrence were identified within the OpACIN, OpACIN-neo, and PRADO trials.

Results: Compared to their counterparts without recurrence, clinical characteristics are different regarding sex, age, BRAF mutation status, depth of pathologic response and frequency of immune-related endocrinopathies. Immune activation-related gene expressions are increased at recurrence after major pathologic response (MPR), but not after pathologic partial response (pPR), and TCR diversity nor clonality are different between baseline and recurrence for both MPR and pPR.

Conclusions: No genetic changes explaining tumor immune evasion are found. We propose that disease recurrence may potentially be explained by diminishing of the initial therapy-induced immune response, but not due to genetic changes in the tumor cells mediating immune evasion.